ImClone Systems Inc (formerly IMCL)

[biophud]

<The prominent discussion of 11F8 on the recent CC and BMY’s buyout offer are not unrelated>. I tend to agree. However, I am still puzzled by the Adnexus purchase where BMY bought a competing technology to generate extracellular protein antagonists to receptor tyrosine kinases (the same RTKs that IMCL is working on). Given this purchase, do you think that there are any regulatory barriers/anti-trust issues in the BMY purchase of IMCL?

Regards,

biophud

[JT1101]

Bristol-Myers Squibb (BMY) advances ImClone Systems Inc. (IMCL) Partnership, Proposes Acquisition
http://www.beaconequity.com/index.php?option=com_content&task=view&id=1377&Itemid=27

[DewDiligence]

Transcript of today’s BMY CC:
#msg-31121127.

[DewDiligence]

The prominent discussion of 11F8 on the recent CC and BMY’s buyout offer are not unrelated, IMHO.

[Bigstud is here]

Buyout for 60 bucks

NEW YORK, Jul 31, 2008 (BUSINESS WIRE) -- Bristol-Myers Squibb Company (NYSE: BMY) today announced that it has proposed to enter into an agreement to acquire ImClone Systems Incorporated (NASDAQ: IMCL), a global leader in the development and commercialization of novel antibodies to treat cancer, for $60.00 per share in cash, or a total payment of approximately $4.5 billion, to equity holders of ImClone, other than Bristol-Myers Squibb. Bristol-Myers Squibb currently owns approximately 17 percent of all outstanding shares of ImClone.

[biophud]

Thanks for your opinion. 11F8 is an EGFR-drug, specifically a phage derived human anti-EGFR. Strictly speaking 11F8 is NOT a humanized/CDR-grafted antibody. I'm not sure how this will be treated from a legal standpoint.

The question that I have is the following: does 11F8 have any meaurable efficacy advantage over Erbitux?

We will see what happens in a couple of months.

Regards,

biophud

[caravon]

Regardless of what, in just 2 months, the BMS/IMCL commercial agreement leaves both parties to develop & market in N. America any product including ones directly competing with C225 (Erbitux).

Now the question: is 11F8 a EGFr-drug or not?

[biophud]

Significance of the BMY/Adnexus purchase. I reread the restriction on competing products that corky posted on the yahoo board (see below) and I have a few thoughts. Based on the BMY purchase of Adnexus it would appear that they are pursing adnectin-based technology as a strategy to block the extracellular domains of receptor tyrosine kinases. I cannot find the link but I recall a presentation in which BMY/Adnexus were investigating antagonists of VEGFR, EGFR, IGFR, as well as dual targeted agents. If BMY is pursuing an adnectin-based EGFR antagonist, this would appear to violate the restriction on competing products--Could this be the reason that IMCL has 100% right to 11F8?. It would seem that after buying Adnexus, it would be redundant for BMY to partner the IMCL pipeline. As I recall, the Adnexus purchase went for ~400 million, significantly less than it would cost to purchase IMCL. Comments appreciated.

biophud

RESTRICTION ON COMPETING PRODUCTS. During the period from the date of the Commercial Agreement until September 19, 2008, the parties have agreed not to, directly or indirectly, develop or commercialize a competing product (defined as a product which has as its only mechanism of action an antagonism of the EGF receptor) in any country in the Territory. In the event that any party proposes to commercialize a competing product or purchases or otherwise takes control of a third party which has developed or commercialized a competing product, then such party must either divest the competing product within 12 months or offer the other party the right to participate in the commercialization and development of the competing product on a 50/50 basis (provided that if the

[DewDiligence]

OK—I agree with your explanation.

[biophud]

Dew--I'm not sure, but my understanding is that companies like IMCL licence phage display technology from DYAX and use the technology themselves to isolate antibodies directed toward specific targets.

Here is a patent for anti-FGFR antibodies generated by IMCL using DYAX phage technology. Note that IMCL is the only assignee listed on the the patent.

http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=45&f=G&l=50&co1=AND&d=PG01&s1=dyax&OS=dyax&RS=dyax

My understanding is that DYAX will collect milestones payments and royalities on future sales if a product comes to market.

Regards,

biophud

[DewDiligence]

>As far as I know IMCL does not have a patent on a fully human phage-derived anti EGFR-antibody.<

Wouldn’t DYAX be the patent holder?

[biophud]

Comments regarding recent Yahoo postings on 11F8 and humanized c225. Corky mentioned that 11F8 and humanized C225 are not the same thing. I think that this is an important point that raises several questions. Specifically how are these two molecules treated in terms of intellectual property? and how are these two entities treated in terms of IMCL's contractual agrements?

IMCL has a patent on a CDR-grafted humanized c225. See below.

http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=2&f=G&l=50&co1=AND&d=PTXT&s1=imclone.ASNM.&OS=AN/imclone&RS=AN/imclone

As far as I know IMCL does not have a clinical trial with a CDR-grafted humanized c225 antibody

11F8 is a fully human phage-derived antibody derived from DYAX's phage library technology.

As far as I know IMCL does not have a patent on a fully human phage-derived anti EGFR-antibody.

Comments appreciated,

biophud

[biophud]

FYI--IMCL patent application for psoriasis.

biophud

http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PG01&s1=IMCLONE.AS.&OS=AN/IMCLONE&RS=AN/IMCLONE

[hdenoel2]

Jb,

Would this be a good indicator to invest in RGDX (Resonse Genetics)

cheers, Hector.

[jbog]

Researchers at the University of Colorado Cancer Center have shown that a readily available gene screening test can help doctors know which people with advanced non-small-cell lung cancer will benefit from adding a second cancer drug to standard chemotherapy.

Patients who test positive for the EGFR gene may live twice as long as those who are EGFR- when given the a combination of chemotherapy and cetuximab—a drug that blocks a key pathway particular gene-driven tumors use to grow and spread—as their first-line treatment, the study shows.

“The results of this study could very well change the way lung cancer patients are treated in the future, similarly to how screening for estrogen-driven breast cancer changed how patients with HER2+ breast tumors are treated,” said Fred Hirsch, MD, PhD, professor of Medicine at University of Colorado Denver and the paper’s lead author.

The paper, published in the July issue of the prestigious Journal of Clinical Oncology, is from a phase II randomized study out of the Southwest Oncology Group, a consortium of cancer researchers. It comes on the heels of the large, randomized European FLEX study, which showed that some advanced non-small-cell lung cancer patients who got the combination therapy lived longer than others who got the same therapy.

“We needed a tool to tell us which patients to put on cetuximab, because it does not make sense to give an expensive drug that has side effects for someone it will not help,” Hirsch said. “We believe that EGFR FISH is that tool.”

The EGFR FISH test, which was developed at the University of Colorado Cancer Center, is available in most laboratories, so lung cancer patients around the world could be quickly screened in the future to see if they would benefit from cetuximab plus chemotherapy. They will soon begin a 1,000-patient phase III trial to validate the findings, and they anticipate FDA approval of the tool to select patients for EGFR inhibitors in the near future.

“When we give patients the right drugs for their exact tumor type, we can help them live a longer, more comfortable life with the disease,” said Paul A. Bunn, Jr., MD, UCCC director and professor of Medicine at UC Denver, who co-authored the study. “I am already using this test to screen my patients for this gene, and if they test positive, I am giving them the combination therapy. They are doing very well on it. We are hopeful that this test will shift how we choose which therapies to give to each individual patient, which is key to getting the best results.”

In the UCCC study, EGFR+ patients lived an average of 15 months after diagnosis with the combination therapy, compared to an average of 7 months for EGFR- patients. EGFR+ patients’ tumors also shrunk twice as much on the combination therapy.

The Colorado group, which includes Hirsch, Bunn, and UC Denver professors of Medicine Wilbur Franklin, MD, and Marileila Varella-Garcia, PhD, previously found similar results using the EGFR FISH test to predict which patients would do well on Tarceva (erlotinib), another EGFR inhibitor drug. EGFR also plays a role in colorectal cancer, so the test could also be used to predict which of those patients may benefit from EGFR-blocking drugs.

Approximately 215,000 people in the United States will be diagnosed with lung cancer in 2008, according to the American Cancer Society. Only about 40 percent will be alive one year later, and only about 15 percent will be alive five years later. Because there is no effective screening test for lung cancer, most people are diagnosed when the disease has spread beyond the lung. Lung cancer kills more adults in the United States than any other cancer.

[corky]

OT TONY SNOW


Cancer's Unexpected Blessings

When you enter the Valley of the Shadow of Death, things change.

