June 29, 2010

Catch a rising star.

This past ASCO in Chicago was something like the 18th or 19th one that I have attended, and it has grown from a few thousand physicians to this hectic weekend with over 25,000 attendees. When I first started in this industry, there were maybe a dozen chemo agents for the treatment of all cancers and now there are so many ibs and mabs I have trouble keeping track of them all. It could be that I’m getting old but thank goodness for Google and OBR Radar. Despite the advances in oncology and the number of new products approved there have been remarkably few products that have made a significant difference for patients with metastatic disease. We still consider an improvement in overall survival (OS) in terms of weeks or a few months a major treatment advance. Hence, a huge unmet medical need and opportunity exists for any new treatment that can improve upon the efficacy of existing regimens. The search for new rising stars is the most exciting part of the meeting for me. They also represent investment opportunities.

For this year, I think without question the data demonstrating that ipilumimab (BMS) can improve survival for melanoma patients by almost 4 months was the biggest news. Not only because it is the first treatment that has improved survival in a phase 3 trial for this patient population, but also that it works by activating the immune system. What also struck me is the significant effect maintenance use of a monoclonal antibody can have on patients. Results from the PRIMA study evaluating Rituxan® maintenance therapy in untreated follicular lymphoma, and data from the GOG-0218 trial evaluating maintenance Avastin® in first-line ovarian cancer were both positive.

There were several worthy rising stars coming from smaller companies. The most notable, are the results from Ziopharm’s (ZIOP) phase 2 PICASSO trial in which 67 soft tissue sarcoma patients were randomized to receive doxorubicin + palifosfamide or doxorubicin alone. The results appear pretty remarkable with the initial analysis of median PFS demonstrating a hazard ratio of 0.43 (P=.019) in favor of the palifosfamide arm in a very difficult to treat patient population. However, the stock took a significant fall today from $4.85 to $3.52 when the company announced that the FDA is rejecting PFS as an adequate endpoint for an SPA—ouch. Presumably the agency wants a survival endpoint. The company has reported a favorable survival trend in the phase 2 data but there is certainly more risk in the stock now.

Sunesis (SNSS) reported promising phase 2 studies of their agent voreloxin in patients with AML. I was particularly impressed with the high complete response rate (CR) in 69 refractory patients: 17 of the 20 responding patients achieved a CR. Encouraging results were also reported from phase 2 studies in first-line AML and refractory ovarian cancer. This is an interesting stock to watch, but I would caution investing in it. Why? In short—no control arm. It is very difficult (at least for me) to get a clear picture of how this patient population would respond receiving standard chemotherapy. I do not understand why companies choose not to conduct randomized phase 2 studies in this day and age.

Another interesting ASCO story is that of Delcath (DCTH)—the manufacturer of a proprietary system called PHP (percutaneous hepatic perfusion) which delivers chemotherapy to isolated organs. A phase 3 study of PHP was conducted in 93 melanoma patients with liver metastasis who were randomized to receive high dose melphalan with the PHP system or the physician’s choice of Best Available Care (BAC). Hepatic-PFS was the primary endpoint. Median H-PFS was 245 days in the PHP arm vs. 49 days in the BAC arm (P<.001).

Based on the initial reporting of these results on April 21st, DCTH stock rose to a 52-week high of $16.45 and was at $14.65 the Friday of ASCO. The company also reported that the OS was 298 days in the PHP group vs. 124 days in the BAC arm. After the above results were presented at the meeting, their stock fell to $10.83 at the close on Monday. What happened?

The presentation reported that OS was not statistically significant, but also noted that most patients in the BAC arm eventually crossed over to PHP. A debate then raged in the blogosphere about what this all means. DCTH has stated that H-PFS is in their SPA agreement with the FDA. Will the lack of significant OS put the approval at risk? It appears that this question is the basis for the stock falling. It is not surprising that OS was not significant because it was a secondary endpoint that the trial was not powered to detect—H-PFS was the primary endpoint.

Since DCTH’s SPA with the FDA is based upon H-PFS as the primary endpoint one would expect that approval will be likely—but not so fast. For the FDA to approve PHP with a single trial, the results must demonstrate a clear benefit. In my experience this means the primary endpoint must meet a P<.01—which H-PFS exceeds in this trial. However, will the agency continue to view H-PFS as predictive of a significant clinical benefit for these patients when faced with no survival benefit? From what I have read, the symptoms and complications of liver metastasis are very severe and an extended H-PFS should be a significant clinical benefit to these patients. The drop in the price of DCTH stock may represent a buying opportunity.