Prudential’s pancreatic-cancer notes
from the just-completed ASCO/GI meeting:
[c/o jbog2001]
HIGHLIGHTS
• We attended the annual ASCO GI conference held over the weekend in San Francisco.
• Of particular interest to us were updates on the pancreatic cancer front.
• Genentech’s Avastin and Imclone’s Erbitux are anticipated to fully enroll their respective pancreatic cancer trials in March/April 2006 with survival data available in late 2006/early 2007.
• Full pancreatic cancer results for the two Phase III trials are anticipated at the annual ASCO meeting in 2007.
• There is still a debate on the benefit of the Gemcitabine/Tarceva experience in pancreatic cancer.
• As data mature on Phase III trials of Avastin, Erbitux and Oxaliplatin, the standard of care is likely to change. We estimate a market opportunity of approximately $1B for targeted therapies.
DISCUSSION
We attended the American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium covering multidisciplinary approaches to gastrointestinal malignancies and premalignancies. Of particular interest to us are the role of targeted therapies, such as Genentech’s Avastin (bevacizumab), Amgen’s Panitumumab (ABX-EGF), Imclone’s Erbitux (cetuximab), and OSI Pharmaceuticals’ Tarceva.
Targeted Therapies and Pancreatic Cancer
The Phase III trials of Avastin and Erbitux are the primary interests of physician attendees at the meeting. The general feeling was that pancreatic cancer treatment will evolve from a Gemcitabine backbone to one that adds a targeted therapy. The backbone may eventually be a doublet (e.g., Gemcitabine combined with a platinum agent, such as oxaliplatin or cisplatin), and targeted therapy may involve more than one agent – Avastin, Erbitux, Tarceva, Panitumumab, etc. For example, we expect a Phase II Gemcitabine/Cisplatin/Avastin trial to open in 2006
We anticipate full enrollment of the Phase III Erbitux and Avastin pancreatic cancer trials in March and April 2006, respectively. Conference presenters notified attendees that the Erbitux trial (SWOG S0205) was approximately 95% enrolled with a goal of 704 patients. The Avastin trial (CALGB 80303) is approximately 80% enrolled with a goal of 590 patients.
Though the Avastin trial lags behind the Erbitux one, it is believed that once the latter is fully enrolled that there will be an uptick in the former, resulting in full enrollment for Avastin around April 2006.
Both trials are enrolling ahead of schedule. The Erbitux trial opened in late 2003/early 2004 with an intent of enrolling over five years. It should achieve this goal in just under half of this time. The Avastin trial opened in the second half of 2004 with an intent of enrolling in just over two and a half years (Aug/Sept 2006), it should achieve this in less than two years.
We anticipate overall survival data for both Phase III pancreatic trials in late 2006/early 2007. Both trials are 90% powered to detect an approximate 33% increase in median overall survival from 6 to 8 months. The Erbitux trial is seeking a 33% improvement (6 to 8 months), while the Avastin trial targets a 35% improvement (6 to 8.1 months).
Phase III results for both trials are anticipated at the annual American Society of Clinical Oncology (ASCO) meeting in May/June 2007. Based on a median survival of 6 months for Gemcitabine-treated patients and potentially 8 months for Gemcitabine/targeted therapy treated patients, the top line results should be available in late 2006/early 2007 with full data presentations in May/June 2007. There is an outside chance that these datasets may be available for the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is November 7-10, 2006 in Prague, Czech Republic.
Phase III safety data may be available at the annual American Society of Clinical Oncology (ASCO) meeting in June 2006. We believe that at least Avastin will have a safety update at this year’s ASCO meeting. There may be several reasons for this. First, there is already off label use of Avastin in pancreatic cancer. In an informal poll of approximately 100 doctors at a corporate symposium, 14% of attendees reported using Gemcitabine/Avastin for the treatment of pancreatic cancer. If this trend were to continue, it would be in Genentech’s interests to ensure that it is done in the safest of manners. Second, there are two suspected deaths from bowel perforation in the Phase III trial. While this adverse event is known to be associated with Avastin, Genentech again would want to ensure that the biologic is used in the safest of ways. Finally, we believe that Genentech is motivated to demonstrate Avastin’s efficacy in other indications, and that the safety update may seed the marketplace for later efficacy supplements.
