Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Bavi will live on, but my investment here will likely not. After 11 years following this company through its journey to get bavi approved, I think I may finally pull out of this one. I personally do not think that bavi is dead. I still believe there is value in the bavi platform, but this team does not have access to the resources needed to run the trials needed nor the resources to protect our interests as shareholders. Whether the phase 2 studies were tampered with or not is now moot. I hope they find significant discrepancies with the randomization of patients that may have lead to these results in phase 3, but in either case the "hope" value in this stock has now been completely drained, and their ability to raise the funds necessary to run any further major trials on their own is likely done. I hope that they are able to partner or sell bavi so that someone else can invest the money needed to see it through to approval. Its not unheard of with new treatments to see failures with novel drugs, but this is pretty much a death blow to peregrine doing it on their own, and even if they can unload it, it will be many more years until bavi may end up helping patients. this is a sad and expensive, but also a cleansing day as I no longer see the potential of a 100 bagger, and therefore no reason to invest so much of my wealth in a single company. They may be able to squeeze some value out of what is left but not likely anything worth the equal or greater risk of them deciding to go it alone, raise more money and R/S with little chance of payoff for many many years to come. I am most sad about giving up on what I had hoped would be a major shift in cancer survival and having the opportunity to be part of that through my investment. I wish everyone the best, and pray that Peregrine sees the importance in moving this molecule into the hands of a major player if they still believe in the prospect of it one day actually having a chance to help those with cancer.
I bought my shares back today, getting ready for a move up prior to asco.
Some info on Opdivo's approval process
Opdivo's speedy lung cancer approval is based on Phase II data in which it significantly increased rates of survival among patients with NSCLC. In January, Bristol-Myers divulged that, in a Phase III study pitting Opdivo against the standard cancer-killer docetaxel, the drug demonstrated such superior overall survival compared with the control arm that it hit its primary endpoint ahead of schedule, leading the trial's data monitoring committee recommend the study be terminated early.
The FDA's rolling review for Opdivo was by far the fastest for any treatment in recent memory and again affirms FDA oncology chief Richard Pazdur's penchant for rapidly approving cancer therapies that could improve the standard of care for some of the most dire patients.
"The FDA worked proactively with the company to facilitate the early submission and review of this important clinical trial when results first became available in late December 2014," Pazdur said in a statement. "This approval will provide patients and health care providers knowledge of the survival advantage associated with Opdivo and will help guide patient care and future lung cancer trials."
Opdivo's second trip through the FDA "is the fastest approval I've seen in my 15-year career," Evercore ISI analyst Mark Schoenebaum noted soon after the news hit. And it's an important one. Sketching out some raw sales forecasts for this indication, Schoenebaum concludes that the approval could be worth an additional $1 billion to $1.5 billion in sales. And more work is ahead to expand its dominance in lung cancer.
Behind Bristol-Myers and Merck, Roche ($RHHBY), AstraZeneca ($AZN), and partners Pfizer ($PFE) and Merck KGaA are bringing up checkpoint inhibitors that promise to change the standard of care for many cancers, a new class of therapies expected to bring in about $35 billion a year.
Like its rivals, Bristol-Myers is bankrolling an expansive R&D effort to determine Opdivo's potential in a wealth of cancers, launching combo trials in hopes of further extending the antibody's use.
"Our research program continues through an innovative and robust pipeline that includes more than 20 tumor types and through collaborations with other companies and researchers across the globe," R&D chief Francis Cuss said in a statement.
CheckMate -017 was a landmark Phase III, open-label, randomized, multinational, multicenter clinical trial that evaluated Opdivo (3 mg/kg intravenously over 60 minutes every two weeks) (n=135) vs. standard of care, docetaxel (75 mg/m2 intravenously administered every 3 weeks) (n=137), in patients with metastatic squamous NSCLC who had progressed during or after prior platinum doublet-based chemotherapy regimen. This trial included patients regardless of their PD-L1 (programmed death ligand-1) status. The primary endpoint of this trial was overall survival (OS).
In January, the trial was stopped based on an assessment conducted by the independent Data Monitoring Committee (DMC), which concluded that the study met its endpoint, demonstrating superior OS in patients receiving Opdivo compared to docetaxel. The prespecified interim analysis was conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the Opdivo arm and 113 in the docetaxel arm).
Opdivo is the only FDA-approved monotherapy to demonstrate proven superior OS compared to standard of care in more than 15 years in previously treated metastatic squamous NSCLC. The median OS was 9.2 months in the Opdivo arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3). The hazard ratio was 0.59 (95% CI: 0.44, 0.79; p=0.00025). This hazard ratio translates to a 41% reduction in the risk of death with Opdivo compared to docetaxel.
“The FDA approval of Opdivo introduces an entirely new treatment modality that has demonstrated unprecedented results for the treatment of previously treated metastatic squamous NSCLC, with the potential to replace chemotherapy for these patients,” said Dr. Suresh Ramalingam, MD, Professor and Director of Medical Oncology, Winship Cancer Institute of Emory University. “This milestone brings to fruition the long-held hope that immuno-oncology medicines can be significantly effective in this difficult-to-treat population.”
This trial was first posted on clinicaltrials.gov In July 2012. That's about 16 months ahead of our Sunrise trial. They only enrolled 270 people total. Their interim look-in that ended the trial was based on 199 events. That occurred in January 2015, 2.5 years after the trial started. Determining when these look-ins will occur in our trial is challenging, as we are not being provided with patient counts as the trial has progressed. All we know is that all the patients will be enrolled by december 2015, and that some may have been enrolled as early as the end of December 2013. We also know that enrolment at the beginning of a trial is slow, and that it tends to pick up towards then end.
Based on expectations from the Phase 2 trial, I feel much like the Opdivo trial, our results could potentially be superior enough for the comparative portion of the trial to be ended even at the first look-in. This however, could be further off than most here are guessing. I feel there is a chance that Our first look-in could be more likely towards then end of this year, or early next year, with the second look-in coming 6 months later due to the increasing rates of enrolment as the trial progresses. This is based on the look-ins at 200, and 300 events. This however, combined with our manufacturing ability, combined with the current environment to get new drugs approved quickly means that there is a chance that we could have an approved indication for bavi by early 2017.
Analysts are estimating that Opdivo's annual revenue for squamous cell lung cancer by 2020 will be 1-1.5 billion. Squamous nsclc represents only 25-30% of the nsclc market.
220000 people per year are diagnosed with lung cancer
150000 will be non-squamous nsclc, of which 30 % will go on to second line thereapy = 50 000/year
Opdivo is priced at $12500 a month. lets set the average patient treatment until progession at 4 months, thats $50, 000 per patient
bavi potential sales based on these numbers to me is 2.5 billion annually in USA alone, based on similar pricing.
These are all back of a napkin calculations. Once we have approval for one indication, we are off to the races.
current share count approx 190 million. Burn rate is close to $60 million/year. based on ATM sales that is close to 40-50 million shares per year share count growth for up to another 2 years....I still see us sitting at 250-300 million shares outstanding before the dilution is over. At this point, this is in my opinion the lesser of 2 evils if you believe bavi will be successful. Even under the best of terms, we will be giving away at least half of our IP rights for any substantial partner. I believe the company knows this and will not be partnering until phase 3 success/failure is determined. Even at 300 million share count, this company once bavi gets its first approval will be a rocket. We have complete rights to the PS platform, and we have no competitors with the same MOA. I just wish, as I'm sure many here wish, I found the company 10 years later and didn't have to live through the value destruction that often occurs with small cap biotech in the early stages of drug development. I've been here long enough to wait another 18 months to see this through either way.....I think we end up partnering with a PD-1 marketer down the road to provide a 1-2 punch that their other competitors can't match.
..waiting to re buy more....
Good presentation today. Sounds like lookin could happen by early next year. If you bought my shares at 1.63 Friday you paid too much.
Wash, Rinse, Repeat.
I am a seller here,
I just sold half my shares, will likely sell another 1/4 if there is any pop with PR that is not game changing next week, which I do not believe will be forthcoming right now. There is too little volume to suggest that this is nothing but growing retail optimism. Every week we get closer to partner/trial enrollment etc. but I believe there will be much more volume before that happens.
If you want to see what I mean take a look at sophiris Bio (SPHS). They had an interim lookin of their drug a couple months ago and got crushed. Volume since had been very thin, then out of the blue they trade up 60% with 7 million shares traded when they usually only trade a couple hundred thousand...all with no news...to me that signals somebody knows something. I haven't owned shares in that company since they were finishing their phase 2. Here shares have been trading up, but with volume only 2-3 times the average daily volume (no 35x). To me that signifies there are not a lot of sellers, but the minute we have a CC and conference with no significant news, those that have bid it up in the last couple weeks all run for the exit and we trade back to 1.30...where I will buy my shares again. Wash. Rinse. Repeat. (I hope, but the track record for years has favored this approach).
Don't get me wrong, I am in the bavi is the holy grail camp. I will be very rich with the number of shares I own if bavi succeeds. All the trial news coming out makes me so angry with the bavi phase 2 fiasco, and following shareholder dilution that we have had to endure while management righted the ship. The only good thing is that I have been able to continue to build my pile of peregrine chips.
Haven't posted here in a while.
It was nice having access to the shareholder meeting and presentation via webcast this year, but the presentation was not particularly useful, except for shareholders who may not be familiar with the approval process. Obviously the Q & A was left out as they can't pre-screen who/what people are going to ask.
I feel we are likely at least another year away before we begin to have news that will actually cause any substantial appreciation in share price. I feel the initial catalyst will be full trial enrollment for SUNRISE. This will continue to hang over the share price unless they begin giving updates as to patient enrollment numbers (no numbers = uncertainty as to enrollment success, which leaves timetables for enrollment and completion up in the air...especially when so many doubt managements ability to execute). I feel they are taking this through phase three on their own, and partner will be brought on between phase three success and approval. If it wasn't for Garnick, I would have ended my relationship with PPHM a long time ago, but having followed this company for almost ten years now, I feel confident that the trial will be a success, and he has the skill set to get through the regulatory hurdles efficiently. Overall, I just wish I found this company ten years later than I did! I continue to buy and sell shares and accumulate. If they continue as is we will likely have 300 million shares by the time we have definitive data showing this drug works, which to me is very respectable considering the market potential in second line lung cancer. Then with a partner we can begin running all the trials needed to expand and monetize the bavi platform, and then likely a buyout. I still see no reason why if this all happens this couldn't be a $50-100 dollar stock. Until then, every time the stock is oversold I buy some, and every time the stock is overbought or we get a Pr I sell some.
Geo,
Bavi and radiation may actually turn out to be more effective than the chemo combo. I base this on the immuno-stimulatory effect seen with Bavi, which may be dampened by multiple rounds of chemo. Remember, chemo is not targeted specifically to cancer, it affects all rapidly dividing cells, including the immune cells we are trying to stimulate. We so far have gone after advanced tumors, with local or distant metastasis. These tumors are usually too far advanced to be resectable. Radiation plays a larger role in either shrinking a tumor for resection, or using afterwards to ensure any tumor cells missed from resection are fried with local radiation. OS numbers in these tumor grades are generally much longer, so the trial process could take much longer. Thinking more long term, there have been several preclinical studies showing the up regulation of PS with radiation. Combine that with a stronger, better functioning immune system, and that is where we could see Bavi start to reach its full potential. This is part of why I feel bavi could be the broadest therapy cancer drug on the market in 10 years. For now, I just want to see the partnership and phase 3 second line lung get started and finished. This is all in my opinion obviously, as it needs to b played out in the clinic.
Thanks geo, I should have remembered the chemo dosing/squamous cell inclusion. It would have been nice to see the ORR and pfs numbers increase as a result when comparing our first phase 2 signal seeking trial to the current phase 2 front line nsclc with the above taken into account. One thing that I know has been discussed here is using tumour progression as an endpoint to discontinue Bavi, when there is a possibility that immune activation could initially cause tumour swelling....in turn ending Bavi treatment early when it may be having a positive impact on the tumour. My take is as they continue to gain a stronger understanding of the immune benefits, they will run trials where Bavi will be continued with the change from first/second/third line chemo. Longer Bavi therapy may result in further separation between treatment/control arms = people live longer = more Bavi sold = more revenue per person treated. I have sent an email to IR requesting info with regards to how many people need to pass away in the treatment arm before they will provide mos numbers....will post if I get anything back. Could anyone provide the date that the nsclc front line trial stopped recruiting?
Thanks.
I am having a tough time making up my mind on the front line lung cancer trial. Our earlier phase two had mos of 12.4 months, so I would assume the number from this trial to be around 12 months. However, this trial is supposed to be event driven, and I assumed we would have hit this number already. We reported pfs numbers in march of last year which were around 6 months. One would assume 12 months would be around September 2012. We are now all the way back to march. Can anyone throw out any ideas that might explain why we haven't seen mos when in the last webcast, they said the results were event driven, and would be announced once the treatment arm evented. Also, if the control arm evented some time ago, why would they not announce that, and let the share price build as they did with the second line data as time continued to go by showing increased efficacy of Bavi? Could this have simply been stated in the trial protocol how they would release data? Is it possible the control arm is performing much better than historical trials (seems highly unlikely that the control arm would be out 16-18 months. Does anyone have the date the last patient was enrolled in the trial?
Thanks.
I am very glad to hear the improving tone with regards to 2nd line nsclc data, and pray that it will be sufficient that the FDA will accept it allowing us to move on with phase 3. I was disappointed with the number of shares the company has chosen to sell over the passed 3 months. 30% dilution is significant, and we will likely see another 20% before the data is mature and we partner (based on company timeline to completion of os for 2nd line. The discrepancy issue was a very expensive mistake with regard to potential share value for current shareholders. It will likely result in at least a 50% reduction in future share price value as compared to if the loan would have carried us through till next year when we would have secured a partner, not to mention the share price destruction. I still see tremendous upside potential, and I believe that we will end up with industry leading improvements in all of the trials we are currently running. I have added shares twice since September 24th at .85 and 1.15 and I will add more in January if we hold above 1.17. I firmly believe that .39 last year was our bottom, and just as the road down was rocky and brutal, the road up will likely be longer and more rough than most here think.
Annual Shareholder Meeting
I had really hoped to make the shareholder meeting this year, as I thought it would give me some clarity on the current situation....but due to scheduling it will not be a possiblity. I understand that a number of people on this board are going....is there any chance that someone could record it and post it?
Still holding my 20,000 shares
Could the discrepancy also be that the patients within specific treatment arms were given someone else's specific dose
By that I mean if you have 40 people per treatment arm and they all have varying weights (remember Bavi is dosed by weight) then it is possible that patients got the wrong dose... With Bavi's MOA this may not have impacted the results too heavily, but it would be considered a major discrepency
I have been rereading the PR from today since that is all we have to go on right now. This is what I found useful.