Tony Snow | posted 7/20/2007 02:30PM



Related articles and links | [no previous page] 1 of 3 [next page]



Commentator and broadcaster Tony Snow announced that he had colon cancer in 2005. Following surgery and chemo-therapy, Snow joined the Bush administration in April 2006 as press secretary. Unfortunately, on March 23 Snow, 51, a husband and father of three, announced that the cancer had recurred, with tumors found in his abdomen—leading to surgery in April, followed by more chemotherapy. Snow went back to work in the White House Briefing Room on May 30, but resigned August 31. CT asked Snow what spiritual lessons he has been learning through the ordeal.



Blessings arrive in unexpected packages—in my case, cancer.



Those of us with potentially fatal diseases—and there are millions in America today—find ourselves in the odd position of coping with our mortality while trying to fathom God's will. Although it would be the height of presumption to declare with confidence What It All Means, Scripture provides powerful hints and consolations.



The first is that we shouldn't spend too much time trying to answer the why questions: Why me? Why must people suffer? Why can't someone else get sick? We can't answer such things, and the questions themselves often are designed more to express our anguish than to solicit an answer.

I don't know why I have cancer, and I don't much care. It is what it is—a plain and indisputable fact. Yet even while staring into a mirror darkly, great and stunning truths begin to take shape. Our maladies define a central feature of our existence: We are fallen. We are imperfect. Our bodies give out.



But despite this—because of it—God offers the possibility of salvation and grace. We don't know how the narrative of our lives will end, but we get to choose how to use the interval between now and the moment we meet our Creator face-to-face.



Second, we need to get past the anxiety. The mere thought of dying can send adrenaline flooding through your system. A dizzy, unfocused panic seizes you. Your heart thumps; your head swims. You think of nothingness and swoon. You fear partings; you worry about the impact on family and friends. You fidget and get nowhere.



To regain footing, remember that we were born not into death, but into life—and that the journey continues after we have finished our days on this earth. We accept this on faith, but that faith is nourished by a conviction that stirs even within many nonbelieving hearts—an intuition that the gift of life, once given, cannot be taken away. Those who have been stricken enjoy the special privilege of being able to fight with their might, main, and faith to live—fully, richly, exuberantly—no matter how their days may be numbered.



Third, we can open our eyes and hearts. God relishes surprise. We want lives of simple, predictable ease—smooth, even trails as far as the eye can see—but God likes to go off-road. He provokes us with twists and turns. He places us in predicaments that seem to defy our endurance and comprehension—and yet don't. By his love and grace, we persevere. The challenges that make our hearts leap and stomachs churn invariably strengthen our faith and grant measures of wisdom and joy we would not experience otherwise.



'You Have Been Called'

Picture yourself in a hospital bed. The fog of anesthesia has begun to wear away. A doctor stands at your feet; a loved one holds your hand at the side. "It's cancer," the healer announces.



The natural reaction is to turn to God and ask him to serve as a cosmic Santa. "Dear God, make it all go away. Make everything simpler." But another voice whispers: "You have been called." Your quandary has drawn you closer to God, closer to those you love, closer to the issues that matter—and has dragged into insignificance the banal concerns that occupy our "normal time."



There's another kind of response, although usually short-lived—an inexplicable shudder of excitement, as if a clarifying moment of calamity has swept away everything trivial and tinny, and placed before us the challenge of important questions.



The moment you enter the Valley of the Shadow of Death, things change. You discover that Christianity is not something doughy, passive, pious, and soft. Faith may be the substance of things hoped for, the evidence of things not seen. But it also draws you into a world shorn of fearful caution. The life of belief teems with thrills, boldness, danger, shocks, reversals, triumphs, and epiphanies. Think of Paul, traipsing though the known world and contemplating trips to what must have seemed the antipodes (Spain), shaking the dust from his sandals, worrying not about the morrow, but only about the moment.



There's nothing wilder than a life of humble virtue—for it is through selflessness and service that God wrings from our bodies and spirits the most we ever could give, the most we ever could offer, and the most we ever could do.



Finally, we can let love change everything. When Jesus was faced with the prospect of crucifixion, he grieved not for himself, but for us. He cried for Jerusalem before entering the holy city. From the Cross, he took on the cumulative burden of human sin and weakness, and begged for forgiveness on our behalf.



We get repeated chances to learn that life is not about us—that we acquire purpose and satisfaction by sharing in God's love for others. Sickness gets us partway there. It reminds us of our limitations and dependence. But it also gives us a chance to serve the healthy. A minister friend of mine observes that people suffering grave afflictions often acquire the faith of two people, while loved ones accept the burden of two people's worries and fears.



Learning How to Live

Most of us have watched friends as they drifted toward God's arms not with resignation, but with peace and hope. In so doing, they have taught us not how to die, but how to live. They have emulated Christ by transmitting the power and authority of love.



I sat by my best friend's bedside a few years ago as a wasting cancer took him away. He kept at his table a worn Bible and a 1928 edition of the Book of Common Prayer. A shattering grief disabled his family, many of his old friends, and at least one priest. Here was a humble and very good guy, someone who apologized when he winced with pain because he thought it made his guest uncomfortable. He retained his equanimity and good humor literally until his last conscious moment. "I'm going to try to beat [this cancer]," he told me several months before he died. "But if I don't, I'll see you on the other side."



His gift was to remind everyone around him that even though God doesn't promise us tomorrow, he does promise us eternity—filled with life and love we cannot comprehend—and that one can in the throes of sickness point the rest of us toward timeless truths that will help us weather future storms.



Through such trials, God bids us to choose: Do we believe, or do we not? Will we be bold enough to love, daring enough to serve, humble enough to submit, and strong enough to acknowledge our limitations? Can we surrender our concern in things that don't matter so that we might devote our remaining days to things that do?



When our faith flags, he throws reminders in our way. Think of the prayer warriors in our midst. They change things, and those of us who have been on the receiving end of their petitions and intercessions know it.



It is hard to describe, but there are times when suddenly the hairs on the back of your neck stand up, and you feel a surge of the Spirit. Somehow you just know: Others have chosen, when talking to the Author of all creation, to lift us up—to speak of us!



This is love of a very special order. But so is the ability to sit back and appreciate the wonder of every created thing. The mere thought of death somehow makes every blessing vivid, every happiness more luminous and intense. We may not know how our contest with sickness will end, but we have felt the ineluctable touch of God.



What is man that Thou art mindful of him? We don't know much, but we know this: No matter where we are, no matter what we do, no matter how bleak or frightening our prospects, each and every one of us, each and every day, lies in the same safe and impregnable place—in the hollow of God's hand.

[jbog]

More Evidence That Erbitux Improves Survival in KRAS Wild Type Tumors


KRAS analysis of NCIC CTG CO.17 study shows significant improvement in median overall survival and once again validates Erbitux use in metastatic colorectal cancer (mCRC). At the ongoing World Congress on Gastrointestinal Cancer in Barcelona, Spain, clinical data of a KRAS analysis from a study of Erbitux (NCIC CTG CO.17) was presented. The study concluded that, in pre-treated advanced CRC, there is an almost doubling of median overall survival (OS) and progression free survival (PFS) in patients on Erbitux with wild-type KRAS tumors while no significant benefit is observed in patients with mutant KRAS. In the study, mCRC tumor samples were retrospectively collected and analyzed. Recall NCIC CTG CO.17 is a Phase III clinical trial of Erbitux plus best supportive care (BSC) versus BSC alone in EGFR positive mCRC patients and who had been previously treated with chemotherapy. We view these results as encouraging and likely to spur additional use in this population, as well as avoidance of use in patients with KRAS mutations. Net-net, we consider the NCIC CTG CO.17 results as positive for IMCL. Along with the results of the CRYSTAL study in frontline mCRC patients we view today's additional KRAS data provides a strong rationale for routine KRAS testing in mCRC across all lines. We believe Erbitux has shown consistent survival benefit in the KRAS wild type patients irrespective of prior therapy.


KRAS analysis. KRAS data was collected from 69% (n = 394) of the original intent to treat population (N = 572). Of these, 42% (N = 164) were mutant while 58% (N = 230) were wild type. The wild-type KRAS patients had a median OS of 9.5 months with Erbitux vs. 4.8 months with BSC (HR, 0.55; p<0.0001). Median PFS for wild-type patients was 3.8 months with Erbitux and 1.9 months with BSC (HR, 0.40; p < 0.0001). Within the mutant KRAS group median OS was 4.5 months with Erbitux vs. 4.6 months with BSC (HR, 0.98; p=0.89), and the median PFS was the same (1.8 months) for both groups (HR, 0.99; p=0.96) (Please refer to figure 1, page 2).


