Pharma Strategy Blog

This morning, Exelixis announced results from the cabozantinib phase III EXAM trial in medullary thyroid cancer (MTC).  I last wrote about this compound as XL184 in MTC three years ago in the phase I trial, so it’s definitely time for an update!  A lot has happened since then, including BMS, Exelixis’ then partner, deciding not to pursue the agent’s development.

With a new announcement today from Exelixis, it now appears that median progression free survival (PFS) in the phase III trial, based on a planned interim analysis, was superior in the cabozantinib arm compared to that of placebo. Topline analysis yielded an improvement of 7.2 months (11.2 months versus 4.0 months, HR=0.28, p < 0.0001). The primary endpoint was PFS and no overall survival (OS) is yet available.

A meeting with the FDA is no doubt planned in the light of the interim findings:

“Exelixis will consult with the FDA to determine whether the trial conduct should be changed as a result of these data in conjunction with the SPA. The company is requesting permission to begin a rolling submission of the New Drug Application (NDA) for cabozantinib in this indication to the U.S. Food and Drug Administration (FDA).

It is anticipated that the filing will be completed in the first half of 2012.”

However, if the DSMC do recommend crossing over to cabozantinib, we likely won’t know if patients will live longer (OS). This is always the conundrum with PFS as a primary endpoint in clinical trials.

Earlier this year, the FDA approved AstraZeneca’s vandetanib (Caprelsa) in MTC, the first therapy approved for this indication. Vandetanib differs from cabozantinib in that it is a dual VEGF-EGFR inhibitor, whereas cabozantinib targets MET, RET and VEGFR2. While it was encouraging to see a new targeted therapy available for MTC, vandetanib has some challenges, namely prolongation of QT, causing irregular heart beat and thus it was made available under a Risk Evaluation and Mitigation Strategy REMS agreement. This essentially means that only certified prescribers can prescribe Caprelsa under a restricted program.

That said, many will be interested in how these drugs compare, although it should be noted that it appears the cabozantinib EXAM trial included patients with progressive disease at screening, whereas vandetanib did not. If that was the case, then one would therefore expect the PFS to be shorter in the cabozantinib trial.

According to the April FDA press release, the efficacy data for vandetanib was as follows:

“Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. It is too early to determine the median progression-free survival in patients treated with vandetanib or to tell whether they will live longer (overall survival) compared to patients treated with placebo.”

Overall, I think these are encouraging results for patients with MTC, although perhaps the absolute PFS values are a little shorter than I was expecting, but if the side effect profile does not require a REMS strategy as per vandetanib, which is arduous for both physician and patient in terms of monitoring, then that would certainly be a big plus for cabozantinib.

I look forward to hearing the progress of the upcoming meeting with Exelixis and the FDA.