Quote:
--------------------------------------------------------------------------------
major discrepancies between some patient sample test results and patient treatment code assignments.
--------------------------------------------------------------------------------
My interpretation of this is that sample lots were tested when they were made at Avid to verify the concentrations
as probably done for GMP regulations. The results of those concentration tests were compared with the coded
assignments of dosage to the patients and errors were found.
I agree, and if there were anomalies in the placebo group, I would assume that it would have been caught when the trial was initially unblinded...meaning if bavi was turning up in patient test results like blood work, when they were supposed to be in the placebo group. It seems to me that perhaps one or both of the treatment arms reached MOS this passed week, which made the data available for review, and that is when things were not matching up. For example, blood results were not correlating with the treatment arm they were supposed to be.
This would explain why all three treatment arms had similar base line characteristics, and there was such a difference between the placebo and treatment arms, but why now, when all the data is available, we are seeing discrepancies.
This to me is the most rational explanation...not ruling out some more malicious outcome, but I usually try to go with the most logical explanation
I am struggling with this news today.
How does one manage to erroneously cross code the placebo and treatment arms, and still end up with such a substantial survival benefit? I could see this if the blinding was somehow compromised as well, but that was not discussed in the press release. It has already been brought up, but if the placebo group was actually getting drug, and some of the treatment arms were getting placebo, that would reduce the benefit, not improve it. Also, management stated that the pfs and mos numbers were similar for each geographical region. Why did they not clarify which region(s) were affected, unless all the regions are affected. Was this third party agent responsible for all the randomization, coding and distribution, or just one piece of the job? In my opinion, I feel that as long as they can determine who received the active drug and who didn't, then they should be able to recalculate response and survival. If they can, then this was just a horrendous short term f$$$$$$k up. Remember, the mos benefit had a p value of 0.0154, which means if all the treatment arms were completely botched, there is only a 1.5% that you could end up with the trials results we got... Not impossible, but very unlikely. From what has been disclosed, there is still a high probability that the results once sorted out will positive, theoretically, they could be even better. I would lean towards the idea that the treatment arms themselves 1mg and 3 mg are the arms that got mixed up....but no one really knows until they come clean with the details. If this whole trial is a bust and is not useable, I think it will be very difficult to get any partners, unless the liver or pancreatic results are stellar and released before the end of the year. Without backing and our now collapsed share price, we cannot afford to run this trial again....at least I won't be giving them any more of money to dilute while we wait.
I remember when I first bought shares in this company seven years ago when bavi was just finishing its first phase 1 trial... the potential I saw in the drug platform, it truly amazed me....I thought for sure I had picked the stock of the century...then seven years slowly passed with each year seeming to bring more positive trial developments but ever lower share prices. PIPES, then more PIPES, then RS, then ATM....it was brutal....but I couldn't bring myself to sell, as I felt if it were a scam, it was one worth getting burned on...there seemed to be too many highly regarded professionals in the medical community willing to get involved for the whole thing to be a scam...but management never gave me any comfort..so every time I bought more shares I always felt a bit like an idiot...then May 21st happened...then the webcast removing any doubt that management was not releasing MOS..and now we have our first truly unbiased glimpse at what bavi and the whole anti-PS platform may accomplish. I truly hope we have hit the tipping point, and we begin to see some of the value that we all felt was in the platform, start to be represented in the share price.
nuke661,
R84 is not human bavi...it has nothing to do with anti-PS. It is more of a direct competitor with avastin (anti-VEGF), meaning it works through the same MOA but is more specific to tumors so hence less SE. This change in the contract should have no impact on Bavi or its human version.
Regards.
In the meantime, it takes money to keep things moving.
No matter how you try to spin it, repeating a phase II trial is not progress.
Regards,
moby
No matter how you try and spin it, your understanding of clinical trials and process with the FDA are lacking. Do you really think that the FDA would grant a phase 3 study in the US for lung cancer after an overseas open label phase 2 trial with 45 patients??? Give your head a shake...
This trial is progress, and with Garnick working with the FDA, and Bavi's potential, there is a chance we get accelerated approval based on this trial.
could someone with some charting knowledge explain why despite the high volume and declining price, the chaikin money flow continues to be positive.
Thanks.
Bungler,
you wrote:
Ludicrous! It is also difficult to understand why the company is not doing a Phase III instead of yet another Phase II? As anyone with a realistic brain knows, Phase III comes after Phase II, not another Phase II! Even the GEICO caveman knows that! In fact, the correct way to manage and run this company is so obvious, it boggles the mind that it is not being done.
Please remember that only phase 1 had been completed in the US, and while they were waiting for the phase 1 trial to be completed they were able to move on to several phase 2 trials outside of the US to gain valuable data with regards to efficacy. By doing this they were able to determine that Bavi's greatest apparent efficacy may lie in treating lung cancer, which is a very large market, and a potentially easy one to gain access to if our efficacy to date can be repeated (refering to second line NSCLC, which could provide more than a billion a year in revenue in the US alone). With this data they went back to the FDA with both safety and efficacy data, and were able to get a phase 2 double blind placebo control trial with power that could prove that bavi works, and exceeds current treatment. They have also brought on probably the single most experienced person to work with the FDA, being Rob Garnick, to make sure things go smoothly. It has been stated that if there is a sufficient improvement over current therapy, Bavi could be available for use prior to completing a full phase 3 (realize the trial we are running really has all of the standards of a phase 3, but with fewer patients), which means you could have a drug available for use in 2-3 years. I personally do not see how they could position bavi to enter the cancer market faster than they have been doing. The end goal here is a drug on the market, and I personally respect managements strategy wiht regards to this. I also believe that if they can get bavi to market themselves, i will be far richer than if they had done a licencing deal with a 10% royalty a year ago, or even now.
I believe bavi is one of the crown jewels currently being developed, and has potential to be one of the biggest blockbusters to come to market. Peregrine being such a small company, provides huge leverage.
I am however, like most here quite frustrated at the current share price, but realize that dilution now, perhaps enough to get the going concern removed, will quickly be rewarded if we are holding full rights to this drug two years from now with phase 2b results showing results that everyone here who follows the science believes is possible.
I bought shares in this company more than five years ago when I was 21. My holdings have gone from 1000 to 8500, and I add from time to time, with the goal of acquiring 20000 before it takes off. If bavi fails, my investment will likely be worthless, and I will move on. If it is successful I might be retired at 30. Time will tell, the noise in between will only provide buying opportunities for those with the balls and the stomach.
Good Luck ;)
Can anyone expand on this:
I have heard that there is legislation mixed in with the new health care reform bill in the US concerning biosimilars, and market exclusivity. Could someone with more info/a greater understanding of this outline the risks/benefits concerning our push for biosimilars.
11/2/2009
Biosimilars Provision Included in House Health Care Reform Bill — The Time Has Finally Come
Legal News Alert: Life Sciences
On October 29, 2009, the Democratic leadership of the House of Representatives released the Affordable Health Care for America Act, H.R. 3962. The proposed legislation contains provisions that, if enacted, would result in numerous changes in the way that health care insurance is provided and paid for in the United States.
H.R. 3962 includes section 2575 entitled, “Licensure Pathway for Biosimilar Biological Products,” which is intended to give the U.S. Food and Drug Administration (FDA) the authority to approve biosimilar versions of biotech drugs.
Similar to previous bills, H.R. 3962 provides for the approval of biosimilar products, defined as those “ … being highly similar to the reference product, [i.e., the brand name biologic that is referenced by the biosimilar product], notwithstanding minor differences in clinically inactive components” and “no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency of the product.” H.R. 3962 also includes a section allowing for, but not mandating, “interchangeable” biosimilars, defined as a product that meets certain standards and can be “substituted for the reference product without the intervention of the health care prescriber who prescribed the reference product.” There also are exclusivity provisions for the first interchangeable biological product. The biosimilar product would be required to bear a name that distinguishes it from the reference product. The bill also permits the FDA to issue guidance documents concerning the licensure of biologic products; however, such issuance, or non-issuance, of any such guidance cannot preclude the review or action on any application.
The bill also strikes a balance by providing incentives for brand companies to develop new therapies. The bill provides a 12-year period of market exclusivity from the date of approval of the reference product. The length of this period of market exclusivity has been the subject of much debate. An application for a biosimilar cannot be submitted for four years from the date of approval of the reference product. There also is a six-month pediatric exclusivity period. There is no period of exclusivity for supplements providing for changes to the reference product, if the change (other than a modification to the structure of the biological product) results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength, or if the modification of the structure of the biological product does not result in a change in safety, purity, or potency. This is quite different from the current exclusivity scheme under Hatch-Waxman for approved drugs.
Patent Disputes Addressed
The bill establishes a new, complex procedure for resolving patent disputes before a biosimilar is approved.
As provided in the current bill, a biosimilar applicant, within 30 days of its application being accepted by FDA, must provide the reference product sponsor with a copy of the application and information concerning the biosimilar product and its production. This information is required to include a detailed description of the biosimilar product, its method of manufacture, and materials used in the manufacture of the product.
Within 60 days of receipt of the above information, the reference product sponsor is required to provide notice to the biosimilar applicant a listing of all relevant patents — patents that could be reasonably asserted against the biosimilar applicant due to the unauthorized making, using, or sale or offer for sale in the United States or materials used in the manufacture or a method of treatment — for the reference product. New patents granted or licensed by the reference product sponsor are required to be provided to the biosimilar applicant within 30 days of the patent grant or license.
Third parties with relevant patent interests also may provide notice to the biosimilar applicant concerning relevant patents. Within 30 days of receipt of such a notice, the biosimilar applicant must provide the interested third party with a copy of the application and information concerning the biosimilar product and its production. This information is required to include a detailed description of the biosimilar product, its method of manufacture, and materials used in the manufacture of the product. Within 90 days of receipt of this information, the interested third party is required to provide the biosimilar applicant with a list of all relevant patents. New patents granted or licensed by the interested third party after the list is provided to the biosimilar applicant are required to be provided to the biosimilar applicant within 30 days of the patent grant or license.
The reference product sponsor or interested third party is required to provide a written statement to the biosimilar applicant that: (1) explains why each relevant patent would be infringed; (2) states whether the patent is available for licensing; and (3) provides the patent number and expiration date of each relevant patent.
The biosimilar applicant, within 45 days of receiving the above written statement is required to send a written statement regarding each identified patent to the party that identified the patent. The written statement should state that the biosimilar applicant will not commence marketing prior to the expiration of the patent and has requested that the FDA not grant final approval until the patent expires, or the statement should:
(1) Set forth the reasons why the biosimilar applicant believes the making, using, or sale or offer for sale of the biosimilar in the United States or materials used in the manufacture of the biosimilar or a method of treatment using the biosimilar indicated in the biosimilar application would not infringe the patent
(2) Set forth the reasons why the biosimilar applicant believes the patent is invalid or unenforceable
The reference product sponsor or interested third party may instigate patent litigation in federal court as long as it is within 60 days of receipt of the notice from the biosimilar applicant. If a court determines that at least one patent is infringed prior to the expiration of applicable exclusivity provisions, the FDA will make the approval effective for the biosimilar product on the day after the date of the expiration of the last expiring relevant patent.
The bill also provides for submission and review by the assistant attorney general and Federal Trade Commission of agreements made between the reference product sponsor and biosimilar applicant and between biosimilar applicants that relate to the manufacturing, marketing, or sale of the biosimilar product. Such agreements are required to be submitted within 10 business days of being executed and prior to the first commercial marketing of the biosimilar product that is the subject of the agreement. Agreements that deal solely with purchase orders for raw materials, equipment and facility contracts, employment or consulting contracts, or packaging and labeling contracts are exempt from the notification requirement. There are certification requirements with respect to such agreements as well as civil monetary penalties and other judicially ordered equitable relief for noncompliance with the notification provisions.
Battle of the Associations
Two major trade associations, the Generic Pharmaceutical Association (GPhA) and the Biotechnology Industry Organization (BIO), each having constituents with significant interests in biosimilars, had opposing views of some of the basic approaches reflected in the bill, particularly with respect to the 12-year exclusivity provision.
On October 27, 2009, GPhA sent a letter to President Obama, requesting the president to “urge congressional leaders to strike the biogeneric language from pending health care reform legislation unless the provisions are materially altered to ensure timely entry of safe and affordable biosimilars and biogenerics to the market. The inclusion of the current fatally flawed language is arguably worse than the effective monopoly that the biotech industry enjoys because it represents an empty promise to Americans who may falsely believe that the legislation will provide for meaningful competition. This simply will not increase access or contain drug spending costs; rather, it represents little more than camouflaged protection of the unacceptable and unsustainable status quo.” (http://tinyurl.com/ye38b7o). GPhA is advocating a much shorter period of exclusivity.
On October 30, 2009, BIO responded by stating that “GPhA's request to the Administration is a cruel trick to the millions of patients who are awaiting the benefits of biosimilars. GPhA is asking the Obama Administration to hold patients and consumers hostage unless it gets its way on this critical provision of health care reform. … The innovator biotechnology industry actively supports efforts to expand competition in our sector through our strong support of the bipartisan Committee-passed regulatory pathway for biosimilars. … Creating a pathway for biosimilars that includes 12 years of data exclusivity will help the biotech industry realize this potential, to the benefit of millions of patients worldwide. Congress should act now to establish a balanced, pro-patient pathway to biosimilars.” (http://tinyurl.com/yedore7).
A Glimpse Into the Future
Given the disagreements among industry associations about the market exclusivity provisions of H.R. 3962, Foley will continue to monitor the situation and provide information about the provisions that are ultimately passed by Congress and signed into law by President Obama. With other controversial provisions concerning health care reform proposals, it remains to be seen how the section on biosimilars ultimately will proceed during the upcoming debates in the House and the Senate.
--------------------------------------------------------------------------------
Legal News Alert is part of our ongoing commitment to providing up-to-the-minute information about pressing concerns or industry issues affecting our clients and colleagues. If you have any questions about this alert or would like to discuss this topic further, please contact your Foley attorney or any of the following individuals
Apparently, in cancer trials, one arm is given standard of care (SOC) + placebo while the other arm is given SOC + (Bavi)
Yes, I'm aware of the use of a placebo in that sense in order to keep everyone in the dark on if the patient is receiving just the SOC or the candidate + SOC.
Now, go back and read the transcript of the last conference call. Dr. Garnick never mentioned an SOC for the phase II trial they're designing.
If I managed to overlook that, please let me know.
As per Dr Garnick...
We’re in the process of designing a randomized blinded and placebo controlled Phase II clinical study for bavituximab in 2nd-line NSCLC. This type of study is typically the gold standard in the U.S. for drug development and this study is intended to play a major role in our future approval strategy for this product.
The placebo in this trial would be SOC + placebo infusion vs SOC + bavi infusion. This is what is meant by his use of placebo controlled trial....unless you are trying to say that he means that we would actually give only bavi vs a placebo, which is ludicruous and would never be approved by the FDA d/t ethical reasons that you have mentioned before.