What does the new data mean to the mCRC market? According to our data from Oncology, Inc., Erbitux market share in the second line mCRC setting is currently in the mid-teens, while it is in the single digits in the front line setting (Figure 2, 3). The overall market share of Erbitux in the third line setting is 37.1%. In our view there is certainly plenty of room to grow across all lines of therapy. Specifically in the third line setting today's data release may help Erbitux either to increase its market share and/or increase the average duration of therapy. Net-net, it is our view that the use of KRAS as a predictive biomarker for response, OS and PFS improvement will be beneficial for Erbitux use .


Study background. NCIC CTG CO.17 study is Phase III study (n = 572) comparing mCRC patients who were EGFR positive and had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin. The patients underwent randomization to an initial dose of 400 mg of Erbitux per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus BSC (287 patients) or BSC alone (285 patients). The primary end point was overall survival (OS). In comparison with BSC alone, Erbitux treatment was associated with a significant improvement in OS (hazard ratio for death, 0.77; P = 0.005) and in progression-free survival (PFS) (hazard ratio for disease progression or death, 0.68; P<0.001). The median OS was 6.1 months in the Erbitux group and 4.6 months in the group assigned to supportive care alone.


We reiterate Market Outperform rating and price target of $62. We reach our target using a Discounted Cash Flow (DCF) valuation. We forecast sales and individual expenses until 2015 to calculate the free cash flow in each year. Assuming a terminal growth rate of 4% to calculate the terminal value, we discount the numbers to 2008 by using the Weighted Average Cost of Capital (WACC) of 10.8% to achieve the value of the firm. Subtracting the long-term debt of$612 MM, we derive the value of equity. IMCL remains one of our top names for 2008.

[jbog]

KRAS Mutation status is a predictive biomarker for cetuximab benefit in the treatment of advanced colorectal cancer

Results from NCIC CTG CO.17: A phase III trial of cetuximab versus best supportive care.

Christos Karapetis1, Shirin Khambata-Ford2, Derek Jonker3, Chris O'Callaghan3, Dongsheng Tu3, Niall Tebbutt1, John Simes1,
Christiane Langer2, Malcolm Moore3, John Zalcberg1
1Australasian Gastrointestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; 2Bristol-Myers-Squibb Company, Princeton NJ & Wallingford CT, USA; 3National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, ON, Canada.

ABSTRACT

Background:
Cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) and preserves quality of life in patients with advanced colorectal cancer (CRC) that has progressed after chemotherapy. The presence of wild type K-Ras (WT) may predict which patients will optimally benefit from cetuximab in this setting. In addition, the prognostic significance of K-Ras mutation status is unclear.

Methods:
CRC tumour samples were collected and analysed as part of a phase III clinical trial of cetuximab plus best supportive care
(BSC) versus BSC alone (NEJM 2007; 357(20): 2040-8). Activating mutations in exon 2 of the K-Ras gene were detected in tumourderived genomic DNA by direct gene sequencing without knowledge of clinical outcome. The predictive effect of K-Ras mutation status on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction.

Results:
K-Ras mutation status was ascertained in 394 (69%) of the total study population (198 cetuximab, 196 BSC). Mutant K-Ras was detected in 164 (42%) patients. Within the mutant K-Ras group the median PFS was the same (1.8 months) for both groups (HR,0.99; 95% CI, 0.73 to 1.35; p=0.96), while median OS was 4.6 months with cetuximab and 4.5 months with BSC (HR,0.98; 95% CI,
0.70 to 1.37; p=0.89).

In the 230 (58%) WT patients, median PFS was 3.8 months for the cetuximab treated group and 1.9 months with BSC (HR, 0.40; 95% CI, 0.30 to 0.54; p < 0.0001).

The survival of patients with WT K-Ras was longer when they were treated with cetuximab, with a median OS of 9.5 months with cetuximab vs. 4.8 months with BSC (HR, 0.55; 95% CI, 0.41 to 0.74; p<0.0001).

The test for interaction between K-Ras mutation status and cetuximab treatment demonstrates that the effect of cetuximab on OS (p=0.01) and PFS (p=0.0001) is significantly greater in the K-Ras WT group than mutant group.

The difference in the OS of patients with either WT or mutant K-Ras in the BSC arm was not significant (HR, 1.01; 95% CI, 0.74 to 1.37; p=0.97).

Conclusions: In the setting of pre-treated advanced CRC, there is an almost doubling of median overall and progression free survival in patients with WT K-Ras tumours while no significant benefit is observed in patients with mutant K-Ras. K-Ras mutation status did not demonstrate a prognostic effect within a ‘no treatment’ group. In this population, K-Ras mutation status is a strong predictive biomarker and K-Ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR targeted therapy

[jbog]

SmithBarney

Imclone Systems Inc. (IMCL)

Erbitux Looks Likely to Receive NCCN Recommendation in Lung Cancer

Yaron Werber, MD


 Conclusions — We spoke to a key opinion leader involved with NCCN Guidelines for Lung Cancer. He suggested that the NCCN may add Erbitux to the guidelines under the same category where Avastin is listed. Further, he noted his willingness to prescribe Erbitux to Avastin-ineligible patients and to
eligible patients who decide not to take Avastin due to risk of bleeding.

 Erbitux Likely Category 2a — NCCN has 4 different categories for listing of new cancer drugs. Category 1 includes those with evidence-based trials, no disagreements and successful meta-analyses confirming the benefit of the drug. Next down is category 2a (where Avastin is listed in NSCLC), which are
drugs supported by large evidence-based trials and with no disagreements among NCCN members. Erbitux would likely be listed under category 2a in combination with vinorelbine/cisplatin, although physicians are likely to use it with other chemo combos as well.

 Decision Coming — A listing of Erbitux on the NCCN guidelines should come within ~2 months. Preliminary discussions have already occurred and a draft is circulating for approval from all NCCN guideline members.

 Positive on Erbitux — Our consultant noted he would use Erbitux in both Avastin-ineligible patients and eligible patients who opt against Avastin (20%–25% in his view) because of the drug's rare toxicities including bleeding, heart attacks and strokes.

 Sample Collection — According to our consultant, sample collection for EGFR testing is not an issue. Also, since in FLEX only one cancer cell was needed to be stained positive for EGFR by IHC test, 85% of patients tested positive to get Erbitux and were included in the study. While NCCN should adopt similar guidelines, EGFR testing should not be a barrier.

 Radiation Therapy — It was also pointed out that there could be significant upside for Erbitux if it can be combined with radiation therapy in stage IIIA and IIIB lung cancer. A ph 2 study (RTOG-0324) combining Erbitux, paclitaxel, carboplatin and radiation showed positive results and supports ph 3 studies.

 Sensitivity Analysis — Our sensitivity analysis suggests that in 2009, every 1% Erbitux market share gain in lung cancer in U.S. should boost sales by $17M, and increase non-GAAP earnings by $0.08.

Investment Strategy
We rate the shares of ImClone Systems Buy/High Risk (1H). We like the favorable risk/reward in front of the FLEX study data release, given the large market opportunity in lung cancer and low investor expectations for this trial.

In addition, ImClone is one of the more attractive M&A

Insights
Biotechnology
Buy/High Risk 1H
Price (19 Jun 08) US$38.11
Target price US$52.00
Expected share price return 36.4%
Expected dividend yield 0.0%
Expected total return 36.4%
Market Cap US$3,298M
IMCL Company Metrics
52-Week Range US$48.75–US$30.36
Div (E) Nil
Est. 5-Yr Growth 13.0%
P/E (12/08E) 41.3x
P/E (12/09E) 35.9x

US Portfolio Strategist
26 June 2008
Citi

[DewDiligence]

Preemptive treatment of EGFR rash:

http://biz.yahoo.com/bw/080626/20080626006165.html

[Biowatch]

Interactive webcast on colorectal cancer June 30

Explore These Critical Case Reviews:

* Frontline Metastatic Colorectal Cancer:
Unresectable Liver Metastases
* Frontline Metastatic Colorectal Cancer:
Resectable Liver Metastases
* Adjuvant Treatment for Colorectal Cancer:
Stage II and Stage III
* Refractory Colorectal Cancer

For continuing medical education credit (i.e., intended for clinicians.)

http://tumorboard.stream57.com/June08/

[jbog]

ASCO 2008: The Practice-Changing Findings
2008 Jun 18, Lee Schwartzberg, MD, Editor-in-Chief

I always approach ASCO with an almost palpable sense of excitement. As the premier venue for presentation of important cancer clinical trials, ASCO holds out the promise each year that I may hear about breakthrough study results that are strong enough—even based on the weight of 1 trial—to literally change practice when I return from the meeting.



