Gone for good.
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You are talking about how long people lived. There really isn't much room for dispute about that. Hard to fake it.
The MOS for treatment and control are either statistically significantly different or not. I can't see how that can be
ignored. Survival is the ultimate goal and determining factor. Even though the PFS for Avastin in MBC doubled,
and was statistically significant, the fact that survival did not increase led to Avastin's approval for MBC withdrawn.
No, I don't think you are mistaken. I think if the MOS for treatment is 2X the control then it probably will be
statistically significant and application for AA could be made on that. We will know the value of the treatment
MOS much sooner than we will know whether it is statistically significant or not. The data collected during the
trial was still done under randomized, double-blind, placebo controlled conditions so I don't think the survival
data will be tainted.
Right, the data for ORR, the primary outcome. They can still do follow up on the survival status of the
remaining patients and compute the statistics of MOS later when the statistical threshold has been reached.
But I think we are now agreed that MOS for the treatment arm can be released when it is triggered.
It is instructive to read the first page or so of the FDA Commissioner's Decision on Avastin and MBC
dated Nov 18, 2011. It is interesting to note that the original trial used to grant AA was an open-labeled study.
http://www.clinicaltrials.gov/ct2/show/study/NCT00028990?term=NCT00028990&rank=1
COMMISSIONER'S DECISION
Avastin (bevacizumab) is a drug that has been approved by the Food and Drug
Administration (FDA) for the treatment of several types of cancer. On February 22, 2008,
FDA's Center for Drug Evaluation and Research (CDER) approved Avastin for use in
combination with paclitaxel in the treatment of patients who have not received chemotherapy for
metastatic HER2-negative breast cancer. This approval was under the rules for accelerated
approval set forth in FDA regulations (21 C.F.R. § 601.40-46) and the Federal Food, Drug, and
Cosmetic Act (21 U.S.c. § 506). Accelerated approval may be granted to drugs to treat life threatening
conditions for which there is unmet medical need in circumstances in which there are
not sufficient data to justify a regular approval of a drug, but the evidence that is available
provides a reason to hope that, once more testing has been completed, a the drug's safety and
effectiveness will be confirmed. Accelerated approval is granted upon the condition that the
drug's sponsor must diligently conduct additional studies to confirm and describe its benefit.
Drugs that have been granted accelerated approval are subject to accelerated withdrawal of
approval if the studies fail to verify clinical benefit or if the drug is not shown to be safe and
effective.
CDER's decision to grant accelerated approval for Avastin's use in the treatment of breast
cancer was not based on a showing that the drug helped patients live longer or improved their
quality of life during the time during which they battled their cancer. There was not, at the time
of approval, credible evidence of increased overall survival or increased quality of life, and there
is no such evidence now. Instead, CDER based its accelerated approval on a different measure,
referred to as "progression free survival" (PFS). PFS measures the interval between the time a
patient is assigned to the control or investigational arm of a drug trial and either death or
evidence, generally from radiological assessments, that the size of the tumor has increased. For a
drug like Avastin, which has serious side effects, a small increase in PFS without a showing of
improved survival or improvement in quality of life does not provide a clinical benefit that is
meaningful to patients. But at the time of the accelerated approval decision, there was evidence
of a 5.5 month increase in median PFS, which was both statistically significant and of sufficient
magnitude, based on one clinical trial. That increase was the basis for the approval.
Thurly, but as you said the primary outcome listed is ORR, there are no secondary outcomes listed for
the trial on the ClinicalTrials.gov. So, the trial was unblinded when ORR was determined, and
PFS was released too. So isn't it unblinded now and forever more?
I am not sure if that would be an issue. The FDA could grant accelerated approval based on the ORR
and PFS data, which were blinded. AA is always granted with the condition that a phase 3 is done to
prove improvement in survival. That is what happened with Avastin and metastatic breast cancer, and the
survival was then not shown to be significantly increased when the phase 3 was done, so approval was withdrawn.