Mojojojo,
I could be wrong but my understanding is that patients get a one week rest period between cycles
No, there is no rest period between cycles. A 21 day cycle means every 21 days the therapy is repeated.
Patients were randomly assigned to receive paclitaxel at a dose of 200 mg per square meter of body-surface area and carboplatin at a dose calculated to produce an area under the concentration–time curve of 6.0 mg per milliliter per minute, administered intravenously on day 1, or paclitaxel and carboplatin plus bevacizumab at a dose of 15 mg per kilogram given intravenously on day 1.15 Chemotherapy was repeated every 21 days for a total of six cycles unless there was evidence of disease progression or intolerance of the study treatment. Patients in the paclitaxel–carboplatin–bevacizumab group continued to receive bevacizumab monotherapy every 3 weeks until evidence of disease progression or unacceptable toxic effects developed. [/b]
Irregardless, bavi's PFS of 6.5 months is similar to avastin's 6.2 months. The median number of treatment cycles in the avastin trial was seven. This was most likely six cycles of chemo/avastin and just one additional cycle of avastin as a mono therapy.
Yes, exactly. So on average, the combination of paclitaxel + carboplatin and avastin = 1 extra cycle of chemo + an additional cycle of avastin as monotherapy.
The median number of cycles of therapy was five in the paclitaxel–carboplatin group and seven in the paclitaxel–carboplatin–bevacizumab group (including the cycles of bevacizumab monotherapy). Of the 407 patients starting treatment with paclitaxel and carboplatin plus bevacizumab for whom we had adequate information on the duration of treatment, 215 (53%) continued with bevacizumab monotherapy, and of these, 107 (50%) received more than five cycles of monotherapy
In my opinion the current bavi phase 2 protocols have a flaw that I hope gets dealt with.
With regards to this post you made, I feel you've hit on an important point ragarding bavi's MOA. You are correct with regards to bavi monotherapy being stopped once disease progression is established, and I agree this could be a flaw which could result in a lower overall survival number. If bavi truly is immunostimulatory on its own, then you would assume bavi's benefit might continue even after progression, resulting in a longer overall survival. I think we will have to wait for more data concerning overall survival in the current phase 2 study. Perhaps the numbers are compelling enough that this concern does not need to be addressed until a later time.
here is also some info concerning NSLC and its treatments from the BC Cancer Agency, which is recognized as one of the leading cancer institutes in North America
http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Lung/6ManagementPolicies/641NonSmallCellLungCancer/14PalliativeChemotherapyofAdvancedNSCLC.htm
Palliative Chemotherapy of Advanced NSCLC
Updated February 2008
Guideline: There is evidence from meta-analyses of a small survival benefit of chemotherapy over best supportive care in performance status 0-2 NSCLC patients.1 If symptom control and quality-of-life are the outcomes of interest, chemotherapy appears to be of benefit based on randomized trials analyzing chemotherapy for this purpose.2-6 Chemotherapy is an option for palliative therapy of patients with NSCLC provided there is a full discussion of the benefits, limitations and toxicities of the treatment.
Level of Evidence: I (survival benefit), I (quality-of-life, symptom control)
Grade of Recommendation: A (survival), A (quality-of-life, symptoms)
Chemotherapy modestly improves median and one year survival in patients with distant metastatic NSCLC compared with best supportive care, but is not curative. The results of three recently published meta-analyses indicate that cisplatin-based chemotherapy yields an improvement in median survival of approximately 6 to 8 weeks in stage IV disease. One year survival improves from 10-15% to 25-35%. The evidence supporting chemotherapy is based on patients entered on clinical trials with good performance status and other selection criteria that may not be representative of typical clinical practice. Many recent randomized trials assessing aggressive regimens allow only patients with ECOG performance status of 0 and 1. Survival results of such trials appear superior to older trials but the patient populations are not comparable.
Patient Selection for Palliative Chemotherapy
Palliative chemotherapy patients should have performance status of ECOG 0, 1, or 2. Extensive previous radiotherapy is associated with increased chemotherapy toxicity and symptomatic disease within a previous radiotherapy volume may be less chemosensitive. Renal, hematologic and hepatic function must be adequate.
Active patient participation in decision-making is crucial. Outcome measurements should reflect more than just the selected disease measures (e.g. survival), but other concerns as well, including symptom control and quality-of-life, patients’ value or meaning of life, their feelings about themselves, and their perceptions and attitudes about a specific treatment.
Palliative Chemotherapy Regimens
Of the chemotherapeutic agents with activity against NSCLC, platinum-based chemotherapy has historically been considered the most effective and remains the "backbone" of current chemotherapy. It is recognized that doublet therapy provides the best balance of benefit and toxicity in comparison to single agent or triplet treatment. Multiple trials have established that platinum combinations with vinorelbine, gemcitabine, docetaxel and paclitaxel were equivalent with respect to response rate and survival benefit.7-10 Fit patients with advanced NSCLC therefore should be offered first line doublet platinum-based chemotherapy.
Comparisons of the two commonly used platinum agents in NSCLC, cisplatin and carboplatin, have been undertaken. A meta-analysis of abstracted data comparing the platinum agents indicated that cisplatin plus a new agent yielded an 11% longer survival than the same carboplatin doublet.11 When older chemotherapeutic regimens were included, the survival benefit was not statistically significant. Toxicity was noted to be lower with carboplatin-based chemotherapy. Subsequently, the CISCA meta-analysis looked at individual patient data and found an improvement in response rate with cisplatin over carboplatin. However, the survival benefit was not statistically significant (HR for death, carboplatin vs cisplatin 1.07 p=0.101).12 Again, carboplatin was better tolerated. For patients with good performance status and limited co-morbidities, cisplatin is the preferred agent for palliative therapy.
Non-platinum third-generation regimens have been compared to platinum doublets in the phase II and III setting. Meta-analyses suggest that outcomes are similar for both groups, but the toxicity profiles differ depending on the combination.13 Platinum doublets remain the mainstay of advanced NSCLC therapy.
Efforts have been made to combine doublet chemotherapy with biologic agents to improve first line outcomes. Combinations with epidermal growth factor tyrosine kinase inhibitors, matrix metalloproteinase inhibitors and hypoxic cytotoxins have all failed to demonstrate an improvement over standard therapy.
ECOG 4599 was the first trial to show a survival benefit with the addition of a targeted therapy. Patients were randomized to carboplatin and paclitaxel with or without bevacizumab, an antibody directed against vascular endothelial growth factor.14 Due to risk of bleeding and toxicity with this agent, patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status were excluded. The median survival of chemotherapy alone was 10.3 months in comparison to 12.3 months in the bevacizumab group. While this represented a significant improvement, it was tempered by the fact that there were 15 treatment related deaths in the bevacizumab arm of which 5 were pulmonary hemorrhage. A second phase III trial comparing cisplatin and gemcitabine with or without bevacizumab at two different doses was conducted in chemo naïve NSCLC patients.15 The preliminary results of this trial were presented at ASCO 2007. There was a small but statistically significant improvement in progression free survival (approximately 2 weeks). Overall survival data is anticipated in 18 months. The apparent limited benefit of adding bevacizumab in this trial may have been impacted by the frequency of evaluation (every 3 months as opposed to 2 months in ECOG 4599). However, this is speculative. Current practice at the BCCA does not incorporate bevacizumab in standard therapy as the results of confirmatory trials are awaited.
Chemotherapy Duration
There is no evidence that continuing chemotherapy beyond 3-4 months in responding patients prolongs survival, and cumulative treatment toxicity is a concern and should be minimized.
References:
1. Anonymous: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Bmj. 311:899-909, 1995
2. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 17:3188-94, 1999
3. Helsing M, Bergman B, Thaning L, et al: Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicentre randomised phase III trial. Joint Lung Cancer Study Group. Eur J Cancer 34:1036-44, 1998
4. Thongprasert S, Sanguanmitra P, Juthapan W, et al: Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy. Lung Cancer 24:17-24, 1999
5. Gridelli C: The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. Oncologist 6 Suppl 1:4-7, 2001
6. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91:66-72, 1999
7. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New England Journal of Medicine. 346:92-8, 2002
8. Fossella F, Pereira JR, von Pawel J, et al: Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non-Small-Cell Lung Cancer: The TAX 326 Study Group. J Clin Oncol 21:3016-3024, 2003
9. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. Journal of Clinical Oncology. 20:4285-91, 2002
10. Kelly K, Crowley J, Bunn PA, Jr., et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. Journal of Clinical Oncology. 19:3210-8, 2001
11. Hotta K, Matsuo K, Ueoka H, et al: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:3852-9, 2004
12. Ardizzoni A, Tiseo M, Boni L, et al: CISCA (cisplatin vs. carboplatin) meta-analysis: An individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 24:7011-, 2006
13. D'Addario G, Pintilie M, Leighl NB, et al: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23:2926-36, 2005
14. O'Brien M SA, Popovish A, et al.: Xyotax vs. gemcitabine or vinorelbine for the treatment of performance status 2 patients with chemotherapy naive non small cell lung cancer (NSCLC): the STELLAR 4 phase III study. Lung Cancer 2005;49(suppl 2):S37, 2006
15. Manegold C, von Pawel J, Zatloukal P, et al: Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naive patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. ASCO Meeting Abstracts 25:LBA7514-, 2007
Bevacizumab Plus Platinum-Based Chemotherapy
In Advanced Non-Small Cell Lung Cancer
I hope this post works, this is the major avastin trial data which we will be trying to exceed:
key points from study:
A The addition of bevacizumab to standard chemotherapy significantly
delayed disease progression in two large, randomized,
phase III trials in chemotherapy-naive patients with advanced,
nonsquamous NSCLC. In the open-label E4599 trial, median
overall survival duration was significantly extended by 2 months
and median progression-free survival was significantly increased
by 1.7 months when intravenous bevacizumab 15 mg/kg once
every 3 weeks was added to first-line carboplatin/paclitaxel
therapy compared with carboplatin/paclitaxel alone.
A In the double-blind AVAiL trial, median progression-free
survival was significantly increased (by 0.6 and 0.4 months) by
the addition of intravenous bevacizumab 7.5 or 15 mg/kg once
every 3 weeks to first-line cisplatin/gemcitabine therapy compared
with placebo plus cisplatin/gemcitabine. However, median
overall survival duration was not significantly improved
(13.6 and 13.4 months vs 13.1 months).
A Response rates in the E4599 and AVAiL trials were 30-35% in
patients receiving bevacizumab plus platinum-based chemotherapy
compared with 15% and 20% without bevacizumab.
Antona J. Wagstaff, Susan J. Keam and Paul L. McCormack
Wolters Kluwer Health I Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia,
Pennsylvania, USA
Contents
Abstract 187
1. Pharmacodynamic Profile 188
2. Pharmacoi<inetic Profile ; 188
3. Therapeutic Efficacy 188
4. Tolerability 192
5. Dosage and Administration 195
6. Bevacizumab Plus Platinum-Based Chemotherapy in Advanced Non-Small Cell Lung Cancer: Current Status 195
Abstract
A Bevacizumab is a recombinant, humanized vascular endothelial
growth factor (VEGF) monoclonal antibody that inhibits tumor
growth and tumor métastases. VEGF stimulates angiogenesis
in tumors, is involved in early metastatic processes, and
is overexpressed.in non-small cell lung cancer (NSCLC).
A The addition of bevacizumab to standard chemotherapy significantly
delayed disease progression in two large, randomized,
phase III trials in chemotherapy-naive patients with advanced,
nonsquamous NSCLC. In the open-label E4599 trial, median
overall survival duration was significantly extended by 2 months
and median progression-free survival was significantly increased
by 1.7 months when intravenous bevacizumab 15 mg/kg once
every 3 weeks was added to first-line carboplatin/paclitaxel
therapy compared with carboplatin/paclitaxel alone.
A In the double-blind AVAiL trial, median progression-free
survival was significantly increased (by 0.6 and 0.4 months) by
the addition of intravenous bevacizumab 7.5 or 15 mg/kg once
every 3 weeks to first-line cisplatin/gemcitabine therapy compared
with placebo plus cisplatin/gemcitabine. However, median
overall survival duration was not significantly improved
(13.6 and 13.4 months vs 13.1 months).
A Response rates in the E4599 and AVAiL trials were 30-35% in
patients receiving bevacizumab plus platinum-based chemotherapy
compared with 15% and 20% without bevacizumab.
A The safety and tolerability profile of bevacizumab-containing
treatment regimens in patients with advanced NSCLC was
generally manageable in the E4599 and AVAiL trials, and in two
large, ongoing, trials (the open-label SAiL and the observational
ARIES studies).
Features and properties of intravenous bevacizumab (Avastin®)
Featured indication
First-line treatment of unresectable, locaily advanced, metastatic or recurrent,
nonsquamous, non-smaii celi iung cancer, in combination with platinum-based
chemotherapy
Mechanism of action
Bevacizumab is a recombinant, humanized vascular endotheiiai growth factor
(VEGF) monoclonal antibody that binds with VEGF to prevent tumor angiogenesis
Dosage and administration
Dose
Frequency
Duration (pius piatinum-based chemotherapy for up to six
cycies of treatment, then as a singie agent)
Route of administration
Pharmacokinetic profile in patients with cancer
Peai< serum concentration after a 7.5 or 15 mg/kg dose
Volume of distribution in the central compartment
Clearance (wide interindividuai variation)
Terminai elimination half-life (wide interindividuai
variation)
7.5 or 15 mg/kg
Once every 3 wk
Until disease
progression
intravenous infusion
182and363ng/mL
=3L
=3 mL/kg/d
-20 d
Most frequent grade £3 adverse events of special Interest In the large, openlabel
SAiL trial (incidence of each was <5%)
Thromboemboiism, bleeding, congestive heart failure, gastrointestinai perforation
188 Wagstaffetal.
In the year 2000, lung cancer was the cause of more deaths
than any other cancer.t'' Most lung cancers are categorized as
the difficult-to-treat non-small cell lung cancer (NSCLC).P'
Only a few patients with NSCLC are eligible for potentially
curative surgery and, for the remainder, chemotherapy alone is
associated with a poor prognosis (median survival duration
is 18 months in locally advanced NSCLC and 9 months in
metastatic NSCLC).^'^]
Thus, platinum-based chemotherapy doublets (historically,
the standard of caret'*') plus concomitant specific targeted
therapies, including those blocking the effects of vascular endothelial
growth factor (VEGF), are currently under consideration
for initial treatment of advanced NSCLC^^' VEGF stimulates
angiogenesis in tumors, is involved in early metastatic processes
and is overexpressed in NSCLC.t^'^'
Bevacizumab (Avastin®) is a reeombinant humanized
VEGF monoclonal antibody. The focus of this article is the use
of intravenous bevacizumab in combination with platinumbased
chemotherapy doublets in chemotherapy-naive patients
with locally advanced or metastatic NSCLC. Medical literature
on the use of bevacizumab in this indication was identified
using MEDLINE and EMBASE, supplemented by AdisBase
(a proprietary database of Wolters Kluwer Health I Adis).