In reality, this happens only rarely. However, in recent memory, I think that the presentation of the adjuvant trastuzumab data in 2005 was perhaps the most emotional and transformative ASCO session I have witnessed in almost 25 years of attending the meeting, and I believe that most oncologists would agree with me on that score. A well-deserved standing ovation greeted the results, and, overnight, oncologists changed the way they treated HER2-positive breast cancer—even if insurers and the FDA took a lot longer to follow suit.



So, after reviewing the ASCO 2008 abstract book in advance and waiting for the plenary and late-breaking abstracts to be distributed on site, the question I pondered was, what would be this year's practice-changing presentations? Now that I’ve had time to reflect on ASCO 2008, I feel that while none of the presented studies had breakthrough results per se, several key findings with the potential to alter practice were reported.



Gastrointestinal cancers

The KRAS story in MCRC. Previous reports have indicated that monoclonal antibody–mediated epidermal growth factor receptor (EGFR) inhibition appears to be more effective in the 50% to 60% of patients with metastatic colorectal cancer (MCRC) tumors that express wild-type KRAS, compared with those who harbor a mutated KRAS gene. This makes biologic sense, given that EGFR signals downstream through KRAS, and a mutated gene could be constitutively active, preventing modulation from upstream signaling. Multiple retrospective analyses presented at ASCO this year firmly established the KRAS story. Most notable was an analysis of the large phase III Cetuximab Combined with Irinotecan First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, a study first presented at last year’s ASCO. This study randomized patients to receive FOLFIRI plus cetuximab as first-line therapy for MCRC. When analyzed by KRAS mutation status, the results were striking: A 32% improvement in progression-free survival and significant improvement in response rate were observed in patients with wild-type KRAS tumors who received cetuximab. In contrast, patients harboring a mutant KRAS gene derived no benefit from cetuximab.



Other retrospective analyses included a randomized phase II trial of FOLFOX plus cetuximab, which showed similar findings, as did a smaller retrospective analysis of cetuximab in irinotecan-refractory patients. Taken together, the cetuximab studies—along with similar previously reported findings from patients treated with panitumumab, another monoclonal EGFR inhibitor—provided strong evidence that essentially all the benefit from EGFR inhibitors occurs in wild-type KRAS tumors. Moreover, sorting patients by KRAS markedly improves the benefit of monoclonal antibody EGFR inhibition.



It is relatively simple to obtain KRAS status from paraffin-embedded primary tumor samples at commercial laboratories in a fairly short time frame. Thus, this approach should now become the standard of care for MCRC. Patients with wild-type KRAS could be considered for first-line FOLFIRI plus cetuximab followed by second-line FOLFOX and bevacizumab as 1 new approach to the paradigm of exposing patients to all active drugs in MCRC. Of course, many other combinations or approaches are conceivable as well. As soon as I came back from ASCO, I informed my practice that KRAS status should be ascertained in all newly diagnosed MCRC patients.



Adjuvant gemcitabine in pancreatic cancer. Also noteworthy in the gastrointestinal tumor area was a positive study of gemcitabine in the adjuvant treatment of pancreatic cancer after a primary resection, whether or not patients achieved an R0 status. A doubling of long-term (5-year) survival was achieved after a 6-month course of adjuvant gemcitabine. Notably, no postoperative radiation therapy was given in this trial. This approach thus becomes a new treatment option for patients who undergo resection, an encouraging development in a poor-prognosis group.



Breast cancer

ABCSG-12 trial. The primary results of the Austrian Breast and Colorectal Cancer Study Group-12 (ABCSG-12) trial were most interesting. This trial compared the aromatase inhibitor (AI) anastrozole with tamoxifen (along with goserelin to achieve ovarian suppression) and also compared zoledronic acid given IV every 6 months with placebo. Zoledronic acid improved both disease-free survival (DFS) by a significant 36% and relapse DFS at a median of 5 years of follow-up. A trend toward improved overall survival (OS) was also observed. No significant increase in serious adverse events was noted with the addition of zoledronic acid. Importantly, the 94% DFS and 98.2% OS for the entire study group represent a remarkable achievement, demonstrating the power of adjuvant endocrine therapy in an estrogen receptor–positive group of breast cancer patients.



While the ASCO discussant of this paper did not feel that this single trial was sufficient basis to make a practice-changing decision, I respectfully disagree. The secondary endpoint of this trial, improvement in bone density for the zoledronic acid group, has been reported previously and shows a clear benefit of the addition of this potent bisphosphonate in maintaining bone mineral density. Moreover, other trials in which zoledronic acid was given along with AIs in postmenopausal women have shown similar results. Therefore, the preponderance of evidence supports the view that twice-yearly IV administration of zoledronic acid in hormone receptor–positive patients receiving AIs or premenopausal patients receiving ovarian suppression plus tamoxifen is a reasonable therapeutic choice, particularly given the apparent improvement in breast cancer–specific outcome, as well as the preservation of bone health. This therapy will be a serious consideration for me as I see my next patients who fit this profile.



Lung cancer

FLEX trial. As in other human malignancies, the role of EGFR in non–small cell lung cancer (NSCLC) continues to be a major and ever-expanding focus of research and treatment. Small-molecule tyrokinase inhibitors of EGFR show clear benefit in certain subgroups of NSCLC. The First-Line in Lung Cancer with Erbitux (FLEX) study, presented at the ASCO plenary session this year, assessed the addition of the monoclonal EGFR inhibitor cetuximab to chemotherapy with cisplatin and vinorelbine in stage IIIB/IV NSCLC. Eligibility criteria included EGFR expression by immunohistochemistry, defined as >1 positive tumor cell. The vast majority (85%) of screened patients met this criterion. Patients randomized to the active treatment arm received a median of 4 cycles of chemotherapy and a median of 18 weeks of cetuximab. Of these patients, 80% were eligible for maintenance cetuximab therapy, which continued until disease progression. Over half the patients in both groups received post–first-line treatment.



The study was significantly positive for its primary endpoint, OS, with a hazard ratio of 0.87; this translated to a net improvement in median survival of 1.2 months. Response rate was significantly increased as well, but progression-free survival was not. Serious adverse events that occurred more commonly in the cetuximab treatment group were a 10% incidence of grade 3 rash and a statistically significant, but numerically small, increase in febrile neutropenia and infusion reactions.



These findings open the door to a new option for patients with advanced NSCLC. In particular, for the large group of patients who are ineligible for bevacizumab-containing regimens for 1 reason or another, the addition of cetuximab to a platinum-based doublet becomes an attractive alternative. The landscape of NSCLC has finally changed with the addition of biologicals, allowing a significant number of patients to experience meaningful improvements in OS and quality of life.



The virtual meeting

ASCO has become an incredibly huge and complex event that is very difficult for the generalist oncologist to negotiate. Indeed, community-based American oncologists seemed to be underrepresented at this year’s meeting, which, as a record gathering of the world’s cancer community, spawns an enormous number of secondary symposia, advisory boards, and business meetings occurring outside the scientific discussions.



One morning at the convention center, I found it very interesting that while I was trying to get to a clinical science session, I was among only a few individuals walking toward a huge meeting room against the tide of a veritable sea of individuals coming out of the hall. I panicked. What unbelievably important finding in the program had I missed that so captivated the vast hoard of attendees? When I finally made it inside the room, I found out that everyone had just attended the Highlights of the Day session, consisting of summaries of selected presentations from the previous day by experts in the field.



These overview discussions are a welcome addition to ASCO. However, I believe that there is no substitute for hearing the primary data from the principal investigator who conducted the study. So my bias is to encourage attendees to go to the sessions that pique their interest to hear the data themselves, to walk through the poster sessions to speak to the investigators, and to participate in the clinical science symposia to learn about state-of-the-art translational research. Of course, even those who share my bias and want to hear the data first hand cannot possibly go to every session of interest, however. Thankfully, the technology that is now employed by ASCO allows almost every session to be available on the society’s website in both video and slide form, including the Highlights of the Day discussions.



While the wonderful days of Dr. James Holland getting up after every oral session to ask a cogent question about study design are gone, occasionally one still hears a dramatic debate or thought-provoking discussions at an annual meeting. There is plenty of time for reading a secondary analysis of the data in the weeks and months after the meeting. Today’s technology enables the enormous amount of information presented in both oral and poster form at ASCO to be available electronically in an enduring fashion, providing all oncologists, whether they made the journey to Chicago or not, with the ability to learn from and ponder about the data. The virtual meeting itself is therefore potentially practice changing.