Okay, here is what I am missing. If the primary outcome was ORR and so the trial was unblinded when ORR
met its predetermined trigger point, then isn't the trial no longer blinded? So then the treatment arm MOS
could be announced when reached? Is the data available to Peregrine at unblinding and then blinded again?
My question is, if the MOS for the control arm was "already determined at less than 6 months",
why didn't they just tell us the exact number? What is with the mystery here? To me that sounds
like it is 5.9 months. It makes them seem like used car salesmen.
A preventive vaccine for Dengue may be near. Bavi could maybe work as a therapeutic.
Insight: Dengue vaccine in sight, after 70 years
Tue, Jun 5 2012
By Ben Hirschler
LONDON (Reuters) - One of the grimmest legacies of the war in the Pacific is still being fought 70 years on, but a victory over dengue, the intensely painful "breakbone fever" which that conflict helped spread around the world, may be in sight.
The U.S. Army, which like its Japanese enemy lost thousands of men to the mosquito-borne disease in the 1940s, has piled resources into defeating the tropical killer. But it may be about to see the battle to develop the first vaccine won not in the United States but by French drug company Sanofi.
The Paris-based firm hopes for positive results in September from a key trial among children in Thailand that would set it on course to market a shot in 2015 which would prevent an estimated 100 million cases of dengue infection each year. Of 20,000 annual deaths, many are of children.
For Sanofi, which has invested 350 million euros ($440 million) in a new French factory to make the three-dose vaccine, it could mean a billion euros in yearly sales as half the world is exposed to the disease, notably in fast-expanding tropical cities from Rio and Mexico to Manila and Mumbai.
But like British rival GlaxoSmithKline, whose new malaria shot has shown promise against another mosquito-carried scourge, Sanofi is also preparing for pressure to make its drug accessible to billions too poor to pay the likely market price.
It has been long wait. Identified in local outbreaks in the Americas, Africa and Asia since the 18th century - and noted as a serious military hindrance by U.S. generals in their 1898 war against Spain in Cuba and the Philippines - dengue was spread to global pandemic proportions in part due to the massive movements of armies through the Pacific theatre in World War Two.
That conflict, in which some 90,000 American troops were put in hospital by dengue, prompted the first efforts to develop a vaccine, as U.S. and Japanese scientists isolated the virus spread by the bite of the Aedes aegypti mosquito. But the disease, which can cause intense joint and muscle pain, has gone on sapping the health of troops, from Vietnam to Somalia and Haiti, and made lives miserable for millions of civilians.
In the past 50 years there has been a thirty-fold jump in cases. The World Health Organisation officially puts infections at 50 to 100 million a year, though many experts think this assessment from the 1990s badly under-estimates the disease. Most patients survive but it is estimated to kill about 20,000 every year, many of these children less able to fight it off.
TALE OF TWO VACCINES
The U.S. Army's quest for a vaccine had most recently been pursued in partnership with GlaxoSmithKline. But Sanofi now seems closest to offering a viable treatment. And, unlike GSK's malaria injection designed for African babies, it promises to be the commercial blockbuster the French firm needs to refresh a portfolio weakened by expiring patents.
Its estimate of over 1 billion euros in annual sales - Sanofi's 2011 turnover was 33.4 billion euros - assumes that it is added to routine immunization schedules in Latin America and Asia and is also adopted by travelers from farther afield and by military medics in the United States and Europe.
Meeting that sales potential, while getting the vaccine to hundreds of millions who need it across the tropics, will require a careful balancing act on pricing and supply of a product that has yet to be given a commercial brand name.
Orin Levine, executive director of the International Vaccine Access Center (IVAC) at the Johns Hopkins Bloomberg School of Public Health, says the new vaccine is a potential breakthrough but warned its roll-out may not be straightforward.
First up, the vaccine needs to be given in three installments over the course of a year in order to counter the threat from four different types of dengue virus, none of which confers immunity for the others.