Additional references were identified from the reference lists of
published articles.
1. Pharmacodynamic Profile
The pharmacodynamics of bevacizumab have been described
in detail previously.'^' This profile provides a brief
summary of the relevant data.
• Bevacizumab binds specifically to all VEGF isoforms, and
the subsequent steric hindrance of the VEGF molecule prevents
it from binding to the relevant receptor tyrosine kinases on
vascular endothelium and bone marrow-derived cells.'^'^'
• In vitro studies have demonstrated bevacizumab-associated
inhibition of VEGF-stimulated endothelial cell proliferation,
survival, permeability, migration, and nitric oxide and tissue
factor production.'*'^'
• In in vivo models, bevacizumab inhibited tumor growth and
métastases, decreased the diameter, density, and permeability
of tumor vessels, reduced interstitial fluid pressure, increased
intratumoral uptake of chemotherapy, and increased radiationassociated
tumor oxygénation and growth inhibition.''"' The
effects of bevacizumab on dendritic cell function also improved
antitumor immune responses.'^'
• Antiangiogenic and antitumor effects (reduced tumor
perfusion, blood volume, microvascular density, and interstitial
fluid pressure, and increased tumor apoptosis) associated with
intravenous bevacizumab monotherapy have been demonstrated
in patients with rectal or breast cancer.'^'
• Free serum VEGF levels were significantly decreased
with intravenous bevacizumab 0.1-10 mg/kg (four doses over
6 weeks) in patients with advanced cancer.'"' Response rates
(33% vs 8%; p = 0.01), but not survival, were significantly
improved in patients with NSCLC who had high VEGF levels
at baseline and who received carboplatin/paclitaxel plus
bevacizumab compared with those with high VEGF levels
receiving carboplatin/paclitaxel alone.''^'
2. Pharmacokinetic Profile
Pharmacokinetic data on intravenous bevacizumab are
available from two fully published studies in patients with advanced
cancer who received bevacizumab 0.1-10.0 mg/kg on
days 0, 28, 35 and 42 (n=25)'"' or 3 mg/kg weekly for 8 weeks
plus chemotherapy (n= 12).''^' Data are also available from two
abstracts of studies in patients with cancer receiving multiple
infusions of bevacizumab 0.1-10.0 mg/kg over 4-24 weeks, as
a single agent or with antineoplastic agents,'*'*''^ and from the
manufacturer's prescribing information''^''^ (n = 52-491). Serum
bevacizumab concentrations were measured using ELISA.
• The pharmacokinetics of intravenous bevacizumab follow a
linear profile.'"' Mean peak serum concentrations were 182 and
363 ng/mL with bevacizumab 7.5 or 15 mg/kg given on day 1 of a
3-week cycle.''^ Accumulation is not clinically significant;'' '' the
accumulation ratio after lOmg/kgevery second week was 2.8.''^'
Steady state is reached after approximately 100 days.''^'
• The volume of distribution of bevacizumab in the central
compartment is =3 L (intersubject variability 25%).''^*''^'
• Clearance is =3 mL/kg/day (intersubject variability 44%).''*'
Clearance varies with sex (higher in males) and tumor burden
(higher in patients with more severe disease).''^-'^' No dose
adjustments are required for age or sex.''^'
• The initial half-life has been reported as 1.4-1.85 days, and the
mean terminal half-life as 13-21 days (one source suggested a
mean of =20 days with a range of 11-50 days''''').'"''3''4.i6.i7]
3. Therapeufic Efficacy
The efficacy of intravenous bevacizumab in combination with
platinum-based doublet chemotherapy has been investigated in
adult, chemotherapy-naive patients with locally advanced, metastatic,
or recurrent NSCLC in two fully published phase III
trials,''*'''' a fully published phase II trial,'^*'' and several noncomparative
studies.'^''^^ These studies included chemotherapynaive
patients with stage IIIB or IV''*"^''' or recurrent" *-2°-2^'
NSCLC and an ECOG (Eastern Cooperative Oncology Group)
© 2009 Adis Data Information BV. All rights reserved. Biodrugs 2009:23 (3)
Bevacizumab: Adis Drug Profile 189
performance status of 0 or 1 ,['8-19,21,23,24,26] QJ. <2.[2O] several trials
also specified nonsquamous histologyJ'*-'^'^'"^^ Where exclusion
criteria were specified, all trials excluded patients using therapeutic
anticoagulants and those with significant cardiovascular
diseaseJ'^'^'*'^*'^^ Patients with CNS métastases, history of gross
or grade >2 (i.e. > Vi teaspoon of bright red blood per event) hemoptysis,
thrombotic or hemorrhagic disorders, or recent major
surgery or radiation therapy were also excluded in most trials.
E4599 Trial
In the phase III, randomized, open-label, multicenter ECOG
E4599 trial, intravenous bevacizumab 15 mg/kg every 3 weeks in
combination with carboplatin/paclitaxel therapy was compared
with carboplatin/paclitaxel alone (n = 878).t'*' Patients received
intravenous bevacizumab plus first-line intravenous carboplatin
(dosage adjusted to achieve a target area under the concentrationtime
curve [AUC] of 6mg/mL per minute) and paclitaxel
200mg/m^ on day 1 of a 3-week cycle (for six cycles). Bevacizumab
was continued after the completion of chemotherapy
until disease progression.^'*' In the E4599 trial, 53% of bevacizumab
recipients continued with monotherapy and half of
these received more than five doses.t'^' There was a small imbalance
in the demographics of the treatment groups in that fewer
men were randomized to the group receiving the bevacizumabcontaining
regimen (50% vs 58%; p=0.03).t'^l The primary endpoint
was median overall survival duration (time from randomization
to death), and primary efficacy analyses were performed
on évaluable patients (28 randomized patients were excluded).^*'
• The addition of intravenous bevacizumab to carboplatin/
paclitaxel therapy significantly improved therapeutic outcomes
in chemotherapy-naive patients with nonsquamous, advanced
NSCLC in the E4599 trial (figure 1).
• Median overall survival (primary endpoint; figure 1) was
extended by 2 months in recipients of bevacizumab 15 mg/kg
plus carboplatin/paclitaxel (n = 417) compared with that in
recipients of carboplatin/paclitaxel alone (n=433) [HR for
death 0.79; 95% CI 0.67,0.92; p=0.003].['«l Survival rates in the
carboplatin/paclitaxel plus bevacizumab and carboplatin/
paclitaxel alone groups were 51% versus 44% at 1 year and
23% versus 15% at 2 years.
• Likewise, median progression-free survival was increased by
1.7 months in recipients of bevacizumab 15 mg/kg plus carboplatin/
paclitaxel versus those receiving carboplatin/paclitaxel
alone (HR 0.66; 95% CI 0.57, 0.77; p<0.001) [figure I].!'»'
• Response rates (assessed using RECIST [Response Evaluation
Criteria in Solid Tumors] criteria) in patients with measurable
disease receiving bevacizumab 15 mg/kg plus carboplatin/
a CAR/PAC/BEV 15
D CAFVPAC
Overall survival Progression-free survival
E4599 trial
H CIS/GEM/BEV7.5
D CIS/GEM/BEV15
D CIS/GEM/PL
Overali survival Progression-free survival
AVAiL trial
Fig. 1. Therapeutic efficacy of intravenous bevacizumab (BEV) plus platinum-
based chemotherapy in chemotherapy-naive patients with advanced,
nonsquamous, non-small cell lung cancer. Every 3 weeks, patients received
(a) intravenous carboplatin/paclitaxel chemotherapy alone (CAR/PAC) or
with BEV 15 mg/kg (CAR/PAC/BEV 15) in the open-label E4599 trial
(n=878);l^8l or (b) intravenous cisplatin/gemcitabine chemotherapy plus BEV
7.5 mg/kg (CIS/GEM/BEV 7.5) or 15 mg/kg (CIS/GEM/BEV 15) or placebo
(CIS/GEM/PL) in the double-blind AVAiL trial (n = 1043).'^ä28l See section 3
for full chemotherapy dosage details. * p=0.03, " p=0.003, " * p< 0.001 vs
non-BEV-contalning regimens.
paclitaxel (n = 381) were significantly greater than those seen with
carboplatin/paclitaxel alone (n = 392) [35% vs 15%; p<0.001].['^l
• A retrospective analysis of treatment outcomes in E4599
according to tumor histology subtype indicated that for the major
subgroup of patients with adenocarcinoma (602 of 878 patients;
69%), combined treatment with bevacizumab plus carboplatin/
© 2009 Adis Data Information BV. All rights reserved. Biodrugs 2009:23 (3)
190 Wagstaffetal.
paclitaxel was associated with a median overall survival of
14.2 months compared with 10.3 months in those receiving
carboplatin/paclitaxel alone (HR 0.69; 95% CI 0.58, 0.83).P9]
• Similarly, in the adenocarcinoma histology subgroup,
median progression-free survival was 6.6 months in bevacizumab
plus carboplatin/paclitaxel recipients compared with
5.0 months in those receiving carboplatin/paclitaxel alone
(HR 0.65; 95% CI 0.54, 0.78).P9] Data in patients with other
histology subtypes were inconclusive, because of small numbers
of patients in each subgroup.t^^^
• In a retrospective analysis of data for the subgroup of
older patients (aged >70 [median 74] years) from E4599,['^l
111 received bevacizumab 15 mg/kg plus carboplatin/paclitaxel
and 113 received carboplatin/paclitaxel alone.t^"' There were
no significant differences between these groups in median
progression-free survival (5.9 vs 4.9 months) or median overall
survival (11.3 vs 12.1 months).P"'
• The addition of bevacizumab to carboplatin/paclitaxel therapy
is unlikely to be cost effective according to estimates from a US
study using 2005 costing and data obtained from the E4599 triait'*'
(SUS 345 762 per life-year gained; reported as an abstract).'^']
AVAiL Trial
Intravenous bevacizumab 7.5 or 15 mg/kg or placebo were
administered every 3 weeks with cisplatin/gemcitabine therapy in
the phase III, randomized, double-blind, multicenter AVAiL
(Avastin in Lung) trial (n= 1043).[''l Patients received bevacizumab
or placebo on day 1 in addition to first-line intravenous
cisplatin 80 mg/m^ on day 1 and intravenous gemcitabine
1250mg/m^ on days 1 and 8 of a 3-week cycle (median of
5-6 cycles were given). Bevacizumab was continued after the
completion of chemotherapy until disease progression or unacceptable
toxicity.f ' Patients were followed for a minimum of
7 months; 42% of bevacizumab recipients received 7-10 doses,
20% received 11-14 doses, and 7-8% received >14 doses.'"' The
primary endpoint was the median progression-free survival
duration (time from randomization to documented disease progression
or death), and primary efficacy analyses were performed
on the intent-to-treat populations (all randomized patients).t'^'
• The addition of intravenous bevacizumab to cisplatin/
gemcitabine therapy significantly improved median progression-
free survival, but did not prolong overall survival in
chemotherapy-naive patients with nonsquamous, advanced
NSCLC (figure 1).
• Median progression-free survival (primary endpoint) in the
AVAiL trial was 6.7 months in patients receiving bevacizumab
7.5 mg/kg plus cisplatin/gemcitabine (n = 345) [HR for disease
progression 0.75; 95% CI 0.62, 0.91; p = 0.003], 6.5 months in
those receiving bevacizumab 15 mg/kg in addition to cisplatin/
gemcitabine (n = 351) [HR 0.82; 95% CI 0.68, 0.98; p = 0.03]
and 6.1 months in those receiving cisplatin/gemcitabine plus
placebo (n = 347) [figure l].t'^l Figure 2 summarizes progression-
free survival data from the AVAiL trial over the first year.
• The effect on progression-free survival was generally
consistent across subgroups based on geographic region, sex,
disease stage, ECOG performance status score, age, histology,
race, smoking status, and bodyweight loss.!'''
• When the results were adjusted to correct for the 6-9% of
patients in each group who had received nonprotocol antineoplastic
therapy before disease progression, the HRs for
disease progression with cisplatin/gemcitabine plus bevacizumab
7.5 and 15 mg/kg were 0.68 and 0.74 (p = 0.0001 andp = 0.002).['^l
• Median overall survival in AVAiL was 13.6 months with
bevacizumab 7.5 mg/kg plus cisplatin/gemcitabine (HR 0.92; 95%
CI 0.77, 1.10) and 13.4 months with bevacizumab 15 mg/kg plus
cisplatin/gemcitabine (HR 1.02; 95% CI 0.85,1.22) compared with
13.1 months for cisplatin/gemcitabine alone.t^^' A retrospective
subgroup analysis in 304 patients aged >65 (median 68) years
confirmed the efficacy data observed in the overall population in
AVAiL, with no negative impact on tolerability (section 4)P'^^
• In AVAiL, objective response rates (assessed using RECIST
criteria) in patients with measurable disease at baseline receiving
concomitant cisplatin/gemcitabine plus bevacizumab 7.5 or
15 mg/kg or placebo were 34% (p< 0.0001 vs placebo), 30%
(p=0.0023), and 20%, respectively.t'^' The median durations of
response were 6.1 months each in recipients of cisplatin/
A CIS/GEM/BEV 7.5
D CIS/GEM/BEV 15
O CIS/GEM/PL
0 mo 3 mo 6 mo 9 mo 12 mo
Fig. 2. Progression-free survival (PFS) In chemotherapy-naive patients
with nonsquamous, advanced non-small cell lung cancer receiving intravenous
bevacizumab pius cispiatin-based chemotherapy. Patients received
intravenous cisplatin/gemcitabine chemotherapy plus bevacizumab
7.5mgy1<g (CiS/GEM/BEV 7.5) or 15mg/kg (CIS/GEM/BEV 15) or placebo
(CIS/GEM/PL) every 3 weeks in the double-blind AVAiL trial (n = 1043).i^3i
See section 3 for full chemotherapy dosage details. The figure shows the
percentage of progression-free patients at 3, 6, 9, and 12 months from triai
initiation.