Imclone’s Erbitux Trial
The Erbitux trial is sponsored by the Southwest Oncology Group (SWOG S0205). It is a Phase III trial that randomizes 704 patients to Gemcitabine with or without Erbitux. It has a 90% power to detect a 33% increase in median overall survival (OS) from 6 to 8 months. We believe that the trial is approximately 95% accrued with full enrollment anticipated in March 2006.
Erbitux trial enrollment may have benefited from results of another anti-EGFR study. Physicians anecdotally commented that the positive results of the PA3 study, which added the oral, small molecule EGFR inhibitor, Tarceva (DNA/OSIP/RHHBY), to Gemcitabine, may have subtly added interest in the Erbitux trial based on the shared mechanism of action. This was compounded by Erbitux’s proven benefit in other gastrointestinal (GI) disorders, such as colorectal cancer (CRC) – an area, which Tarceva has not been of significant impact.
Other Erbitux Trials of Note
The CetCisGem trial is a Phase II study of the Gemcitabine/Cisplatin doublet in combination with Erbitux. It is sponsored by either Bristol Myers Squibb or Merck KGaA. The trial will be performed with molecular profiles. There were no updates on this trial at the meeting.
Genentech’s Avastin Trial
The Avastin trial is sponsored by the Cancer and Leukemia Group B (CALGB). It is a Phase III trial that randomizes 590 patients to Gemcitabine with or without Avastin. It has a 90% power to detect a 35% increase in median overall survival (OS) from 6 to 8.1 months. We believe that the trial is approximately 80% accrued with full enrollment anticipated in April 2006.
Tarceva and Pancreatic Cancer
Tarceva has not been established as a standard of care in pancreatic cancer. It is one of two Phase III studies to now demonstrate a survival advantage in this indication with the other being the chemotherapy doublet of Gemcitabine plus Xeloda (Capecitabine). Thought leaders believe that the standard of care in pancreatic cancer is likely to evolve. There is still debate on the benefit of the Tarceva experience; and as data mature on the Phase III trials of Avastin, Erbitux and Oxaliplatin, the paradigm of care will shift.
The Phase III PA3 study of Tarceva demonstrated a statistically significant improvement in median overall survival of 23.5%. The hazard ratio (HR) was 0.81 with a p-value of 0.025. Median overall survival (mOS) was 6.37 months and 5.91 months for the Gemcitabine plus Tarceva and Gemcitabine alone arms, respectively. Progression free survival (PFS) also demonstrated statistically significant improvement with median PFS of 3.75 months and 3.55 months for Gemcitabine/Tarceva and Gemcitabine/Placebo, respectively. The hazard ratio was 0.76 with a p-value of 0.003. Improvement in one-year survival balance the relatively minor improvement in median overall survival (e.g., two weeks). Detractors of the Tarceva pancreatic study, both clinicians and investors, have focused on the modest amount of difference in overall survival of about half of a month. However, advocates note the more significant improvement in one-year. One-year survival was 24% and 17% for the combination and single agent arms, respectively over a 40% survival benefit.
Pancreatic Cancer
Pancreatic cancer is one of the most lethal cancers. In 2005, there were estimated to be 32,180 new cases of pancreatic cancer and 31,800 deaths. It is the 10th most common malignancy in males (16,100; 2%) and females (16,080; 2%). It is the 4th leading cause of cancer deaths in men (15,820; 5%) and the5th in women (15,980; 6%). The one-year survival rate is one of the lowest at 23%, and the same applies to the 5-year survival rate, which is a lowly 4.4%.
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