"There are going to be some challenges," says Levine. "There's really good economic potential from this vaccine but I think it may take a ramp-up of three to five years."
SANOFI'S BET
In an ideal world, healthcare experts would like a single-dose or, at most, a two-dose vaccine for mass immunization.
A simpler regimen would also be better for travelers, although Pascal Barollier of Sanofi Pasteur, Sanofi's vaccine arm, says many users will be people making regular trips to see families in Latin America or Asia with time to plan ahead. The military, too, often has lead time for troop movements.
In any case, Sanofi is putting its money where its mouth is by spending 350 million euros on a new dengue vaccine factory near Lyon, which is already in test production.
It is a substantial gamble, since Sanofi will only learn whether the vaccine really works when it analyses data from a first study of its efficacy on 4,000 Thai children.
Results from that clinical study, in what is known as the Phase IIb of the international standard three-stage process of assessment, are expected in the third quarter - most likely September. They will also be presented for scientific scrutiny at the annual meeting of the American Society of Tropical Medicine and Hygiene in Atlanta in November.
If the data is good, Sanofi will file for market approval in countries where dengue is endemic like Australia, Malaysia, Singapore, Thailand and Mexico in 2013, suggesting a regulatory green light in 2014 and commercial launch in early 2015.
Submissions in other countries and for the travelers market would follow in 2014 and 2015.
LOOKING GOOD
Early tests have shown a balanced immune response against all four dengue types and Duane Gubler of the Duke-N.U.S. Graduate Medical School, who has researched dengue for four decades, is optimistic.
"Everything they've done so far looks very good," he says. "I think it will be a much better vaccine than malaria."
He expects Sanofi's vaccine will show an efficacy rate of at least 75 to 80 percent, well above the 50 percent or so seen with GSK's malaria shot, which faces the added technical problem of fighting a complex parasite rather than a virus.
The efficacy rate refers to the reduction in the prevalence of subsequent infection among those vaccinated.
Despite both being transmitted by mosquitoes, dengue and malaria are notably different enemies.
Malaria, which is carried by a different mosquito, typically attacks rural populations living near swamps. Dengue, by contrast, has adapted to life in the city and is one of the winners of mankind's accelerating rush to urbanize.
The number of people living in urban areas is projected to rise to 6.3 billion by 2050 from 3.4 billion today, leading to more mega-cities with poor sanitation where dengue and other diseases can thrive, according to a study in The Lancet medical journal last week.
Globalization has also brought cases of dengue into southern Europe and the United States, particularly Texas and Florida, although Gubler believes higher living standards mean it is not likely to take off in these regions.
PRICING DECISION
For the middle classes of Latin America and Asia, an out-of-pocket purchase of a dengue vaccine probably seems affordable and worthwhile, especially for their children. Yet dengue takes its biggest toll among the poor, who lack money for immunization and are also less likely to get medical help when the disease leads to potentially deadly haemorrhagic fever.
Getting vaccine to them will need the involvement of international agencies like the GAVI Alliance, which provides routine childhood immunizations in poor countries with funds granted by public and private donors.
Nina Schwalbe, GAVI's managing director for policy and performance, says she is monitoring the dengue vaccine program closely but needs hard evidence that it offers value for money, based on public health impact, efficacy and price.
Sanofi is not ready to set a price before it sees the full clinical trial results and has a clearer sense of vaccine yields at its factory. But the drugmaker will embrace "tiered pricing" to make the product affordable, Barollier at the company said.
That has not stopped the guessing.
"I would expect, for middle-income countries, they would be looking at prices similar to those of other new vaccines - for example HPV (human papillomavirus), pneumococcal and rotavirus vaccines - which sell for $15 to $70 per course in countries like Brazil, South Africa, Venezuela and Thailand," said IVAC's Levine.