© 2009 Adis Data Information BV. Aii rigiits reserved. Biodrugs 2009; 23 (3)
Bevacizumab: Adis Drug Profile 191
gemcitabine plus bevacizumab 7.5 or 15 mg/kg, and 4.7 months
in recipients of cisplatin/gemcitabine plus placebo.''^'
• An exploratory, retrospective analysis found that during the
postchemotherapy maintenance phase of the AVAiL trial,
median progression-free survival with bevacizumab 7.5 or
15 mg/kg was 4.6 months in each group compared with
3.2 months with placebo.'^-''
• Modelled analyses estimated that in France, Italy, Spain,
and Germany the mean total cost of induction and maintenance
therapy in patients with advanced or recurrent NSCLC would
be lower with bevacizumab-based regimens than cetuximabbased
regimens (in France and Germany, savings of €11 829 and
€4713 per patient) or pemetrexed-based therapy (in Italy, a saving
of €5761 per patient) [available as abstracts].^^^^' Analyses used
progression-free survival rates from pivotal trials and local drug
acquisition and administration costs; year of costing was not
reported.
Other Trials
A phase II, randomized, open-label, multicenter trial investigated
intravenous bevacizumab 7.5 or 15 mg/kg every
3 weeks in combination with carboplatin/paclitaxel therapy
versus carboplatin/paclitaxel alone in patients with advanced
NSCLC (n=99);poi this trial included additional single-blind
analysis by an independent review facility. Patients received
intravenous bevacizumab plus intravenous carboplatin (dosage
adjusted to achieve a target AUC of 6mg/mL per minute)
and paclitaxel 200 mg/m^ on day 1 of a 3-week cycle (for 6-7
cycles).t^''l A median 8-10 doses were given, and bevacizumab
was continued after the completion of chemotherapy for a maximum
of 18 doses.t^°l The co-primary endpoints were median
time to progression and response rates, and primary efficacy
analyses were performed on the intent-to-treat population.P"'
Several small, noncomparative trials have also investigated the
efficacy of intravenous bevacizumab 15 mg/kg every 3 weeks in
combination with platinum-based doublet chemotherapy in patients
with advanced, nonsquamous NSCLC. A trial of bevacizumab
in combination with oxaliplatin/gemcitabine therapy
(n = 44)P'l and another in combination with carboplatin/
pemetrexed (n=49)^^1 have been fully published. Preliminary results
are available (in abstract form) from four others investigating
bevacizumab in combination with carboplatin/pemetrexed
(n=12),P^l carbopladn/docetaxel (n=19),P^l oxaliplatin/pemetrexed
(n = 58),P^l and cisplatin/docetaxel (n=ll).P'*l Where reported,
medians of 3-7 cycles were given, and in all trials,^'"^^'
bevacizumab (plus pemetrexed in one study^^') was continued
after the completion of chemotherapy until disease progression.
Preliminary efficacy results of the large (n = 2166), ongoing,
noncomparative, international SAiL (Safety of Avastin in
Lung) trial in which patients with advanced, metastatic, or recurrent,
nonsquamous NSCLC received bevacizumab 7.5 or
15 mg/kg in combination with platinum-containing chemotherapy
as first-line treatment for up to six cycles, then as
maintenance therapy (see section 4 for study details) are also
available (in abstract form).'^^'
• In the phase II comparative study, the median times to
progression (co-primary endpoint) in bevacizumab 7.5 and
15 mg/kg plus carboplatin/paclitaxel recipients (n = 32 and 35)
were 7.0 and 4.1 months versus 5.9 months in those receiving
carboplatin/paclitaxel therapy alone (n = 32) in the single-blind
independent review, and 7.4 and 4.3 months versus 4.2 months
in the nonblind investigator assessment.'^*^'
• Response rates (co-primary endpoint; assessment criteria
not reported) were 40% and 22% in bevacizumab 7.5 and
15 mg/kg recipients versus 31% in those receiving carboplatin/
paclitaxel alone in the single-blind assessment, and 32% and
28% versus 19% in the nonblind investigator assessment.f'^°'
• Overall survival duration in the total population was not
significantly affected by the addition of bevacizumab 7.5 or
15 mg/kg to carboplatin/paclitaxel (17.7 and 11.6 months vs
14.9 months with carboplatin/paclitaxel alone).
• While disease progression results are not yet available for
three of the noncomparative trials.f^^"^''' median time to tumor
progression and overall survival were 5.5 and 13.7 months
(1-year survival rate 55%) with bevacizumab plus oxaliplatin/
gemcitabine,'^'' and median progression-free survival and
overall survival were 7.8 and 16.7 months with bevacizumab
plus oxaliplatin/pemetrexedP^l and 7.8 and 14.1 months with
bevacizumab plus carboplatin/pemetrexed^^l in the other trials.
• Response rates with bevacizumab plus chemotherapy regimens
in the noncomparative trials varied among chemotherapy
regimens. For instance, response rates were 55% (RECIST)'^^'
and 60% (at median 20 weeks' follow-up)'^^' with carboplatin/
pemetrexed, 74% with carboplatin/doeetaxel (RECIST),f231
43% with oxaliplatin/gemcitabine at median 13 weeks (RECIST),
P'l 26% with oxaliplatin/pemetrexed,t25] and 82% with
cisplatin/docetaxel (RECIST)!^''' [duration of follow-up and
response criteria not always reported]. Where reported, disease
control (response plus stable disease) rates were 88%,'^^'
75%,[221 1OO%,[231 80%,[2'l and 91%.[241
• Preliminary results from the SAiL trial indicate that in
patients with advanced, metastatic, or recurrent, nonsquamous
NSCLC who received bevacizumab plus chemotherapy as initial
treatment followed by bevacizumab maintenance therapy.
© 2009 Adis Data Information BV. All rigtits reserved. Biodrugs 2009; 23 (3)
192 Wagstaffetal.
S CAR/PAC/BEV15
D CAR/PAC
Neutropenia
Hypertension
Febrile neutropenia
Bleeding events
Hyponatremia
Headache
Proteinuria
Rash/desquamation
Thrombocytopenia
10 15 20
Occurrence (% of patients)
25 30
Fig. 3. Tolerability of intravenous bevacizumab plus carboplatin-based chemotherapy in chemotherapy-naive patients with advanced, nonsquamous, nonsmall
cell lung cancer (E4599 trial). Patients received intravenous carboplatin/paclitaxei chemotherapy pius bevacizumab 15 mg/kg (CAR/PAC/BEV 15;
n=427) or carbopiatin/paclitaxel alone (CAR/PAC; n=440) every 3 weeks.'^*' See section 3 for full chemotherapy dosage detaiis. The figure shows the
incidence of severe adverse events (grade >3) occurring significantly more often in CAR/PAC/BEV recipients than in CAR/PAC recipients. * p < 0.05, " p < 0.01,
" • p< 0.001 vs CAR/PAC.
median overall survival duration was 15.3 months and median
time to progression was 7.8 months.t^^^
4. Tolerability
This section on the tolerability of intravenous bevacizumab
7.5 or 15 mg/kg given concomitantly with platinum-based chemotherapy
and then as maintenance therapy in patients with
advanced NSCLC focuses on data from the two large, phase III,
randomized trials (E4599 and AVAiL) described in section
3 [18,19,30.32.38.39] ^j^j interim results (published as abstracts and
posters) from two large, ongoing, noncomparative studies, the
international SAiL trialP''.'«>-'M] and the US ARIES (Avastin®
Regimens: Investigation of treatment Effects and Safety) observational
cohort study .t'*^ Data from retrospective, combined
analyses of randomized, controlled trials of bevacizumab in patients
with NSCLCt''*' and/or other cancers^'*''! and the subgroup
of patients with NSCLC and CNS métastases in the ATLAS and
PASSPORT studies!"**' are briefly discussed. ATLAS is a phase
III study of bevacizumab plus standard first-line chemotherapy,
followed by bevacizumab plus erlotinib or bevacizumab plus
placebo as maintenance therapy in patients with advanced, recurrent,
or metastatic nonsquamous NSCLC, while PASSPORT
is an open-label, phase II study of bevacizumab plus first- or
second-line chemotherapy in patients with metastatic nonsquamous
NSCLC with previously treated CNS métastases.!"*^'
Reporting of specific adverse events was limited to hématologie
adverse events of grade >4 and nonhematologic adverse
events of grade >3 severity in the E4599 trial,t'^' and to adverse
events of grade >3 severity in the AVAiL trial.t'^'-'^'
• The adverse events profile of bevacizumab in combination
with chemotherapy in patients with advanced, nonsquamous
NSCLC in the E4599 (figure 3) and AVAiL (figure 4) trials was
generally manageable.!'*-'^'^^'
• In the first three cycles of the E4599 trial, severe (grade >3)
adverse events occurred in 18% of patients receiving carboplatin/
paclitaxel plus bevacizumab 15 mg/kg and 13% of those
receiving carboplatin/paclitaxel alone (n = 427 and 440).^'*'
Treatment-related deaths were more common in patients
receiving bevacizumab than in those receiving chemotherapy
alone (15 vs 2; p = 0.001). Deaths from pulmonary hemorrhage
occurred in five bevacizumab-treated recipients and none
receiving standard chemotherapy alone.
• Most adverse events reported during the AVAiL trial were
grade 1 or 2 in severity.''^'^^' At least one severe (grade >3)
adverse event was reported in most patients across all treatment
arms (80% and 83% of patients receiving cisplatin/gemcitabine
plus bevacizumab 7.5 or 15 mg/kg, and 77% of those receiving
© 2009 Adis Data Information BV. All rights reserved. Biodrugs 2009:23 (3)
Bevacizumab: Adis Drug Profile 193
cisplatin/gemcitabine plus placebo); the overall incidences of
serious adverse events were 39%, 45%, and 36%, respectively.t^^l
• Few patients (4-5%) in any of the AVAiL treatment arms
died as a result of adverse events.''^' The incidences of
hypertension and proteinuria in bevacizumab-containing regimens
appeared to be dose-dependent.t'^-'^''^'
• A retrospective analysis indicated that adverse events of grade
>3 severity were reported in significantly more elderly (aged >70
years; n= 111) than younger (aged <70 years; n==306) patients
receiving bevacizumab 15 mg/kg plus carboplatin/paclitaxel in
E4599 (87% vs 70%; p< 0.001).™ In addition, more elderly
patients receiving bevacizumab 15 mg/kg plus carboplatin/
paclitaxel reported adverse effects grade >3 than those receiving
carboplatin/paclitaxel alone (87% vs 61%; p<0.001).[3''l
• In contrast, a subgroup analysis of the AVAiL trial indicated
that bevacizumab 7.5 or 15 mg/kg tolerability in older patients
(aged >65 years; n = 304) was acceptable.'^^' There were no
episodes of severe hemoptysis in older patients, and patient age
had no effect on the incidence of hypertension or febrile
neutropenia, or on the incidence of treatment-related deaths.I^^l
• The incidence of severe hemoptysis (grade >3) was 0.9% and
0.9% with bevacizumab 7.5 or 15 mg/kg plus cisplatin/
gemcitabine and 0.3% with placebo plus cisplatin/gemcitabine
in AVAiL (statistical analysis not reported).f''^'
• Combined analysisl''^! of data from E4599,['»l AVAiL,['»l
and a randomized phase II study^"' found that severe
pulmonary hemorrhage was infrequent in bevacizumab-treated
patients (1.8%; 21 of 1152 patients). There was no clear
relationship between baseline clinical and radiographie risk
factors and early-onset severe pulmonary hemorrhage.t'*^'
• Combined analysis of safety results in patients from the
E4599 and AVAiL studies (n=1854) showed that CNS
hemorrhage (none of which was fatal) was reported in 6 of
1086 bevacizumab-treated patients and 3 of 768 patients who
did not receive bevacizumab.'^^'
• Interim analysis of data from the subgroup of patients with
NSCLC and CNS métastases in the ATLAS and PASSPORT
studies (n = 26 and 63) indicate that there were no symptomatic
CNS adverse events during the main treatment phase with
bevacizumab-containing therapy (prior to disease progression).['*^]
One symptomatic, grade 2 CNS hemorrhage was
reported during the post-progression treatment phase (progression
was CNS metastasis) in a patient who had received
14 cycles of bevacizumab in the ATLAS trial.I'*^'
H CIS/GEM/BEV 7.5
• CIS/GEM/BEV 15
D CIS/GEM/PL
Neutropenia
Thrombocytopenia
Anemia
Vomiting
Leukopenia
Venous thromboembolic events
Hypertension
Asthenia
Bieeding
Arterial thromboemboiic events
Proteinuria
Febriie neutropenia
10 15 20 25 30 35
Occurrence (% of patients)
40 45 50
Fig. 4. Tolerability of intravenous bevacizumab plus cisplatin-based chemotherapy in chemotherapy-naive patients with nonsquamous, advanced non-small
cell lung cancer (AVAiL trial). Patients received intravenous cisplatin/gemcitabine chemotherapy plus bevacizumab 7.5 mg/kg (CIS/GEM/BEV 7.5; n=330) or
15 mg/kg (CIS/GEM/BEV 15; n=329) or placebo (CIS/GEM/PL; n=327) every 3 weeks.^si See section 3 for full chemotherapy dosage detalls.l^^) The figure
shows the incidence of severe (grade >3) adverse events, including those of special interest, reported in >2% of CIS/GEM/BEV recipients (statistical analysis not
d)l33l
© 2009 Adis Data Information BV. All rights reserved. Siodrugs 2009:23 (3)
194 Wagstajf et al.
• Retrospective exploratory analyses in patients with CNS
métastases secondary to various solid tumor types, including
NSCLC confirmed these results. Rates of CNS hemorrhage in
patients who received bevacizumab-containing regimens were low,
and were consistent with the historical background rates of CNS
hemorrhage in patients with CNS metastases.t"*^ Data analyzed
were from 8443 patients in randomized, controlled phase II and III
trials, 3252 patients in noncomparative observational studies
(including the SAiL study), and 89 patients with NSCLC and
treated CNS métastases in the ATLAS and PASSPORT trials.!'*^
• As a consequence of these results, the contraindication for
bevacizumab in patients with CNS métastases in the European
Medicines Agency summary of product characteristics was
removed in 2009 (this contraindication was never included in
US prescribing information).''*''
Ongoing Studies
SAiL is a large (n = 2240), multicenter trial to assess the
safety and efficacy of bevacizumab 7.5 or 15 mg/kg in combination
with platinum-containing chemotherapy as first-line
treatment (for up to six cycles), then as maintenance therapy in
patients with advanced, metastatic, or recurrent, nonsquamous
NSCLC.[^''l The primary endpoint is the safety of bevacizumab
(based on the incidence of treatment-related serious adverse
events and adverse events of special interest); secondary endpoints
include safety of the drug in the subgroups of patients
developing CNS métastases during treatment or in the
6 months after ceasing treatment, and efficacy (see section 3).'^^'
The multicenter ARIES study is evaluating the efficacy and
safety of first-line treatment with bevacizumab in combination
with standard chemotherapy regimens in =2000 patients with
advanced NSCLC in a general practice setting.''*^'
Adverse events of special interest related to bevacizumab
therapy include hypertension, proteinuria, wound-healing
complications, gastrointestinal (GI) perforations, arterial and
venous thromboembolic events, hemoptysis, CNS bleeding,
other bleeding, and congestive heart failure (CHF).'^^'''^'
• In an interim analysis (n = 2166) of data from SAiL, median
patient age was 59 years, and most were male (60%), had stage
IV disease (81%), adenocarcinoma (86%), and an ECOG
performance score of 0 or 1 (94%)P'^^ Patients received a
median seven cycles of bevacizumab and five cycles of
chemotherapy. The most common chemotherapy regimens
were carboplatin or cisplatin doublets (49% and 38%).'^^!