Conclusions

ASCO 2008 again confirmed that steady, solid progress—coupled with the occasional breakthrough—is being made in the treatment of human cancers. Behind these practice-changing trials is a huge array of preclinical and early and late clinical developments presented at the meeting, which sets the stage for the next series of dramatic therapeutic advances.

[corky]

http://icahnreport.com/

[Stock]

Within the TOU, of course. Unless you are Martha Stewart.

[caravon]

This MB has no moderator. It is good.

This MB can provide free flow of ideas and information without any censorship.

[biophud]

IMCL intrabody patent

http://www.wipo.int/pctdb/en/fetch.jsp?SEARCH_IA=US2007083222&DBSELECT=PCT&C=10&TOTAL=73&IDB=0&TYPE_FIELD=256&SERVER_TYPE=19-10&QUERY=%28FP%2Fimclone%29+&ELEMENT_SET=B&START=1&SORT=41238427-KEY&RESULT=1&DISP=25&FORM=SEP-0%2FHITNUM%2CB-ENG%2CDP%2CMC%2CAN%2CPA%2CABSUM-ENG&IDOC=1531780&IA=US2007083222&LANG=ENG&DISPLAY=STATUS

biophud

[biophud]

T-cells and anti-EGFR therapy

http://www.ncbi.nlm.nih.gov/pubmed/18481381?dopt=AbstractPlus

biophud

[biophud]

EGFR extracellular polymorphism associated with response to Erbitux.

http://www.ncbi.nlm.nih.gov/pubmed/18544172?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

biophud

[DewDiligence]

#msg-29792371

[jbog]

KRAS predicts response to cetuximab for CRC
Published: 02/06/2008 - PDF Version (83 KB)



KRAS status predicts whether patients with newly diagnosed metastatic colorectal cancer will respond to cetuximab

A multinational team of investigators has discovered that patients whose tumours contain the normal form (wild-type) of the gene KRAS are most likely to benefit from the addition of cetuximab (Erbitux) to chemotherapy as part of first-line treatment of metastatic colorectal cancer, compared to patients who have a mutation in the KRAS gene. Cetuximab is a targeted therapy that blocks the epidermal growth factor receptor (EGFR), common in many types of cancer.


"While our initial study indicated that cetuximab has the potential to become part of the standard treatment for patients with newly diagnosed metastatic colorectal cancer, this study helps us to identify which patients are most likely to benefit from adding the drug to treatment," said Eric Van Cutsem, MD, PhD, professor at the University Hospital Gasthuisberg in Leuven, Belgium, and the study's first author.

"KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient."

KRAS mutations, which are found in 30 to 45 percent of all colorectal tumours, have previously been shown to predict whether patients will benefit from EGFR-inhibiting drugs in the second-line or later setting. The CRYSTAL trial was the first randomized study to compare patients who received chemotherapy alone to those who received chemotherapy plus cetuximab as part of initial therapy.

Researchers presented data last year that showed that adding cetuximab to a chemotherapy regimen known as FOLFIRI resulted in longer progression-free survival than treatment with chemotherapy alone.

The current study is an extension of that trial and sought to determine whether certain subsets of patients benefited more from the addition of cetuximab than others.

Researchers had access to tumour material from 587 of the 1,198 patients in the original trial, and used these samples to determine each patient tumour's KRAS status. KRAS mutations were detected in 35.6 percent of patients' tumours. Investigators found that among patients with normal KRAS, 59.3 percent responded to treatment with chemotherapy and cetuximab (their tumours shrank by more than half), compared to 43.2 percent who responded to chemotherapy alone. Among patients with mutated KRAS in their tumours, there was no difference in response rates between those who received chemotherapy alone and those who received chemotherapy and cetuximab.

In the overall study including all patients, the addition of cetuximab to FOLFIRI resulted in a 15 percent decreased risk for progression. When KRAS was evaluated, the normal KRAS gene group was shown to have a 32 percent decreased risk for progression from the addition of cetuximab. Patients with a mutant KRAS gene in their tumour did not have additional benefit from adding cetuximab to chemotherapy.

[jbog]

Lung cancer: Cetuximab and platinum chemo
Published: 02/06/2008 - PDF Version (81 KB)

Cetuximab plus platinum-based chemotherapy improves survival for patients with newly diagnosed advanced lung cancer

A large phase III study announced in Chicago at ASCO 2008, has found that the targeted therapy cetuximab (Erbitux), combined with platinum-based chemotherapy, is effective as a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). This is the first time a targeted drug has shown a survival benefit as a first-line treatment for patients with NSCLC, including all subtypes of the disease.

Lung cancer is the leading cause of cancer death among men and women, with 161,840 lung cancer deaths expected this year in the United States alone. NSCLC is the most common type of lung cancer, comprising 85 to 90 percent of all cases; more than 80 percent of NSCLC patients have tumours that express the EGFR gene. For patients with the most advanced form of the disease, one-year survival is about 30 percent and five-year survival is just 1 to 2 percent.

"Patients with advanced NSCLC have limited treatment options and life expectancy is short, so the survival increase shown in this study is an important step for these patients" said Robert Pirker, MD, an associate professor of medicine at Medical University of Vienna in Austria and the study's lead author. "These results clearly establish cetuximab in combination with chemotherapy as a new standard in first-line treatment of NSCLC."

This study evaluated the addition of the EGFR antibody cetuximab to platinum-based chemotherapy (cisplatin and vinorelbine). The current standard of care for newly diagnosed patients with advanced NSCLC is platinum (either cisplatin or carboplatin) combined with a 'third-generation drug' (vinorelbine, gemcitabine, paclitaxel or docetaxel). Earlier studies of different EGFR-targeted drugs, also called tyrosine kinase inhibitors (gefitinib and erlotinib), did not to show an additional benefit to first-line standard chemotherapy and are currently approved for patients whose initial chemotherapy has failed.

In this study, 1,125 patients in 30 countries were randomized to receive either chemotherapy alone (568) or chemotherapy plus cetuximab (557); 94 percent had stage IV disease (meaning the cancer had spread to other parts of the body). Overall survival was higher for those who received cetuximab plus chemotherapy (11.3 months) compared to those receiving chemotherapy alone (10.1 months). Additionally, the response rate was better in the chemotherapy plus cetuximab arm (36.3 percent) versus chemotherapy alone (29.2 percent). The benefit of cetuximab was seen in patients with all histological subtypes of NSCLC, including adenocarcinoma and squamous cell carcinoma, the two most common subtypes. Other targeted therapies for lung cancer have only proven effective against certain subtypes. As expected, the most frequent side effect was an acne-like rash, which was manageable with medication. Moderate rashes were seen more frequently in patients receiving cetuximab (10.4 percent) than in patients receiving chemotherapy alone (0.2 percent).

The authors state that based on these findings, there will be more studies evaluating cetuximab in earlier stages of the disease, such as in combination with chemotherapy or chemoradiotherapy in patients with locally advanced disease or as an additional treatment after surgery in patients with early-stage disease.

[DewDiligence]

Forbes muses on how data for the KRAS biomarker
will affect Erbitux sales in colorectal cancer:

#msg-29705823

Comments?


Let’s talk biotech!
“The efficient-market hypothesis may be
the foremost piece of B.S. ever promulgated
in any area of human knowledge!”

[DewDiligence]

The death of the ASCO leak has been greatly exaggerated:
#msg-29702902.

[genisi]

Merck KGaA says Erbitux receives positive opinion from EU's CHMP

UPDATE| 30 May 2008 | 10:04 AM ET

Merck KGaA said it received a positive opinion from the European Committee for Human Medicinal Products (CHMP) for the use of its cancer drug Erbitux as a first-line treatment of metastatic colorectal cancer in patients with a certain type of tumor.

The CHMP recommends the use of Erbitux in patients who have tumours with the KRAS wild type gene, in combination with chemotherapy, the company said in a statement.

Merck said trials showed that adding Erbitux to standard chemotherapy treatment increased the efficacy compared with chemotherapy. In patients with KRAS wild-type tumours, this effect was even more pronounced, it said.

Up to 65 percent of patients with metastatic colorectal cancer have tumours with the KRAS gene. Merck said that its cancer drug may become less efficient if the KRAS gene has mutated.

Following the CHMP's recommendation, the German drugmaker will change its labels to take into consideration patients' KRAS mutational status.


URL: http://www.cnbc.com/id/24890527/for/cnbc/

[jbog]

MRK:GR
Merck KGAA
ImClone's Erbitux Prolongs Life in Lung Cancer Study (Update3)

By Tom Randall and Michelle Fay Cortez

May 31 (Bloomberg) -- ImClone Systems Inc.'s only drug, Erbitux, extended life by five weeks for lung cancer patients in a study that may help partners Bristol-Myers Squibb Co. and Germany's Merck KGaA win regulatory approval for the new use.