Setting the price will be a test for Sanofi Chief Executive Chris Viehbacher. He reckons his vaccine is about five years ahead of any others and he knows he has a major opportunity to boost his company's reputation by getting the roll-out right.
With no specific drugs to treat or prevent dengue - in contrast to malaria - the world needs a success. Likewise, Viehbacher's shareholders, who have seen the company lose top-selling drugs as patents expire, need a commercial winner.
They will be watching closely those results from Thailand in September.
Some kind of milestone payments based on progress with some upfront money to keep things going.
It would be pocket change for some BP like Roche. We will see.
I guess they will just have to convince some BP to make a deal based on the data available.
Thanks Mojojojo. That is what I thought. Guess we could be in for a wait. In the mean time we will
get more data from the liver and pancreatic cancer trials since they are open label.
Sunstar and Wildhorses, given the MOA for bavi, first- and second-line treatment should work the same.
In first-line the chemotherapy kills off the tumor cells that are susceptible to the particular chemo drug combo used,
however as we now know tumors are very heterogeneous with respect to mutations, so the tumor cells
which are not killed and are resistant to the chemo used then proliferate and you are at second-line therapy.
Bavi works by enabling the immune response to destroy the tumor vasculature leading to necrosis in the core
of the tumor and the collapse of the tumor. Unfortunately some tumor cells on the periphery of the tumor
will survive and the tumor will regrow from those. But that means you could try Bavi again and it should work again.
So Bavi might be able to be used over and over, unlike chemo. This is because the target PS on the endothelial cells
of the tumor vasculature is not under the genetic control of the tumor cells, it gets exposed due to the cellular
stress brought on by the tumors themselves. It is beautiful.
So, if the MOS for first-line and second-line are similar it is evidence that all this reasoning is correct and Bavi
will be a great success. The normal state of things is that MOS for first-line is always greater than MOS for
second-line in the same type of cancer. If you look at my tables you can see this for the NSCLC trials.
It also reflects the fact 11 of the 12 trials are failures since the MOS means for control and treatment are the same.
First-line control mean MOS = 9.8 months
First-line treatment mean MOS = 9.7 months
Second-line control mean MOS = 7.4 months
Second-line treatment mean MOS = 7.3 months
First-line control mean MOS/second-line control mean MOS = 9.8/7.4 = 1.32
First-line treatment mean MOS/second-line treatment mean MOS = 9.7/7.3 = 1.33
So, first-line MOS is about 33% greater than second-line MOS using all kinds of standard chemotherapies.
If using Bavi can change this so that second-line MOS is the same as first-line MOS then you have a real
game changer! It also means that Bavi should be tested on all second-line cancer types.
I repeated the exercise for the first-line treatment arms of the 12 trials. There are a few interesting things to note.
One is that the mean MOS/PFS for these trials is 1.98, considerably less than the 2.84 for the second-line
treatment arms, and less noisy. Also, the Bavi first-line signal-seeking trial had a MOS/PFS = 2.03,
which is totally consistent with these, and had a MOS of 12.4 months, which is exactly the mean of
the two estimates given here for the randomized first-line MOS. This tells me the first-line NSCLC signal-seeking
trial is probably consistent with the randomized first-line trial.
It is also interesting that the mean of the two estimates given for the second-line MOS is 12.4, and agrees
with the mean estimate for the first-line MOS given here. That would be something if adding bavi to docetaxel
for second-line patients could extend survival as much as for first-line patients.
FF, and in both those two trials that you mention the MOS was not statistically significant.
Mojojojo, let me see if I can explain this. The median overall survival is triggered when 50% of the trial
patients have died. It is calculated for both the treatment arm and the control arm. So when 50% of the
control arm have died you know what the MOS is for the control arm. Similarly for the treatment arm.