• Results from the SAiL study confirm that bevacizumab has a
manageable safety profile in patients with locally advanced,
metastatic, or recurrent NSCLC.^''''*^' Serious (grade 3-5)
adverse events were reported in 31% of patients, but were
related to bevacizumab therapy in only 10.5% of patients.
Serious adverse events of special interest were infrequent in
SAiL; thromboembolism (4.8%), bleeding (1.8%, including
hemoptysis [0.4%] and pulmonary hemorrhage [0.2%]), CHF
(1.0%), gastrointestinal perforation (0.9%), hypertension
(0.4%), and proteinuria (0.1%) were most common.t^^'
• Subgroup analyses in the SAiL study indicated that the
incidence of serious adverse events of any severity, adverse
events of special interest of any or grade >3 severity,''"'' or
hypertensive events of any severity''*'*' did not differ between
older (aged >65 years; n=:549) or younger (aged <65 years;
n= 1459) patients. In addition, the overall incidence of adverse
events of special interest did not differ between chemotherapy
groups (46-66% with bevacizumab plus carboplatin, cisplatin,
or non-platinum doublets, or monotherapy).'^^'
• Patients receiving therapeutic anticoagulants in SAiL
(n -152; 90 from study commencement), reported 61 bleeding
events of any severity, while 507 events were reported
in patients not receiving anticoagulants (n= 1547).''*''
Most bleeding events (92% in those receiving therapeutic
anticoagulants and 93% in those not receiving anticoagulants)
were grade 1 or 2 in severity. Few patients in either subgroup
reported grade >3 hemoptysis (1.6% vs 0.6%), epistaxis
(1.6% vs 2.6%) and other bleeding (4.9% vs 3.4%). Most
patients in the anticoagulant therapy group were receiving low
molecular-weight heparins, primarily because of a thrombotic
event.''*''
• The incidence of grade >3 hemoptysis or other bleeding
during the SAiL study was not affected by the method used to
diagnose NSCLC (cytology, histology or both) or whether or
not patients underwent surgical procedures (before/during the
study).''*^' Few patients experienced would healing complications
(1.6% of those undergoing surgery [n = 301] vs 0.7% of
those not undergoing surgery [n= 1383]).''*-^'
• Approximately 20% of patients had at least one episode of
hypertension of any severity during the SAiL study; however,
only six patients (0.3%) had bevacizumab-related grade >3
hypertension.''*'*'
• In an interim analysis of data from the first 1518 patients
enrolled in the ARIES trial''*^' (median follow-up of 7.5 months),
20% of patients were aged >75 years, and most had adenocarcinoma
(67%) and ECOG perfonnance scores <2 (90%). Brain
métastases were present in 8% of patients and 5% were receiving
therapeutic anticoagulants. The most common chemotherapy
regimen was carboplatin plus paclitaxel (64%).
• Adverse events of interest of grade >3 severity were uncommon,
and included hypertension requiring medical management
® 2009 Adis Data Information BV. Ail rigtits reserved. Biodrugs 2009:23 (3)
Bevacizumab: Adis Drug Profile 195
(3.8%), bleeding events (3.0%), serious arterial thromboemboiic
events ( 1.4%), GI hemorrhage (1.1%), severe pulmonary hemorrhage
(0.7%), and CNS hemorrhage (0.1%).['*51 The safety and
tolerability profile of bevacizumab-containing regimens in
special subpopulations (e.g. age >75 years [n = 300], baseline
ECOG performance status >2 [n = 150], presence of brain
métastases [n= 101], or anticoagulant use [n = 77]) was generally
consistent with that in the overall
5. Dosage and Administration
Bevacizumab 7.5 or 15 mg/kg (in the EU)^'*' or 15 mg/kg (in
the US)''^^ is administered as an intravenous infusion once
every 3 weeks in combination with platinum-based chemotherapy
for up to six cycles and then as monotherapy until disease
progression. Surgical incisions should be fully healed before
administration (>28 days following major surgery).^'^! Local
prescribing information should be consulted for detailed information,
including contraindications, precautions, drug interactions,
and use in special patient populations.
6. Bevacizumab Plus Platinum-Based
Chemotherapy in Advanced Non-Small Celi
Lung Cancer: Current Status
Bevacizumab, in combination with platinum-based chemotherapy
(in the EU) or specifically with carboplatin and paclitaxel
(in the US), is indicated for the first-line treatment of
patients with unresectable, locally advanced, metastatic or recurrent,
nonsquamous NSCLC.I'^'''' It has shown clinical efficacy
in two large, phase III, randomized, controlled trials (one
double-blind) in this indication, and has a well characterized,
generally manageable tolerability and safety profile.i^°l
Acknowledgments and Disciosures
The manuscript was reviewed by: V. Hirsh, McGill University Health
Centre, Montreal, Quebec, Canada; C. Manegold, University Medical
Center, Department of Surgery, Mannheim, Germany.
The preparation of this review was not supported by any external
funding. During the peer review process, the manufacturer of the agent
under review was also offered an opportunity to comment on this article.
Changes resulting from comments received were made on the basis of
scientific and editorial merit:
References
1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001 Sep; 2:
533-43
2. Herbst RS, Sandier AB. Non-small cell lung cancer and antiangiogenic therapy:
what can be expected of bevacizumab?. Oncologist 2004; 9 Suppl. 1: 19-26
3. Spicer J, Harper P. Targeted therapies for non-small cell lung cancer. Int J Clin
Pract 2005 Sep; 59 (9): 1055-62
4. National Cancer Institute. Non-small cell lung cancer: treatment (PDQ®)
health professional version [online]. Available from URL: http://www.cancer,
gov [Accessed 2009 Jun 25]
5. Di Costanzo F, Mazzoni F, Micol Mela M, et al. Bevacizumab in non-small cell
lung cancer. Drugs 2008; 68 (6): 737-46
6. Cascone T, Troiani T, Morelli MP, et al. Antiangiogenic drugs in non-small cell
lung cancer treatment. Curr Opin Oncol 2006 Mar; 18 (2): 151-5
7. Lyseng-Williamson KA, Robinson DM. Bevacizumab: a review of its use in
advanced colorectal cancer, breast cancer, and NSCLC. Am J Cancer 2006;
5 (1): 43-60
8. Wang Y, Fei D, Vanderlaan M, et al. Biological activity of bevacizumab, a
humanized anti-VEGF antibody in vitro. Angiogenesis 2004; 7: 335-45
9. Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular
endothelial growth factor monoclonal antibody for the therapy of solid tumors
and other disorders. Cancer Res 1997 Oct 15; 57: 4593-9
10. Gerber H-P, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab
as monotherapy or in combination with cytotoxic therapy in preclinical
studies. Cancer Res 2005 Feb 1; 65 (3): 671-80
11. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic
study of recombinant human anti-vascular endothelial growth factor in patients
with advanced cancer. J Clin Oncol 2001; 19 (3): 843-50
12. Dowlati A, Gray R, Sandier AB, et al. Cell adhesion molecules, vascular endothelial
growth factor, and basic fibroblast growth factor in patients with
non-small cell lung cancer treated with chemotherapy with or without bevacizumab:
an Eastern Cooperative Oncology Group study. Clin Cancer Res
2008 Mar 1; 14(5): 1407-12
13. Margolin K, Gordon MS, Holmgren E, et al. Phase Ib trial of intravenous
recombinant humanized monoclonal antibody to vascular endothelial growth
factor in combination with chemotherapy in patients with advanced cancer:
pharmacologie and long-term safety data. J Clin Oncol 2001; 19 (3): 851-6
14. Hsei VC, Novotny WF, Margolin K, et al. Population pharmacokinetic (PK)
analysis of bevacizumab (BV) in cancer subjects [abstract no. 272]. Proc Am
Soc Clin Oncol 2001 May 12; 20 (Pt 1): 69a
15. Herbst RS, Mininberg E, Henderson T, et al. Phase I/II trial evaluating
blockade of tumour blood supply and tumour cell proliferation with combined
bevacizumab and erlotinib HCl as targeted cancer therapy in patients
with recurrent non-small cell lung cancer [abstract no. 977]. EJC Supplements
2003 Sep; 1 (5): S293. Plus poster presented at the 12th European Cancer
Conference; 2003 Sep 21-23; Copenhagen
16. Roche Products Limited. Avastin 25mg/mL concentrate for solution for infusion.
UK summary of product characteristics [online]. Available from
URL: http://emc.medicines.org.uk [Accessed 2009 May 20]
17. Genentech Inc. Avastin® (bevacizumab) US prescribing information [online].
Available from URL: http://www.gene.com/gene/products/infomiation/pdf/
avastin-prescribing.pdf [Accessed 2009 Jul 3]
18. Sandier A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with
bevacizumab for non-small-cell lung cancer. N Engl J Med 2006 Dec 14; 355
(24): 2542-50
19. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine
with either placebo or bevacizumab as first-line therapy for nonsquamous
non-small-cell lung cancer: AVAiL. J Clin Oncol 2009; 27 (8): 1227-34
20. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase 11 trial
comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and
paclitaxel alone in previously untreated locally advanced or metastatic nonsmall-
cell lung cancer. J Clin Oncol 2004; 22 (11): 2184-91
21. Lilenbaum R, Raez L, Tseng J, et al. Efficacy and safety of oxaliplatin and
gemcitabine with bevacizumab in advanced non-small cell lung cancer.
J Thorac Oncol 2008 May; 3 (5): 511-5
22. Dalsania CJ, Hageboutros A, Harris E, et al. Phase II trial of bevacizumab
plus pemetrexed and carboplatin in previously untreated advanced nonsquamous
non-small cell lung cancer [abstract no. 18163]. J Clin Oncol 2007;
25 (18 Suppl.)
23. William Jr WN, Kies MS, Fossella FV, et al. Phase II study of bevacizumab in
combination with docetaxel and carboplatin in patients with metastatic nonsmall
cell lung cancer [abstract no. 18098]. J Clin Oncol 2007; 25 (18 Suppl.)
© 2009 Adis Data Information BV. Aii rights reserved. Biodrugs 2009:23 (3)
196 Wagstaff et al.
24. Cobo M, Ferrer N, Paredes A, et al. Bevacizumab (Avastin®) in combination
with cisplatin and docetaxel as first line treatment of patients (P) with advanced
or metastatic, non squamous, non-small-cell lung cancer (NSCLC)
[abstract no. 244P]. Ann Oncol 2008 Sep; 19 Suppl. 8: viii95
25. Waples JM, Auerbach M, Steis R, et al. A phase II study of oxaliplatin and
pemetrexed plus bevacizumab in advanced non-squamous non-small cell lung
cancer (an International Oncology Network study, #1-04-015) [abstract no.
19018]. J Clin Oncol 2008; 26 (15 Suppl.): 707s
26. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and
carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab
as first-line therapy for nonsquamous non-small-cell lung cancer.
J Clin Oncol. Epub 2009 May 11
27. Crino L, Mezger J, Griesinger F, et al. MO19390 (SAiL); safety and efficacy of
first-line bevacizumab (BV)-based therapy in advanced non-small cell lung
cancer (NSCLC) [abstract no. 8043]. J Clin Oncol 2009; 27 (15 Suppl.); 417s.
Plus poster presented at the American Society of Clinical Oncology (ASCO)
45th Annual Meeting; 2009 May 29-Jun 2; Orlando (FL)
28. Manegold C, von Pawel J, Zatloukal P, et al. BO17704 (AVAIL); a phase III
randomised study of first-line bevacizumab combined with cisplatin/
gemcitabine (CG) in patients (pts) with advanced or recurrent non-squamous,
non-small cell lung cancer (NSCLC) [abstract no. LBAl]. Ann Oncol 2008
Sep; 19 Suppl. 8; viiil
29. Sandier AB, Kong G, Strickland D, et al. Treatment outcomes by tumor histology
in Eastern Cooperative Group (ECOG) study E4599 of bevacizumab
(BV) with paclitaxel/carboplatin (PC) for advanced non-small cell lung cancer
(NSCLC) [abstract no. 133]. Journal of Thoracic Oncology 2008; 3 (11 Suppl.
4): S283. Plus poster presented at the Intemational Association for the Study
of Lung Cancer (IASLC) Chicago Multidisciplinary Symposium in Thoracic
Oncology; 2008 Nov 13-15; Chicago (IL)
30. Ramalingam SS, Dahlberg SE, Langer CJ, et al. Outcomes for elderly, advanced-
stage non-small-cell lung cancer patients treated with bevacizumab in
combination with carboplatin and paclitaxel; analysis of Eastern Cooperative
Oncology Group trial 4599. J Clin Oncol 2008 Jan 1; 26 (1); 60-5
31. Grusenmeyer PA, Gralla RJ. Examining the cost and cost-effectiveness of
adding bevacizumab to carboplatin and paclitaxel in advanced non-small cell
lung cancer [abstract no. 6057]. J Clin Oncol 2006; 24 (18 Suppl.); 314s
32. Leighl NB, Zatloukal P, Mezger J, et al. Efficacy and safety of first-line bevacizumab
(Bv) and cisplatin/gemcitabine (CG) in elderly patients (pts) with
advanced non-small cell lung cancer (NSCLC) in the BO 17704 study [abstract
no. 8050]. J Clin Oncol 2009; 27 (15 Suppl.); 419s. Plus poster presented at the
American Society of Clinical Oncology (ASCO) 45th Annual Meeting;
2009May 29-Jun 2; Orlando (FL)
33. Mezger J, von Pawel J, Reck M. Bevacizumab (Bv) single-agent maintenance
following Bv-based chemotherapy in patients with advanced non-small cell
lung cancer (NSCLC): results from an exploratory analysis of the AVAiL
study [abstract no. el9001]. J Chn Oncol 2009; 27 (15 Suppl.)
34. Heigener DF, Wiesner C, Aultman R. A cost analysis of treatment with
bevacizumab plus cisplatin and gemcitabine (BCG) versus cetuximab
plus vinorelbine and cisplatin (CVC) in patients with advanced or recurrent
non-small cell lung cancer (NSCLC) in .Germany [abstract no. el7553].
J Chn Oncol 2009; 27 (15 Suppl.)
35. Chouaid C, Vergnenègre A, Florentin V, et al. Analysis of the costs of
bevacizumab plus cisplatin and gemcitabine versus cetuximab plus vinorelbine
and cisplatin in patients with advanced non-small cell lung cancer
(NSCLC) in France: results from a cost modelling study [abstract no. el 7560].