The results could make Erbitux, approved for colon tumors and head and neck malignancies, the preferred therapy for half of non-small cell lung cancer patients who can't take Genentech Inc.'s Avastin because of side effects. Erbitux may work as well as Avastin in some patients who qualify for both drugs, ImClone Chief Executive Officer John Johnson said today in an interview.

Suspense over the outcome of the trial, called Flex, has made the research the top attraction at the American Society of Clinical Oncology meeting in Chicago, where more than 4,000 scientific studies are being presented. Doctors are looking for new ways to fight lung cancer, which killed 161,840 Americans last year, according to the National Institutes of Health.

``Patients with advanced non-small cell lung cancer have limited treatment options and life expectancy is short,'' said lead researcher Robert Pirker, associate professor of medicine at the Medical University of Vienna in Austria. ``The survival increase shown in this study is an important step for these patients.''

With the five-week improvement, doctors treating patients who can't take Avastin will choose Erbitux, adding more than $700 million in annual U.S. sales and boosting shares by 35 percent, said Cowen & Co. analyst Eric Schmidt. Less than $200 million in lung cancer sales have been factored into ImClone's price, he said.

Additional Sales

The findings matched what investors were expecting and aren't dramatic enough to cut deeply into Avastin's ``well entrenched'' position for treating lung cancer patients that can be helped by the drug, Schmidt said in a telephone interview today.

Lung tumors are the most common type of cancer in the U.S. It is diagnosed in more than 215,000 people annually, according to the American Cancer Society. The study included 1,125 patients with advanced non-small cell lung cancer, the most common form of the disease, who hadn't been previously treated.

``A 1,100 patient randomized trial that has a significant survival advantage in lung cancer can't be ignored,'' said Martin Birkhofer, Bristol's vice president of oncology. ``We fully intend to discuss the data with the FDA'' for U.S. approval in lung cancer, he said.

Only about 30 percent of patients with the most advanced forms of the disease, such as those who participated in the study, typically are alive one year after the diagnosis. The five year survival rate is 2 percent or less.

Survival Benefit

In the study, patients getting Erbitux, also known as cetuximab, plus standard chemotherapy had a median survival of 11.3 months, compared with 10.1 months for those given only chemotherapy. More than one in three patients, or 36.3 percent, responded to the combination therapy, compared with 29.2 percent who improved after getting only chemotherapy, the study found.

``Any time you have a significant survival benefit in lung cancer, that's important because it's such a common disease,'' said Roy Herbst, chief of thoracic medical oncology at the University of Texas MD Anderson Cancer Center, in an interview. ``Even incremental progress is good. This is momentum in the right direction,'' he said.

While the Erbitux data wasn't as positive as an earlier trial with Avastin, the patient mix wasn't the same, Herbst said. That makes it impossible to compare the two medications directly to each other, he said. Now doctors and patients will have a choice of drugs, and the decision may come down to side effects, the dosing and further analysis of the data, he said.

``This is important, but I think that more work needs to be done to see which patients really benefited and who should get it first,'' Herbst said.

Lung Cancer Types

Patients with all types of the non-small cell lung cancer benefited from treatment, including those with adenocarcinoma and squamous cell carcinoma, the most common forms. Avastin isn't given to patients with squamous cell cancers or with certain blood disorders, about half the lung cancer population.

Among white patients with adenocarcinoma, who are eligible to take Avastin, patients lived 1.8 months longer with Erbitux and chemotherapy than with chemotherapy alone, making the two drugs comparable among those groups, ImClone's Johnson said.

``For lung-cancer patients, this is just really exciting news,'' Johnson said. ``Less than one in five patients get Avastin. There's a huge opportunity outside of that, and our data is very competitive even in that set against Avastin.''

Asian patients, who in general have a better prognosis, didn't get any additional benefit from adding Erbitux.

Drug Mechanism

Avastin works by starving a tumor of its blood supply. Doctors are reluctant to prescribe it for patients whose illness might be complicated by blood disorders or anti-clotting drugs, according to Bob Mass, cancer medical director at Genentech.

Erbitux blocks receptors that regulate growth of tumors and doesn't have the same side effects as Avastin. Both drugs work on a form of the disease called non-small cell lung cancer, which affects as much as 90 percent of patients, according to the American Cancer Society.

The study of patients from Europe, Asia and Latin America, was conducted and funded by Merck KGaA, which is based in Darmstadt, Germany. ImClone and Bristol-Myers are based in New York.

To contact the reporter on this story: Tom Randall in New York at [e-mail].

[jbog]

http://www.abstract.asco.org/AbstView_55_30338.html


FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC).
Sub-category: Metastatic Lung Cancer
Category: Lung Cancer--Metastatic Lung Cancer
Meeting: 2008 ASCO Annual Meeting




Abstract No: 3
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 3)
Author(s): R. Pirker, A. Szczesna, J. von Pawel, M. Krzakowski, R. Ramlau, K. Park, U. Gatzemeier, E. Bajeta, M. Emig, J. R. Pereira
Abstract: Background: Epidermal growth factor receptor (EGFR) dysregulation is common in NSCLC and is associated with poorer prognosis. This phase III study assessed the efficacy and safety of the EGFR-targeted monoclonal antibody cetuximab in combination with cisplatin/vinorelbine (CV) compared with CV alone in advanced NSCLC. Methods: Patients with EGFR-detectable advanced NSCLC were randomized 1:1 to cetuximab (400 mg/m2 initial dose, then 250 mg/m2/wk) plus C (80 mg/m2 d1) and V (25 mg/m2 d1, d8) q3w (arm A) or CV alone (arm B). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival, tumor response, disease control, and safety. Randomization was stratified by ECOG performance status (0/1 vs 2) and tumor stage (wet IIIb vs IV). Results: 1,125 patients were randomized: 557 to arm A, 568 to arm B, 70% male, median age 59 (18-83) years, 94% stage IV, 47% adenocarcinoma (AC), 34% squamous cell carcinoma (SCC), 83% ECOG 0/1. Survival analysis was performed after 868 events had occurred. OS was significantly improved in arm A (stratified log-rank test). Preliminary results of prespecified subgroup analyses suggest a greater benefit in Caucasians independent of histology and a general better prognosis in Asians. Analyses of secondary endpoints are ongoing. Conclusions: Cetuximab plus CV demonstrated superior survival over CV alone in patients with advanced EGFR-detectable NSCLC. There was a remarkable difference between the outcome of Asian and Caucasian patients. This is the first study to demonstrate a survival benefit of an EGFR-targeted agent in combination with platinum-based chemotherapy in advanced first-line NSCLC irrespective of histology and confirms the clinical relevance of cetuximab in NSCLC. Median
OS (mo)
Arm A Median
OS (mo)
Arm B HR [95% CI] p-value
All (n=1125) 11.3 10.1 0.871 [0.762- 0.996] 0.0441
Caucasians (n=945) 10.5 9.1 0.800 [0.692-0.924] 0.0025
with AC (n=412) 12.0 10.2 0.809 [0.644-1.016] 0.0673
with SCC (n=347) 10.2 8.9 0.794 [0.626-1.007] 0.0567
Asians (n=121) 17.6 20.4 1.179 [0.730- 1.905] 0.4992
HR, hazard ratio

[DewDiligence]

What was the HR and p-value for OS in the entire trial?? The PR gives these metrics for only the Caucasian subset.


Let’s talk biotech!
“The efficient-market hypothesis may be
the foremost piece of B.S. ever promulgated
in any area of human knowledge!”

[corky]

Erbitux Significantly Prolongs Survival in 1st-Line Treatment of Non-Small Cell Lung Cancer
Chicago and Darmstadt, Germany (ots/PRNewswire) -

- New Data Provides the Basis for the Future Role of Erbitux (cetuximab) as a Standard in Combination With Platinum-Based Chemotherapy in the 1st-Line Treatment of Patients With Non-Small Cell Lung Cancer (NSCLC)

- Location: ...

Chicago and Darmstadt, Germany (ots/PRNewswire) -

- New Data Provides the Basis for the Future Role of Erbitux (cetuximab) as a Standard in Combination With Platinum-Based Chemotherapy in the 1st-Line Treatment of Patients With Non-Small Cell Lung Cancer (NSCLC)

- Location: Annual Meeting of the American Society of Clinical Oncology (ASCO) 2008, Chicago, USA

The addition of Erbitux(R) to a platinum-based chemotherapy significantly increased overall survival in the 1st-line treatment of NSCLC.(1) This data was presented today at the plenary session of the 44th American Society of Clinical Oncology (ASCO) congress. The new findings confirm that Erbitux is the first targeted therapy to show a significant survival benefit in NSCLC patients across all histological subtypes.