However, to calculate whether the MOS of the treatment arm is significantly different than the MOS of the
control arm you need to include a certain predetermined number of patients so that you have enough power
to statistically distinguish between the arms. That is why you could know the MOS of both arms now,
but might have to wait months to know whether they are statistically different. Is that about right? So what is
prevent Peregrine from announcing the MOS of the two arms once they are triggered, but also say
it is too early to estimate the level of statistical significance?
Here is a new table of results. These are the treatment arms for second-line NSCLC which correspond to the
control arms shown in my post # 80983, except I have added two more trials I found. The control arms
were all docetaxel given every three weeks and so were the same. Here the treatment arms are not.
This is just to show the wide range of results obtained and as you can see if the MOS from the bavi + docetaxel
trial is 11 months or more it would be fantastic, but again what matters is how the treatment arms of the
bavi + docetaxel compare with the control arm MOS which we know is < 6 months.
Mojojojo, I agree that it is unlikely that the second-line MOS would be greater than the first-line MOS. The only
thing that matters is how much bigger the MOS of the treatment arms are in comparison with the control arm.
I will increase my MOS estimate to 10-10.5 months. with the PR first half of July.
RRdog, makes sense to me. What is your current estimate for the first-line NSCLC MOS?
I have a good feeling about the pancreatic trial, based just on my intuition so far, and the tidbits of data presented.
Holy Cow! RRdog, if your high estimate of 16.25 months is correct I think the FDA will be begging Peregrine
to file for accelerated approval. I will be happy to be utterly wrong about MOS! In my estimates I assume a
uniform rate of accrual over the 17 months since I have nothing else to base it on. Perhaps your estimates
are more like reality in that respect. What number would you get if you used a uniform rate? I am just using a
back-of-the-envelope estimate, nothing fancy at all.
That was just my guess, July 4, 2012. I think you could say that would be based on a lower number for MOS
than has been floated lately. I am happy to wait longer if that means the MOS number is greater.
Mojojojo, in the signal seeking trial there was no control arm so there was no way to compute statistical significance.
The fact that they waited 20 months was based on an arbitrary number, like 80% of the patients dying,
and not on a significance threshold being breached. More likely they felt that with 80% of the survival numbers
known that the final result (100%) would not change much. Of course, that determination was probably
based on some calculation using the data, and their comfort level with the degree of uncertainty.
RRdog, sorry not to answer before but I was on vacation. In all these studies I only report what the paper stated.
The results are better, but not statistically significant, as reported. It is all in how things are calculated and the
spread of the data. The noise in the data plays a part here. The medians may look different but if there is a lot
of variability present the medians can't be statistically distinguished. That can explain the difference from
one trial to the next. That is how I interpret it.
From the paper:
D + C (N = 67), D (N = 65)
Median survival (months) 10.27 7.70 P = 0.550 (Log-Rank test)
Min - Max 0.7 - 36.8 0.5 - 43.2
95% CI (7.07 - 13.47) (3.39 - 12.01)
The 95% confidence limits for docetaxel almost totally overlap the 95% confidence limits for docetaxel + carboplatin
What are we seeing here? I believe it is the synergy of Bavi + gem that was seen in the paper by Beck et al, 2006.
Combination of a monoclonal anti-phosphatidylserine antibody with gemcitabine
strongly inhibits the growth and metastasis of orthotopic pancreatic tumors
in mice
Adam W. Beck1,2, Troy A. Luster1,3,4, Andrew F. Miller1, Shane E. Holloway1,2, Chris R. Conner1, Carlton C. Barnett1,2,
Philip E. Thorpe1,3,4, Jason B. Fleming1,2 and Rolf A. Brekken1,2,4
Figure 3 from the paper shows synergy when 3G4 (mouse bavi) and gemcitabine are used in combination.
Note how Gem only, or 3G4 only, give similar results, but the combination has much reduced number of metatstases.
From the AACR poster results it does seem this is happening with the first two Bavi + gem patients
but not with the second two, which are similar to gem only patients. The question is, what is different between
these patients?