J Clin Oncol 2009; 27 (15 Suppl.)
36. Nuijten M, Chouaid C, Vergnenègre A. The cost savings associated with
bevacizumab plus cisplatin and gemcitabine (bevacizumab-based therapy)
compared with cetuximab plus vinorelbine and cisplatin (cetuximab-based
therapy) in patients with advanced or recurrent non-small cell lung cancer
(NSCLC) across four European countries [abstract no. PCN29]. Value Health
2009; 12(3); A41
37. Nuijten M. The costs of treating patients with advanced or recurrent non-small
cell lung cancer (NSCLC) with bevacizumab plus cisplatin and gemcitabine
compared with pemetrexed plus cisplatin in induction and maintenance
therapy in Germany and Italy [abstract no. PCN30]. Value Health 2009;
12 (3): A41
38. Archer V, Reck M, Sandier A, et al. Risk of symptomatic central nervous
system (CNS) progression and secondary hemorrhage in patients with nonsquamous
non-small cell lung cancer (NSCLC) receiving bevacizumab-based
first-line therapy [poster no. 51C]. American Society of Clinical Oncology
(ASCO) 44th Annual Meeting; 2008 May 30-Jun 3; Chicago (IL)
39. Hirsh V, Ramlau R, von Pawel J, et al. Final safety results of BO17704
(AVAiL); a phase III randomised study of first-line bevacizumab (Bv) and
cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent nonsquamous
non-small cell lung cancer (NSCLC) [abstract no. 8039]. J Clin
Oncol 2009; 27 (15 Suppl.): 416s. Plus poster presented at the American
Society of Clinical Oncology (ASCO)45th Annual Meeting; 2009 May 29-Jun 2;
- Orlando (FL)
40. Jäger E, Wu Y, Mezger J, et al. Safety of first-line bevacizumab (BV) plus
chemotherapy in elderly patients (pts) with advanced or recurrent nonsquamous
non-small cell lung cancer (NSCLC); MO19390 (SAiL) study
[poster no. 240P]. 33rd European Society for Medical Oncology (ESMO)
Congress; 2008 Sep 12-16; Stockholm
41. Griesinger F, Laskin J, Pavlakis N. Safety of first-line bevacizumab-based
therapy with concomitant cardiovascular or anticoagulation medication in
advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) in
MO19390 (SAiL) [poster no. 42D]. The MO19390 (SAiL) study group.
American Society of Clinical Oncology (ASCO) 44th Annual Meeting; 2008
May 30-Jun 3; Chicago (IL)
42. Tsai G-M, Thatcher N. Effects of diagnostic method and surgery on safety of
first-line bevacizumab plus chemotherapy in advanced or recurrent nonsquamous
non-small cell lung cancer (NSCLC): MO19390 (SAiL) [poster no.
43E]. The MO19390 (SAiL) study group. American Society of Clinical Oncology
(ASCO) 44th Annual Meeting; 2008 May 30-June 3; Chicago (IL)
43. Pavlakis N, Hirsh V, Reck M, et al. MO19390 (SAiL); incidence of thromboembolic
events and congestive heart failure with first-line bevacizumab
(Bv)-based therapy in advanced non-small cell lung cancer (NSCLC) [abstract
no. el9003]. J Chn Oncol 2009; 27 (15 Suppl.)
44. Garrido Lopez P, Laskin J, Jiang G, et al. MO19390 (SAiL); incidence and
management of hypertension (HTN) during bevacizumab (Bv)-based firstline
therapy in patients (pts) with advanced non-small cell lung cancer
(NSCLC) [abstract no. el 9002]. J Clin Oncol 2009; 27 (15 Suppl.)
45. Fischbach NA, Spigel D, Brahmer J, et al. Preliminary safety and effectiveness
of bevacizumab (BV) based treatment in subpopulations of patients (pts) with
non-small cell lung cancer (NSCLC) from the ARIES study; a bevacizumab
(BV) treatment observational cohort study (OCS) [abstract no. 8040]. J Clin
Oncol 2009; 27 (15 Suppl.); 416s
46. Sandier A, Archer V, Hirsh V, et al. Retrospective study of clinical and
radiographie risk factors associated with early-onset, severe pulmonary
hemorrhage in bevacizumab-treated patients with advanced non-small cell
lung cancer (NSCLC) [poster no 8074]. American Society of Clinical Oncology
(ASCO) 44th Annual Meeting; 2008 May 30-Jun 3; Chicago (IL)
47. Rohr UP, Augustus S, Lasserre SF, et al. Safety of bevacizumab in patients
with métastases to the central nervous system [abstract no. 2007]. J Clin Oncol
2009; 27 (15 Suppl.); 88s
48. Akerley W, Langer C, Oh Y, et al. Acceptable safety of bevacizumab therapy in
patients with brain métastases due to non-small cell lung cancer [poster no.
8043]. American Society of Clinical Oncology (ASCO) 44th Annual Meeting;
2008 May 30-Jun 3; Chicago (IL)
49. F. Hoffmann-La Roche Ltd. Avastin label updated reflecting confidence in
safety profile; contraindication for patients with untreated brain métastases
Mojojojo,
You bring up a very good point with the phase 2 lung cancer trial, which I would like to expand on
"In the trial's two-stage design, up to 21 patients with NSCLC will be enrolled initially. The study will then be expanded up to a total of 49 patients if promising results are observed in the initial cohort. Secondary objectives of the study include time to tumor progression, duration of response, overall patient survival and safety parameters. Tumor response in the study will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) parameters. Patients may continue to receive bavituximab as long as the cancer does not progress and side effects are acceptable."
Weekly bavituximab dose of 3 mg/kg until disease progression, and up to 6 cycles of carboplatin at a dose of AUC=5 and paclitaxel 175 mg/m2 every 21 days (21-day cycles)
As of right now there are several protocols for advanced NSCLC with using a combo of 2 chemotherapeutics all with relateively equivalent outcomes. Platinum + taxane based combo's are one of the most commonly used such as the platinum based carboplatin and taxane derivative paclitaxel. Concerning the choice specifically of carboplatin and paclitaxel; I believe this choise was decided upon becuase this was the combo used for the Avastin trial in NSCLC, therefore providing the best comparison. Concerning the choice of 6 cycles; this has been determined the optimal dosing regimen, as further cycles do not improve outcomes, and taxane derivatives carry a maximum cumalative dosing d/t risk of heart failure. Now, as I understand, the chemo and bavi were not stopped at the same time. Chemo was up to 6 cycles (4.2 months), likely based on tolerability, and bavi was continued for as long as disease progression (? months) did not occur. Meaning that there could still be patients receiving bavi many months after having stopped the chemo.
I haven't posted on the board for quite some time, but I continue to hold my position in peregrine, and plan to add more this month if peregrine gets oversold again in december. Overall, I was very impressed with the CC this quarter. I felt they went into more detail trying to describe their plan moving forward to advance bavi than they have in the past, and they also did a better job of outlining the benefit of having avid as our supplier for bavi for when future demand is required. There are a couple points I would like to touch on, one of them that realist has repeatedly used to put down peregrine's management. First off, cancer trials take a long time, because markers for success such as PFS and overall survival take long periods of time to collect. Bavi phase 1 cancer was started in the US, and as with many phase 1 trials took a long period of time to enroll, largely due to the competition between various trials, and what were likely very stringent entry requirements due to bavi's very unique MOA (ex the potential for autoimmune related diseases). The purpose of phase 1 trials is first safety, and secondly to establish pharmacokinetic data + maximum tolerated doses to gain some indication of what dosing and intervals will be the basis of further trials. Phase two trials are often designed in two different ways. They can be described as phase 2a and 2b, or also as "signal seeking" and "proof of concept". While our phase 1 cancer trial was running in the US, Peregrine started to run several phase 2a or signal seeking trials outside of the US to gain greater info on efficacy and a greater patient population showing safety, which likely could not be started at that time in the US, nor completed as quickly. they looked at two of the biggest market solid tumor cancers, breast and lung. If King's statements are correct, these trials are all continuing with follow-up, suggesting that survival data has likely already exceeded standard of care. More importantly these trias showed us that lung cancer would appear to be our best bet for successful phase 2b trial efficacy. So now that our phase 1 has finished enrolling, and we have 3 phase 2 trials worth of initial efficacy and excellent safety data, we were likely very well received at the FDA meeting to discuss phase 2b studies to be run in the US. Phase 2b studies, or "proof of concept studies" of the gold standard are placebo controlled, randomised, and double blinded. This means that subjects are randomly put in either the test arm (bavi + chemo) or the placebo arm (placebo infusion + chemo) and neither the patients, nor the doctors performing administration/follow-up are aware of which arm of the study they are involved with. This type of study reduces bias, and confirms efficacy above and beyond placebo. Phase 3 studies are extremely similar to phase 2b studies, however they are larger, designed to increase power to determine statistical significance between placebo and the new drug. Now, if bavi were to replicate efficacy in a phase 2b similar to what is being witnessed in the 2a lung trial (which is excellent and continues to get better), and they designed the trial to have enough patients to prove statistical significance, then via accelerated approval, bavi could be marketed prior to a larger phase 3 trial. That would put bavi in the 2.5 year window for marketing, which in my mind/drug development time lines is just around the corner.
My point being that managements strategy to advance bavi cancer has been bang on in order to maximize the number of people treated to this point. Although the next trial will not be a phase 3, there is a very good chance that we will not need to move through phase 3 first (for initial marketing, as a phase 3 will be needed eventually) d/t managements decisions in trial design to date. Not to mention that phase 2b's are much less expensive, which may allow managment to move the ball alone, and come out not only with a blockbuster drug developed in house, but the manufacturing capability to produce it in house.
In the end, the science will speak louder than all the other noise.
peregrine market cap: 125 million
Genentech market cap when bought by Roche: 100 billion
peregrine goes into that 800 times (not to mention that bavi may be more efficacious, and have a much wider scope of use), so even dillution with another 50 million shares would still offer upside of 400X, much higher than if we partnered and were to receive a 10-15% ROYALTY and up front cash, or if we were bought out, even at the poison pill value.
Being young, I am more than happy to wait as bavi, cotara and the future PS mabs, and other conjugates make their way to market, and the value of these technologies are realized.
Since owning this stock, never has a PR as weak as today caused any substantial and sustained move upwards. We traded 36 million!!!! shares today. Something else is coming, I don't know what, but in my opinion it is going to be substantial. :)
How many years do you have to be invested before being one of the old timers?? probably more than my 3+ years, but none the less, it feels like its been a long wait to see some of the data we are now seeing, validating those of us longs that saw the potential in bavi's MOA. The population pool is still small, but its signifigance grows with each new patient enrolled. How about those two people, one with metastatic breast, and one with metastatic lung cancer that are now cancer free...anybody able to answer how many people avastin cured in all of its phase 2/3 trials??? I am really looking forward to seeing some of the long term survival data out of the Georgia trial, which is where I believe Bavi will truly surpass SOC.
Good luck :)
"No one yet has given me one good reason why it is in my better economic interest to vote against the split. So I will vote for it."
Lafont,
My personal opinion is that a reverse split to stay listed on the nasdaq, if needed, should be approved, but only if it were on terms such that authroized shares were equally reduced by the chosen split, be it 5/1, 10/1 etc. Management has not laid out any business plan, nor given any information to shareholders as to why we should vote for a RS that COULD lead to greater than a 1000% percent dilution in our ownership of the companies assets. I cannot think of a single positive impact this could have on helping to build shareholder equity that could not be achieved through other means. I can not think of any reason why we need to give that blank cheque to management, especially with their previous record of deception, specifically with the last PIPE. I agree with you that maintaining our nasdaq listing is valuable, as it will increase accessibility for investment in the company if our drugs are to continue to succeed, but this needs to be done with an equal reduction in authorized shares, as no institutional investors will invest their money in a company that has option to dilute their share by 10 fold. This is ridiculous.
I will be voting no against the reverse split as it is currently being presented to shareholders. If the requirement for a reverse split approval is necessary for our continued extension to regain nasdaq listing requirements, then management will be left with the choice of providing a more shareholder friendly version.
My opinions,
The trial is going nicely, and with how I believe bavi will work, I believe that those results will improve with time. Most of the things that BOT had stated lately have come true. I believe that we will hear something this upcoming week concerning financing, such as a partnership with avid, or a bank loan with avid as collateral. I do not believe that this company is on its way to zero, as evidenced by the recent deal with avid, and the government funding (I would like to think that they have done enough research to know that a company they are giving money to is not about to close the doors). I do not believe however, that a partnership for avid/bank loan alone is going to get us over a dollar in a week, and any partnerships with other upfront money are likely a longshot at this point...but you never know. I do not rule out a reverse split, but I strongly believe that management will not let PPHM go to the OTC. From the RR report last winter, they stated that they would suggest making a position in the company once updates for the trials had been delivered this summer, funding had been established, and the share structure improved. If RR is having any influence at the company, then these things are likely to be addressed. If they are addressed, I think they may do a second report suggesting that due to the companies drug candidates/trials, sufficient funding, and small float, that PPHM would be a good buy. All in my opinions of course.
also...
I sent IR an angry email about a week and a half ago, which i received a response to today, which answered my questions partially...but I figured I would at least share it with the board... good luck...
Hello, I have been invested in Peregrine now for 2.5 years, and have watched my investment cut by more than 2/3\'s. To date the company has continuously diluted shareholder interest via PIPE financing deals, while not managing to maintain any institutional interest. We now sit with well over 200 million shares outstanding, and have failed to meet nasdaq listing requirements for almost an entire year, meaning that we are about to lose our nasdaq listing. We are almost out of money, meaning that new financing is required likely within the next three months. We are supposed to have 3 bavi phase 2 trials running, yet only one is enrolling. Last summer the CEO said that we would have up to 6 phase 2 trials running by the end of 2007! Last year the CFO said that there would be no more PIPE financing, only to be followed a month later by the largest PIPE they had ever done, which led to Peregrine losing its russel 2000 listing which caused further selling and pps erosion. I am boilling with frustration due to this managements inability to maintain or grow any form of shareholder value. My questions are as follows: The CFO has stated that there will be no reverse split, but how then will we maintain a Nasdaq listing while our share price is at .36? What is managements plan to regain compliance? Will the management allow us to fall to the OTC, guaranteeing that there will be no way of gaining institutional support? How will management gaurantee that there is funding in place to continue trials without another PIPE? Why have the India phase 2 trials still failed to start enrolling when we were told during the last conference call that they were imminent? I love this companies drug platforms, which is why I am invested here. I can not find any other company with anything that compares to what Bavituximab has to offer, but I cannot stand to watch my investment be eaten away by poor, grossly over paid management. Sincerely
We appreciate your concerns and would like you to know that Peregrine management is focusing on advancing the clinical programs that will ultimately be the drivers of the company's value, as evidenced by our initiating patient dosing in our Phase 2 bavituximab lung cancer study this week and in our successful data presentations on our bavituximab and Cotara Phase 1 and Phase 2 cancer programs at the recent ASCO cancer meeting, which were well received by potential partners and our Rodman analyst team.