"Lung cancer is notoriously difficult to treat and these results are particularly exciting as they represent one of the most significant advancements in the treatment of NSCLC in 10 years," commented Professor Robert Pirker, lead investigator and Professor of Clinical Oncology at the University of Vienna, Austria. "This opens new 1st-line treatment options for NSCLC patients, regardless of histological type of cancer and sets a new standard in the treatment of 1st-line NSCLC."

In the pivotal multinational, Phase III FLEX(a) trial, more than 1,100 patients with stage IIIB/IV NSCLC were randomized to receive Erbitux plus standard platinum-based chemotherapy or chemotherapy alone. The results demonstrated that in the 1st-line setting, patients treated with Erbitux experienced significant benefits in overall survival. Median overall survival was prolonged by 1.2 months in the combination arm compared to those receiving chemotherapy alone (11.3 vs 10.1 months).(1)

Patients from the major treatment group (Caucasians, representing 84% of the trial population) experienced a significant increase in overall survival of 1.4 months compared to those receiving chemotherapy alone, reflected also in a hazard ratio of 0.8 (p=0.003). In this group, patients with adenocarcinoma receiving Erbitux had a survival benefit of 1.8 months compared to those in the control arm.(1)

The FLEX trial included patients with all histological subtypes, including adenocarcinoma and squamous cell carcinoma, as well as ECOG 2 patients who have much worse prognosis than patients with a better performance status. "Since 94% of patients in the Erbitux plus chemotherapy arm had stage IV metastatic NSCLC and 17% had performance status 2, these data are not only robust, but also very meaningful for the everyday clinical reality in the treatment of 1st-line NSCLC," commented Dr. Wolfgang Wein, Executive Vice President, Oncology, at Merck KGaA, Darmstadt, Germany. "This is a further verification of the outstanding quality of Erbitux specifically and the oncology program at Merck KGaA in general."

Erbitux was found to be well tolerated in the trial with manageable and expected side effects across the populations.(1)

The current standard treatment for 1st-line NSCLC includes a variety of platinum-based chemotherapy doublets.(2) To date, Erbitux is the first targeted therapy to show a significant survival benefit in a broad population of patients - including all histological subtypes - in the 1st-line treatment of NSCLC when added to standard chemotherapy. The FLEX data support the outcomes of earlier studies investigating Erbitux in combination with standard chemotherapies in the 1st-line treatment of NSCLC, in which the addition of Erbitux increased response rate and overall survival.(3),(4)

Worldwide, lung cancer is the leading cause of cancer death in men and the second leading cause of cancer death in women.(5) Approximately 975,000 men and 376,000 women die from the disease each year.(6) NSCLC accounts for around 80% of lung cancers. Most patients with NSCLC present with advanced disease which is difficult to treat.(7) The overall five-year survival rate for lung cancer is about 16%, compared to 65% for colon cancer, 89% for breast cancer and 99% for prostate cancer.(8)

(a). FLEX: First-line in Lung cancer with ErbituX References (1). Pirker R, et al. ASCO 2008;Abstract No: 3. (2). Pfister D, et al. J Clin Oncol 2004;22:330-353. (3). Butts C, et al. J Clin Oncol 2007;25:5777-5784. (4). Rosell R, et al. Ann Onc 2008;19:362-369. (5). Kamangar F, et al. J Clin Oncol 2006;24:2137-2150. (6). Global Cancer Facts & Figures 2007, American Cancer Society. (7). Corner J, et al. Thorax 2005;60(4)314-319. (8). Lung Cancer Information (www.medicinenet.com, accessed May 2008).

About ERBITUX

ERBITUX(R) is a first-in-class and highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth.

The most commonly reported side effect with Erbitux is an acne-like skin rash that seems to be correlated with a good response to therapy. In approximately 5% of patients, hypersensitivity reactions may occur during treatment with Erbitux; about half of these reactions are severe.

Erbitux has already obtained market authorization in 72 countries. It has been approved for the treatment of colorectal cancer in 71 countries so far: Argentina, Australia, Belarus, Canada, Chile, China, Colombia, Costa Rica, Croatia, Dominican Republic, Ecuador, El Salvador, the European Union, Guatemala, Honduras, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Lebanon, Liechtenstein, Malaysia, Mexico, New Zealand, Nicaragua, Norway, Oman, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Africa, South Korea, Switzerland, Taiwan, Thailand, Ukraine, Uruguay, the US, and Venezuela for use in combination with irinotecan in patients with EGFR-expressing mCRC who have failed prior irinotecan therapy. Erbitux is also approved for single-agent use in: Argentina, Australia, Canada, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Lebanon, Mexico, New Zealand, Nicaragua, Panama, Peru, the Philippines, Russia, Singapore, Thailand, the US, and Venezuela.

In addition, Erbitux in combination with radiotherapy has been approved for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) in 65 countries: Argentina, Australia, Belarus, Brazil, Chile, Colombia, Costa Rica, Croatia, El Salvador, the European Union, Guatemala, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Lebanon, Liechtenstein, Malaysia, Mexico, New Zealand, Nicaragua, Norway, Oman, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Africa, Switzerland, Taiwan, Ukraine, Uruguay, the US, and Venezuela. In Argentina, Chile, Costa Rica, El Salvador, Guatemala, Hong Kong, Israel, Lebanon, Mexico, Nicaragua, Peru, the Philippines, Russia, and the US, Erbitux is also approved as monotherapy in patients with recurrent and/or metastatic SCCHN who failed prior chemotherapy.

Merck licensed the right to market Erbitux outside the US and Canada from ImClone Systems Incorporated of New York in 1998. In Japan, ImClone Systems Incorporated, Bristol-Myers Squibb Company and Merck jointly develop and, upon approval, commercialize Erbitux. Merck has an ongoing commitment to the advancement of oncology treatment and is currently investigating novel therapies in highly targeted areas, such as the use of Erbitux in colorectal cancer, squamous cell carcinoma of the head and neck and non-small cell lung cancer. Merck has also acquired the rights for the cancer treatment UFT(R) (tegafur-uracil) - an oral chemotherapy administered with folinic acid (FA) for the 1st-line treatment of metastatic colorectal cancer.

Merck is also investigating among other cancer treatments the use of Stimuvax(R) (formerly referred to as BLP25 Liposome Vaccine) in the treatment of non-small cell lung cancer. The vaccine was granted fast-track status in September 2004 by the FDA. Merck obtained the exclusive worldwide licensing rights from Oncothyreon Inc., Bellevue, Washington, USA.

[corky]

Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from published series.
Sub-category:

Colorectal Cancer (including liver metastases)
Category:

Gastrointestinal (Colorectal) Cancer
Meeting:

2008 ASCO Annual Meeting

Abstract No:

4035
Citation:

J Clin Oncol 26: 2008 (May 20 suppl; abstr 4035)
Author(s):

F. Di Fiore, E. Van Cutsem, P. Laurent-Puig, S. Siena, M. Frattini, W. De Roock, A. Lièvre, A. Sartore-Bianchi, A. Bardelli, S. Tejpar
Abstract:


Background: Cetuximab, a monoclonal antibody (mAb) directed against the epidermal growth factor receptor (EGFR), is approved in combination with irinotecan (Iri) for the treatment of Iri-refractory metastatic colorectal cancer (MCRC) expressing EGFR. Recent studies have shown that KRAS mutation (mut) confers resistance to anti-EGFR mAbs. We extracted data of 281 patients (pts) from 7 series (Lievre 2006 and 2008, Moroni 2005, Di Fiore 2007, De Roock 2007, Benvenuti 2007, Frattini 2007) to determine the role of KRAS mut in Iri-refractory MCRC patients treated with cetuximab plus Iri based-chemotherapy (CT). Methods: The following data were collected: sex, age, previous CT lines, anti-EGFR regimen, response rate based on RECIST criteria, progression-free survival (PFS), overall survival (OS) and KRAS mutational status. Response rate was evaluated using the Fischer exact test. PFS and OS were calculated using the Kaplan-Meier method and compared with log-rank test. Predictive factors of response and survival were determined by logistic regression and Cox-regression model, respectively. Results: A total of 281 pts were included, 174 men and 107 women with a mean age of 59.8 yrs. Pts received a mean of 2.4 prior CT lines. 77 pts (27.4%) responded (3 complete response (CR) and 74 partial response (PR)), 107 (38.1%) had stable disease (SD) and 97 (34.5%) had disease progression (PD). A KRAS mut was detected in 98 pts including 40/107 (37.4%) pts with SD and 58/97 (59.8%) with PD. All responders were KRAS wild-type. KRAS mut was significantly associated with PD (p< 0.0001). Median PFS and OS were significantly lower in mutated KRAS pts, 12 weeks (wks) vs 24 wks (p<0.0001) and 36 wks vs 44 wks (p<0.0001), respectively. The absence of KRAS mut was identified as predictive factor of disease control (CR+PR+SD) (p<0.0001,OR:0.17;95IC:0.10-0.30) and OS (p<0.0001,OR:0.51;95IC:0.37-0.70), respectively. Conclusions: KRAS mutational status plays a key role in response rate, PFS and OS in Iri-refractory MCRC pts treated with cetuximab and Iri. Our results demonstrate the potentially major impact of KRAS mutation in pts selection.