Significant differences of treatment groups vs. PBS group is indicated by *, p < 0.05;
**, p < 0.001.
Interesting data from the Pancreatic Cancer poster.
I am looking at just the duration of response data here. Note that the second two Bavi + Gem patients
are very similar to the two Gem only patients. I assume that the addition of Bavi did not help these 2 patients.
These 4 patients had a mean DR of 54 days, while the first two Bavi + Gem patients had a mean DR of 170
days, a factor of more than 3 improvement by adding Bavi to patients who could benefit from the treatment.
This is where the use of I124-PGN650 might come in useful. It may be possible to identify these types of
patients at the start of the trial and only select them for the full treatment. Those first two patients are also the
only two left alive.
Can Bavi + Gemcitabine equal this trial from 2011? If it can,
without the high toxicity, then it will be a candidate for the new SOC.
Note the differences in the patients as compared to the Bavi + Gemcitabine
trial as highlighted by CJ.
From Nature Reviews Clinical Oncology, August 2011.
Metastatic pancreatic cancer—is FOLFIRINOX the new standard?
M. Wasif Saif and John Chabot
In the phase III ACCORD 11 trial, FOLFIRINOX was associated with the longest survival ever
reported for patients with metastatic pancreatic cancer (11.1 months). However, toxicities associated
with the four-drug regimen will limit its use to patients with a good performance status.
Pancreatic cancer persists as a major therapeutic
challenge owing to chemotherapy refractory
disease and poor responses to
currently available treatments. Gemcitabine
is the standard chemotherapy for patients
with pancreatic cancer, offering a modest
improvement of tumor-related symptoms
(clinical benefit response) and a marginal
increase in patient survival. Many chemotherapeutic
and targeted agents have been
compared against, or combined with, gemcitabine
in randomized phase III trials,
but none has been shown to be superior
to single-agent gemcitabine. Only the
combination of gemcitabine and erlotinib
improved patient median survival compared
with gemcitabine alone (6.4 months
versus 6.0 months). Although this 2-week
difference in patient survival was statistically
significant, it might not be clinically
relevant because of the increased toxicity
that was associated with the combination
treatment. Therefore, most oncologists
still consider single-agent gemcitabine to
be the standard chemotherapy for first-line
therapy of patients with pancreatic cancer.
Conroy and colleagues have now reported
the results of the ACCORD 11 (PRODIGE 4)
trial, in which 342 patients with pancreatic
cancer and an ECOG performance status
of 0 or 1 were randomly assigned to receive
either gemcitabine or FOLFIRINOX—a
combination of oxaliplatin, irinotecan, leucovorin,
and 5-fluorouracil (5-FU) as first-line therapy.
Thanks, I missed that. Then the ORR so far are 4/15 = 26.7% vs 2/17 = 11.8%, that makes the control
more in-line with the historic controls. Also, this gives more possibility for even more data. looks good.
Still jet-lagged.
Hello, I was flying back from Spain yesterday and thinking about this poster. To me it looks very encouraging.
Obviously the data presented are at an early stage, but even with this very limited set of data it is looking
good to me. Note that 66 patients had been enrolled when the poster was prepared. So far ORR has doubled
to 4/32 = 12.5% from 2/34 = 5.9%, OS is longer, 8.4 vs 7.2 months, and duration of response has doubled,
3.7 vs 1.8 months. Of course with such small numbers all we can say is that it is encouraging, but inconclusive.
Nice to see that Harvard Medical School at the top of the poster. For more info on previous pancreatic trials
see my posts #75608, and #80983
Hi Mojojojo. Do you think that because the signal seeking trials had no control arm that Peregrine waited
for all the patients to die before they released MOS? Might the fact that the randomized first-line
NSCLC has a control arm make a difference? If the MOS for the control arm is 9 months and the
treatment arm 12+ months maybe that could be released earlier than it was for the signal seeking trial.