Undoubtedly delisting concerns are impacting the share price at this time.
Regarding the phase 2 clinical trials of bavituximab in India, Peregrine too is frustrated with the slow pace of the Indian regulatory agency in approving and implementing the protocols for these trials (and those of many other countries of late, we are told.) However those problems now seem to be largely behind us and we expect the trials, once started, to proceed at a good pace. Our clinical experience in the Republic of Georgia with the Phase 2 clinical trial of bavituximab in advanced breast cancer patients has been progressing well, and we are optimistic that both of the Indian trials will be open for enrollment soon and will allow for a similar pace of patient treatment.
Management is continuing to assess the company's options in view of the coming Nasdaq de-listing deadline and Peregrine's cash needs. But please note that Paul Lytle never said the the company would never do a reverse split. He said it was not under consdieration at that time. Management intends to communicate its plans to shareholders before that deadline. The company's programs are now positioned for timely progress and we remain positive and optimistic about our future once we get past the current difficulties. Thank you for your support of Peregrine.
Well, to me it looks like management was actually being smart in waiting to release the initiation of the trial after the finale of the russel selling( liely dosing started before today). This just made sure that no one was selling into this news release. Can anyone remember when the last time was that this stock did not go down when a good pr was released. Also remember that the number for short shares is only around a million shares...the last time it was this low was before we moved from .89 to 1.99....and that was only on safety data from phase 1. If management can manage to do some sort of financing by the end of the month that does not involve dillution, with data coming in the months ahead for phase 2, knowing that it will likley drive a licencing deal...i can smell a run coming. Added 10 000 shares today. Good luck :)
cjdaddy,
When looking at bavi efficacy, it is important to have a good understanding of the general treatment protocols and expected outcomes, for the various types of breast cancer, specifically metastatic breast cancer.
http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Breast/Management/MetastaticDisease.htm
This is a link to the BC cancer agency, largely run out of vancouver. It is one of the premier cancer treatment sites in the world, and has a great website describing every type of cancer, along with treatments and outcomes.
Metastatic breast cancer is not considered curable with currently available chemo regimens, but is generally looked upon as a means of extending life and reducing some symptoms, so it would be very unlikely that we will see anyone cured by the addition of bavi. If you look through the 1st/2nd/3rd/4th line chemo options, you'll have a good understanding of where the patients in the last trial were when they were given bavi
In the previous phase 1 trial, the patients had failed mutiple regimens of chemo, meaning that these regimens had failed to reduce or stabalize the primary tumor and had not stopped metastasis. Also, by having multipe regimens of chemo, their immune systems were likely weaker than similar patients that had received only one failed treatment protocol. In these patients, the two women treated with bavi + docetaxel had COMPLETE resolution of their primary tumors. This is nothing to laugh at, as these patients had failed all avaiable tx options. So, you can see why they chose to pursue bavi with docetaxel in Georgia, and why it appears to be their main focus. The difference with the patients in this second trial is that they have not received a taxane before, meaning their cancer has not had any opportunity to evolve in such a manner gauranteeing its ineffectiveness, and secondly, their immune systems generally should be in a stronger state, which is what bavi relies on to do its heavy lifting once it has bound to its target.
I am hoping that along with the efficacy on primary tumor response they may give us some info on whether metastasis continues to spread in these patients, or if it is largely inhibited, as in many of the animal studies. Some info on survival would be helpful, but I am not sure if that information will be available....But the big thing to keep in mind is that if bavi is having a significant effect on such resistant tumors, then it will not take long for it be used in primary treatment for women with localized disease, or recurrent disease, where the net result of complete response of the primary tumor equates to a cure...not to mention that due to its MOA it may prime the body to prevent recurrence, something current treatment options cannot lay claim to.
Jessme,
"Any data is still just animal data correct?"
Yes, and you may be right as far as its immediate impact on the pps. But, I think what you are missing is the importance of outside validation for our technology. Even if they aren't mentioning bavi by name, these papers that Jazz mentions are important because they are painting the picture as to why PS may be a hugely important mechanism in disease. What jazz is leading to is that these upcomg papers from Duke will involve further validation, and information concerning TARGETING PS, and hopefully, it will show how incredibly promising this is going to be. I am not aware of anyone else who is involved in targeting PS with a proven safe antibody, which means from time of discovery to putting an antibody through animal studies, phase 1, phase 2 trials means that PPHM has a huge leg up on anyone else that wishes to follow suit...meaning if the technology continues to prove itself, especially with the upcoming phase 2 breast cancer data, then we are sitting on a very valuable platform. Add on top of that the fact that we know it should be effective in any solid tumor (vs many antibodies that are specific for one type of cancer, then even specific subtypes of cancer, ex HER-2 + breast cancer and trastuzumab) and the upcomg data out of duke showing its potential effectiveness in HIV, and you have the potential for a huge blockbuster. Not to mention, the fact that we know bavi was originally designed to take a payload of chemo/radiation, and those conjugates will be up next for testing...and also the animal studies showing that bavi with irradiated dead cancer cells acts like a vaccine against future cancer.
realist.
A few things to say,
First off, I have to agree with several others on the board. In the past, when a pipe was in progress, generally, the short interest would increase. Prior to the last pipe, and missing the russel, i believe we had somewhere in the neighborood of 10-15 million shares short. Today, we sit with the lowest short position that I have seen since i bought shares in the company over 2 years ago
If we were likely in the midst of dealing for another PIPE, or it was generally expected that we would get booted from the Nasdaq, I believe we would be seeing a large and growing short position. We are seeing the opposite. This would suggest that in general, there is not a strong opinion in anyones mind that there is money to be made on the down side (including your own as you continue to post negatively, yet refuse to admit to taking a short position.
Secondly, you asked Jazz to:
"LIST any/all possible means of bringing in cash to PPHM that DO NOT INCLUDE selling shares AND that are NOT dilutive."
Unless someone walked into tustin with a free briefcase full of money, and simpy left it on the front desk and walked away, they are not getting something for free. Any licencing/selling of proprietary technology involves us giving up those rights for cash...to which management has said that the key to getting what they want is strong phase 2 data...available at the store near you in about 6 weeks.
Management has been saying for years that they are in talks with various companies, and they have also been telling us that data is what is needed to build value in the bavi platform, and as such, that is what they have been doing. I am sure they could have licenced it to someone prior to showing safety data, but that would have brought in very little value to the company. They likely could have licensed it after proving safety for more, but the important thing that anyone thinking about coughing up money for bavi is efficacy. If management has been properly informed by their SAB, then they likely are aware of the potential value in bavi,and want to wring as much money out of any partnering deal they can make. I think it is possible that they were in talks last year prior to the pipe for alternative financing...but it may have fallen through. Having grown up with several close family members involved in different businesses, I am aware how a deal that seams like it is in the bag can fall apart at the last minute. The whole situation put a sour taste in my mouth, and defitinely pissed me off, but I stayed invested because nothing had changed with bavi.
You keep asking for predictions, but predictions are ridiculous, as none of us know enough to accurately predict the future. All you will hear from anyone long are their hopes, based on their own research. I do not rule out a PIPE, nor will I rule out a RS, but I believe they are not as likely as you seem to make them. Realistically, there are too many potential options even to speculate as to which one will occur. For example they might partner cotara for some upfront cash, see the share price go up, then do a massive pipe with someone wanting to hold shares or own a stake in PPHM, then run phase 3 trials on their own. They could sell cotara all together, generating enough money to run phase 3 trials. They could sell bavi, they could partner bavi, they could sell Avid...they could...
bavi's MOA was discovered by accident, and the scientific community is just beginning to understand how important this MOA could be in fighting disease...yet bavi is already in phase 2 trials, and we own a whole host of similar bavi conjugates. All large pharmaceutical companies have scientific boards of their own...and when they start to take notice of the potential change PS therapy could make in treating disease, they see PPHM with excellent results from phase 2 efficiacy trials, and with a whole host of potentially even better PS mab/conjugates ready to go, someone will pay management what they are looking for.
In summary, I believe there are people that know more about pphm than you, I or anyone else on this board...and currently, their money is exiting the short side of Peregrine. For this reason I do not believe that your argument for pipe/rs/into oblivion is accurate. I believe that we are very close to a major shift in PPHM.
"If you honestly believe that other investors will sit on their shares (as you seem to be saying you will) while the timebomb ticks every closer, you'd be mistaken. Stocks decline in anticipation of negative events - that's a fact - market proven decade after decade. Every day PPHM wastes (and they've wasted plenty) is one more step closer to the cliff."
Then is it possible that a lot of that negative sentiment is already programmed into the share price? And is it possible that with initial results on the first 15 patients out of georgia available in 8, now 7 weeks, that the market may begin to assign an increasing value for peregrine? Is it not possible that management has been telling us the truth, that they have been in talks with several large Pharma's interested in bavi that are not willing to pay management what they want until they see phase 2 data?
This is a speculative biotech...Risk is very high = reward is very high. If I wanted a safer investment, I'd buy a pharmacetucal company that has already partnered, put their drug through trials, had it approved by the FDA, and is expecting rapid sales growth. But...I'd still have to hope that post marketing surveillance didn't reveal some unknown SE that results in it being pulled from the market. The potential pay out would be much lower, becuase as risks are removed from the equation, share price increases. The people that made the majority of money were the ones that held through all of that.
Shopper's Drugmart paid for my school,
So, I am working for them for two years on Vancouver Island. Hopefully I can open my own after that. I was out in Edmonton 2 weeks ago for a friends wedding...no shortage of "now hiring" signs.
bavi India trials...My opinions...
To date, we have seen that bavi is safe. Several years ago I believe that most scientists would have agreed that targeting your own body's tissue (PS) with immunostimulatory antibodies would be a recipe for autoimmune induction. Most scientists today likely feel the same way. Only in the last few months has there been a substantial growing ripple in the scientific community suggesting that PS is immunosupressant, and that targeting it may be a way of treating disease. Peregrine has exclusive licencing rights over this target, and treating disease in this fashion. We are the only company that I am aware of that has an anti-PS antibody in clinical trials. As I said earlier, there is an ever growing body of evidence that bavi is safe. As bavi is the first antibody to target PS, it has a lot to prove...we're not following an already proven target...everything about bavi is completely new.
In the first India phase 1 trial, bavi was used in combination against several metastatic, chemo resistant solid tumors. In that trial, the two women with breast cancer had COMPLETE TUMOR RESPONSES, meaning their primary breast cancer lesions completely disappeared...in 8 weeks. Now there is lots of stuff we don't know about these two women, for example what type of breast cancer they had (ductal vs lobular, progestine +/-, Estrogen +/-, sites/degree of metastasis) or whether there was new metastasis, or if bavi prevented its occurrence. What matters is that there is a phase 2 breast cancer trial currently ongoing, with the first 15 patients already enrolled, and data potentially available in less than 8 weeks. This will be the first real glimpse at bavi's potential efficacy against cancer, specifically the most common cancer in women. This is the sort of data we need to drive partnering discussions that can see bavi begin to attain serious value. If bavi shows real potential, then you can bet large pharmaceutical companies will be lining up to get a piece. Right now, bavi remains largely unproven...and I don't think that anyone is willing to step to the plate and pay what management is asking. If bavi fails to show strong efficacy then i doubt anyone will...but my opinion is that we are going to see something quite remarkable, and we will see a real partnership very close afterwards. As to the other India phase 2 trials...I do not see them as the immediate value driver. I do not know what is with the delay more than anyone else on the board. Anything on this board is only speculation, and there are many hurdles yet for bavi to clear.
Peregrine has been around for a long time...and I have only been here 2.5 years, but they have never been so close to something potentially so big. Bavi = the rights to treating disease in a totally new fashion. Its not just one type of cancer, or one virus.
Bavi and Peregrine are still a long shot, but I believe in the science, and I do not think that management's intentions are sinister. I think they have done what they have had to do, however painful, to get bavi to where it is and to protect the platform. I couldn't bare to sell my shares, becuase if nothing else, bavi always gives me something to be excited about...Good luck longs.
P.S. two more weeks and I'm officially a pharmacist!! so close...PPHM, bring me a grad gift, lol.
The deal states that we will receive a royalty on sales, OR Dios can choose to buy out the royalty for up to 50 million up until 2 years after first commercial sale. As far as I am aware, the drug is not even in phase 1 trials yet...so IF the drug is ever approved, then we might see royalties say in 6-10 years....and it would be unlikely that they would buy out the royalty unless the drug became a huge blockbuster....so don't expect any money any time soon from that deal.
TUSTIN, Calif., May 31, 2007 /PRNewswire-FirstCall via COMTEX News Network/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus (HCV) infection, announced today that it has entered into a development collaboration with Dios Therapeutics, Inc., an emerging biotechnology company founded in 2006. Under the terms of the agreement, Peregrine will provide process development and manufacturing services and know-how to support early clinical development for Dios' proprietary humanized monoclonal antibody for the treatment of thyroid associated ophthalmopathy (TAO) using existing development and manufacturing capacity once Dios provides Peregrine with its lead humanized antibody product candidate. In exchange for these development efforts, Peregrine has the option to convert its development fees into either cash or equity in Dios at a preferential conversion rate after Phase I trials. Peregrine also could receive a royalty on net product sales or Dios has the option to buy out the royalty obligation for a one-time fee which could total up to $50 million dollars. The buy-out option is exercisable anytime for a period up to two years after first commercial sale. Under the terms of the agreement, Dios is responsible for all third party expenses related to manufacturing process development as well as all pre-clinical and clinical trial costs.
"Even with increased demand for our manufacturing services from outside clients, we continue to seek attractive opportunities such as this to create value out of our existing manufacturing expertise and capacity," stated David King, Peregrine's vice president of business development. "We are particularly pleased to enter into this collaboration with Dios for this exciting first-in-class technology that has already shown promising signs of activity."
"We are delighted to enter into this strategic relationship with Peregrine because of its proven capabilities and track record in cGMP manufacturing of monoclonal antibodies and product development," said Dr. Glenn Albrecht, Dios' president and chief executive officer. "We believe this collaboration creates substantial opportunities and upside potential for both companies and is a sign of the potential value of our company and our novel therapeutic."
Trial Results in approx. 8 weeks,
Peregrine always seems to move before the news...I think we could see some significant appreciation between now and then.
BOT, Jazz, keep_trying,
Anybody have some idea as to what is coming out of Duke?
The only thing that I can see being big enough to require national news coverage would be an HIV vaccine/potential cure. Its already been shown to act like one for cancer....any guesses out there?