[corky]

Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data).
Sub-category:

Colorectal Cancer (including liver metastases)
Category:

Gastrointestinal (Colorectal) Cancer
Meeting:

2008 ASCO Annual Meeting

Abstract No:

4001
Citation:

J Clin Oncol 26: 2008 (May 20 suppl; abstr 4001)
Author(s):

S. Tejpar, M. Peeters, Y. Humblet, J. B. Vermorken, G. De Hertogh, W. De Roock, J. Nippgen, A. von Heydebreck, C. Stroh, E. Van Cutsem
Abstract:


Background: We previously demonstrated in the EVEREST trial that, in pts with mCRC after failure of irinotecan-based therapy, the efficacy could be improved by escalating the dose of cetuximab in combination with standard-regimen irinotecan (180 mg/m2 q2w) compared with standard-dose cetuximab for pts with grade 0/1 skin reactions. It has been suggested that KRAS mutation status may be a predictor for tumor response to anti-EGFR treatment. The question remains of whether dose escalation is also able to induce response in pts with mutated KRAS. Methods: Pts with grade 0/1 skin reactions after 22 days of treatment with irinotecan and standard-dose cetuximab were randomized to receive standard dose (250 mg/m2) (Arm A) or escalated (up to 500 mg/m2) (Arm B) doses of cetuximab. Archived tissue from 77 of 89 randomized pts was analyzed for KRAS mutation status. Efficacy parameters were determined and compared with the outcome of KRAS mutation analysis. Results: In Arm A, 45 pts were randomized: 19 pts (42%) were KRAS wt, 19 pts (42%) were KRAS mt, and 7 pts (16%) were non-evaluable for the preliminary analysis. In Arm B, 44 pts were randomized and the figures were 28 (64%), 11 (25%), and 5 (11%), respectively. Updated data including PFS and additional correlations of KRAS status with ligands and mRNA predictive signatures will be presented. Conclusions: These data suggest that patients with KRAS wt achieve considerable benefit from irinotecan plus cetuximab treatment. Patients with KRAS mt did not profit from irinotecan plus cetuximab treatment and cetuximab dose escalation did not increase responses in these patients.
Response rate
Arm A Arm B
KRAS wt 4/19 (21.1%) 13/28 (46.4%)
KRAS mt 0/19 0/11

[corky]

KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience.
Sub-category:

Colorectal Cancer (including liver metastases)
Category:

Gastrointestinal (Colorectal) Cancer
Meeting:

2008 ASCO Annual Meeting

Abstract No:

4000
Citation:

J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000)
Author(s):

C. Bokemeyer, I. Bondarenko, J. T. Hartmann, F. G. De Braud, C. Volovat, J. Nippgen, C. Stroh, I. Celik, P. Koralewski
Abstract:


Background: Efficacy analyses of the randomized phase II OPUS trial have previously failed to show significant improvements in progression-free survival time (PFS) or overall response, although a significantly higher response rate was achieved in patients with good performance status (ECOG 0/1) and a significantly higher curative surgery rate for cetuximab added to FOLFOX versus FOLFOX alone in the first-line treatment of mCRC was observed. KRAS mutation status has been related to the efficacy of anti-epidermal growth factor receptor (anti-EGFR) targeted therapies in different cancer models. Efficacy analyses have been repeated to evaluate the influence of KRAS mutation status in first-line patients treated with standard therapy, with or without cetuximab, under controlled study conditions. Methods: Genomic DNA was isolated from archived tumor material. The KRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay. Best overall response and PFS time (IRC evaluation) are presented by KRAS mutation status. Results: In general, the population with tissue available for KRAS analysis (n=233) was representative of the overall intention- to-treat population (n=337) in terms of demographic and efficacy parameters. KRAS mutations were detected in 42% (99/233) of evaluable samples. Conclusions: These data suggest that the benefit from addition of cetuximab to standard treatment is higher for the population with wild-type KRAS. For patients with KRAS mutations, no benefit could be shown of adding cetuximab to FOLFOX in this study.PFS and overall response rate (RR) by KRAS mutation status
KRAS status Median PFS (mo) Cetuximab + FOLFOX Median PFS (mo) FOLFOX Overall RR (%) Cetuximab + FOLFOX Overall RR (%) FOLFOX
Wild-type 7.7 (n=61) 7.2 (n=73) HR:0.57 p=0.02 61 (n=61) 37 (n=73) p=0.01
Mutation 5.5 (n=52) 8.6 (n=47) HR:1.83 p=0.02 33 (n=52) 49 (n=47) p=0.11
HR, hazard ratio.

[lidopete]

WSJ
Drug Brings ImClone in From Cold
By RON WINSLOW
May 31, 2008

The big annual cancer confab known as ASCO is under way through Monday in Chicago, and it features a return to respectability of sorts for ImClone Systems Inc. after the company's long residency in the biotech doghouse.

ImClone's flagship drug, Erbitux, is the subject of two of the four papers selected for presentation at the American Society of Clinical Oncology's Sunday plenary session -- the showcase slots reserved for the meeting's most important new science.

That amounts to the most attention devoted to the drug at the meeting since 2001, when positive data from a colon-cancer study set Erbitux on a presumed fast track to helping launch the targeted-drug era now transforming cancer treatment.

But the Food and Drug Administration wasn't convinced, and the failure of ImClone founder Sam Waksal to forthrightly disclose the agency's misgivings resulted in an insider-trading scandal that landed both him and style-and-taste doyenne Martha Stewart in jail. Erbitux finally reached the market in 2004.

With the two plenary papers topping a list of some 80 scientific presentations about Erbitux and new drugs in ImClone's pipeline, "this is a breakthrough meeting for us," says John H. Johnson, who became ImClone's chief executive in August. It matters as well to Bristol-Myers Squibb Co., Imclone's North American marketing partner for Erbitux, and Merck KGaA of Germany, which sells the drug in Europe and which sponsored the two featured studies. Combined, the companies reported nearly $1.4 billion of Erbitux sales in 2007.

Analysts are divided about whether the high-profile science is good news for ImClone, with skeptics holding sway in advance of the meeting: its shares are off more than 11% since late April.

It is already known that in one of the featured studies, called Flex, adding Erbitux to chemotherapy improved survival as a first-line treatment for patients with advanced lung cancer. Sunday's presentation will reveal by how much. Some analysts doubt the benefit is enough for the drug to match up well against such rivals as Genentech Inc.'s Avastin. ImClone says whatever the results, half of lung-cancer patients can't take Avastin due to side effects, leaving a sizable new market for Erbitux.

The other study has broader implications. It looks at whether a genetic test will help predict which colon-cancer patients might benefit from Erbitux -- and which wouldn't. Previous smaller studies suggest that 40% of colon-cancer patients carry a mutation or biomarker that makes it unlikely they will respond to the drug. That, some analysts say, could shrink the colon-cancer market for Erbitux.

ImClone argues that therapy guided by biomarkers is the future of cancer treatment. "If you can use a biomarker to increase your probability of success, that's huge in our business," Mr. Johnson says. When drugs work, he adds, patients stay on them longer, offsetting the impact of a smaller market.

Other biomarker papers are on ASCO's agenda. The enduring news out of this meeting may be less about new drugs than about how to use current drugs better.

Write to Ron Winslow at [e-mail]

[corky]

hell they both could fall

[corky]

in nsclc and mcrc they will

corky

[masterlongevity]

no, i think they don't really compete

[p3analyze]

So my prediction is IMCL rises and DNA falls. Throwing in Panitumumab to the mix, 2 EGFr's against 1 VEGF, DNA will lose out.

[corky]

erbitux will be able to compete with avastin

[p3analyze]

how about erbitux eats half of avastin's lunch

[corky]

avastin no one will eat that for lunch


corky

[p3analyze]

so you don't think erbitux will eat avastin for lunch?