Hi Cj, I have been in Spain since Tuesday. I found another abstract on the AACR website
when I searched for Bavituximab. Not sure about it.
Poster Session B Wednesday, June 2012:30 p.m.-2:30 p.m. In alphabetical order, not board
assignment order
3D MR imaging of ECM alterations in mouse model of pancreatic cancer (PC).
Palamadai N. Venkatasubramanian, Paul J. Grippo, Gheorghe Iordanescu, Richard H. Knop, Alice M. Wyrwicz A diet...
That is a good point. PGN650 is the Fab end of PGN635 (humanized bavi), which means a lot of the
immune stimulating properties of bavi are lost without the Fc end, except for the effects of masking PS.
I think that it could be used in phase I trials just to make sure the ADC is going where you think it is.
Once that is established then other trials could be run without using 124I-PGN650. Also, it could be given
as part of the enrollment criteria to select patients with tumors that have plenty of PS exposed, or to decide on
how much chemotherapy is needed for each patient, but after that it is not used, or maybe after the
treatment cycles are done. Another idea is that it could be part of the trial design so that the approval
depends on both the ADC and 124I-PGN650 used together. I am sure you can come up with more ideas.
Here is a picture from Seattle Genetics which shows how antibody-drug conjugate (ADC) works.
They have developed their own ADC which has an antibody which targets the CD30 protein (receptor) on
Hodgkins lymphoma cells and delivers a cytotoxic drug. They also want to sell their technology linking their
cytotoxic drugs to antibodies developed by other biotech companies, like Herceptin (targets HER2)
and DM-1 (ImmunoGen). In the picture note number 5. This is where 124I-PGN650 can come in handy.
Say you are a biotech and have developed a monoclonal antibody that targets a particular protein on a
tumor cell. You make a deal with SGEN to link your antibody to a cytotoxic drug to kill the tumors you
are targeting. How do you know it works unless you run a full clinical trial? You use 124I-PGN650 after you
dose the patients with your ADC. If it is working then the tumor cells die by apoptosis (number 5) and
expose PS on their surface. The PGN650 antibody fragment (Fab2) binds to the PS with the radioisotope I-124.
You do a PET scan and see that 124I-PGN650 has attached to the tumors you had earlier imaged with CT or
MRI, so you know your ADC has attacked those tumors. So you can monitor the treatment of the tumors with
your ADC. Is that about it?
FireFox, thanks for that. It could be too that they will be able to identify specific
cancer types that express PS on the tumors cells in patients, and not just from tumor cell
lines, in addition to the tumor vasculature. For example, there is some evidence that
ovarian cancer cells express PS. Since we now know that cancer is much more variable
than thought before there could also be patient to patient variations that will show up
with PS imaging. So maybe if one patient's tumors express a lot of PS then less chemo
could be used with bavi, while another patient may need more.
RRdog, I am keeping my fingers crossed that the MOS is 9 months, or greater. It would be
incredible if it was 10 months or greater, but as far as the FDA goes it is the
comparison with the control arm of the trial which matters, not the mean of the 10 other
control arms. Since we know the control arm MOS is less than 6 months I feel 9 months
is excellent. I just like to be a little cautious about my expectations.
Like you say preparations should be underway for good results. How does one get two
publications in the NEJM coming out at the same time the results are announced at ASCO?
It takes a lot of preparation. It doesn't hurt that the trials were run by clinical oncologists
at Johns Hopkins School of Medicine and funded by BMS.
The longer we have to wait the better I think. The way these things are calculated it is possible
I believe that they could be less than 8 months currently. Mojojojo might give us a better idea.
But really, a 35% increase over the control arm is very good, 50% would be remarkable.
I forgot to mention that 8 months ago today the last patient in the second-line NSCLC trial was enrolled.
I am very confident now that the MOS for the second-line NSCLC will be a good improvement over the control.
I am still hoping for a 50% improvement. As I have recently tried to point out, this would be unprecedented in
the history of trials for second-line NSCLC. Of course some people will say that it isn't statistically significant, if it isn't.
That might be true, but given the size of the trial not too surprising if true. Most phase II trials aren't I believe,
and are not usually powered to show significance. It is interesting to see all the hoopla around the BMS PD-1
trials reported in the NEJM. These were very large phase I trials, no mention of statistical significance, as you would expect.
Several articles have pointed out that these trials showed responses in NSCLC above 10% and that is
taken as very noteworthy. The number I have read often is 18%. However, from the actual NEJM papers you
get the whole story. Across all doses it is 18% of the 76 patients with pre-treated NSCLC. If you look at their
breakdown of the types you see that for squamous they had ORR of 33%, which is very good. But for non-squamous,
which is the type the Bavi + docetaxel trial treats, the ORR is only 12% across all three doses, with 0/12 patients
at 1 mg/kg, 3/13 at 3 mg/kg, and 4/31 at 10 mg/kg, for the 56 patients. Note that their best response
is at the same dose as ours. In the journal Nature yesterday there was a news article about the anti-PD-1 trials.
"Antibody alarm call rouses immune response to cancer"
....
"By contrast, anti-PD-1 therapy produced responses in 18%
of patients with lung cancer, 28% of patients
with melanoma and 27% of patients with
kidney cancer. “If we break the 10% ceiling,
it’s becoming even more important and clinically
relevant,” Ribas says.
That the drug also works in lung cancer —
which kills more people each year than any
other cancer — is a breakthrough, says Jedd
Wolchok, an oncologist at the Memorial Sloan-
Kettering Cancer Center in New York, who is
testing therapies aimed at blocking PD-1 in
clinical trials. “The most important lesson
that the practising oncologist is going to take
away is that immunotherapy is now relevant
to some of the very common diseases that they
see,” Wolchok says.
Because stimulating the immune system can
induce deadly autoimmune responses, a major
concern with any immunotherapy is safety.
Three patients in the anti-PD-1 trial — 1% of
those treated — died from lung inflammation
caused by the trial drug. Overall, 11% of the
patients had serious side effects.
“If we can get away from the significant
adverse events that we’ve seen and help larger
numbers of patients, then immunotherapy can
be a game changer,” says Ira Mellman, vicepresident
of research oncology at Genentech
in South San Francisco, California."
....
Pancreatic cancer treatment has not progressed. Can Bavi make a difference?
The only regimen that has shown improvement in OS in the last 15 years is almost too toxic to use.
Bavi + Gem might have a good shot at becoming the new SOC if the trial can get fully enrolled.
World J Gastroenterol 2012 February 28; 18(8): 736-745
Developments in metastatic pancreatic cancer: Is gemcitabine still the standard?
INTRODUCTION
In 2010, there were an estimated 43 140 new cases and 36 800 deaths from pancreatic cancer in the United States[1]. This represents the 10th most common new cause of cancer and the fourth most common cause of cancer-related death in 2010, highlighting the disproportionate mortality associated with this disease. Additionally, unlike most of the more frequent causes of cancer mortality (lung, colon, prostate, and breast), whose death rates are declining, the death rate for pancreatic cancer has remained relatively stable, which also indicates the limited progress in this field.
....
CONCLUSION
As a first-line therapy, Gem has been the standard treatment for pancreatic cancer since 1997, despite its low RR and short OS. Trials for Gem-based combination regimens have failed to improve survival. Striking, FOLFIRINOX regimen increased median OS from 6.8 mo to 11.1 mo (P < 0.0001), and RR was 31.6% for patients with a good PS. Thus the question that arises is whether FOLFIRINOX should be considered standard therapy for advanced pancreatic cancer instead of Gem. Does this trial represent the start of a change for the management of advanced pancreatic cancer? The FOLFIRINOX regimen was quite toxic because nearly half of the patients suffered grade 3/4 toxicity.
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