Yesterday, Exelixis (EXEL) announced Cometriq (cabozantinib) failed to improve overall survival in a pivotal study in prostate cancer. Cometriq is already approved for MTC (medullary thyroid cancer, a rare tumor type) and prostate cancer was viewed as the drug’s most significant opportunity given the large commercial opportunity ($1B+).
Following the failure in prostate cancer, investor focus moves to Exelixis’ MEK inhibitor (cobimetinib, partnered with Roche) and Cometriq in other indications. Although the news are obviously disappointing, Exelixis still has several irons in the fire, which will provide important catalysts over the next 12 months. I previously discussed these catalysts earlier this year. Cobimetinib data at ESMO
Roche will report phase III data for cobimetinib in BRAF+ melanoma at ESMO later this month (26-30 September). Roche already announced the trial, which evaluated cobi+Zelboraf vs. Zelboraf, had a positive outcome in terms of PFS (progression free survival). At ESMO, cobi’s performance will be analyzed in the context of GSK’s (GSK) MEK inhibitor, Mekinist, which was evaluated in a similar setting (BRAF+ melanoma in combination with a BRAF inhibitor).
Investors will compare 3 parameters: (i) magnitude of PFS benefit (ii) trend of improved overall survival (OS) (iii) safety profile.
Mekinist, when added to GSK’s BRAF inhibitor (Tafilnar) demonstrated a marginal PFS benefit (9.3 vs. 8.8 months, HR=0.75), which was viewed as clinically irrelevant and as a negative harbinger for the future of MEK inhibitors in general. Consequently, GSK had to withdraw its regulatory application in Europe. Since then, sentiment has changed based on a strong trend in overall survival (HR= 0.63) in favor of Mekinist + Tafinlar as well as another trial in which the combination demonstrated a statistically significant survival benefit over Zelboraf.
The PFS benchmark (a 2-week improvement) set by GSK should be easily met by the Roche’s/Exelixis’ combination but in order to differentiate cobimetinib from Mekinist the companies will have to present a 2-month difference. Some may claim that even a 2-month difference will not be sufficient for differentiation as the GSK combo demonstrated a 1.5 month PFS difference in a retrospective analysis that included patients who progressed without a confirming scan.
Down the road, the overall survival will be the more important metric (should be available next year). The overall survival benefit seen with Mekinist bodes well for cobi’s likelihood of improving OS, especially if the latter has a superior PFS benefit. Roche started its phase III trial 6 months after the initiation of the two GSK trials, so one factor that plays against cobi is the growing availability of PD-1 antibodies that may have a confounding effect on overall survival.
Cobi’s safety profile will become important only if it has comparable efficacy to Mekinist. The drugs belong to the same class and will probably have overlapping toxicities. One potential differentiator is the frequency of chills/fever which appears to be unique to Mekinist. Severe chills have often led to dose interruptions with Mekinist and there is no way to identify in advance patients who are more susceptible to developing it. Therefore, if cobi maintains a clean safety profile, it should be regarded as a minor advantage.
Roche is conducting additional combination studies with cobimetinib, the most important of which is with its PD-L1 antibody. The trial appears to have reached the expansion stage and is now focusing on melanoma, lung cancer and KRAS-mutant colorectal cancer. Initial data from the trial may be available in 2015.
Cometriq – Opportunities beyond prostate cancer
Cometriq is being evaluated in over 30 clinical trials across a variety of tumor types. The most relevant indications with clear catalysts in the foreseeable future are MTC, NSCLC with rare gene-fusion mutations and renal cancer.
MTC – The drug is generating sales in the US ($6.6M in Q2) and may start to generate revenues in Europe next year. An overall survival update of the phase III study is expected later in 2014. Survival benefit in RET-mutated patients will be of particular interest.
RET+ lung cancer (and potentially additional mutations) – Cometriq generated preliminary signs of activity in a small study in RET+ NSCLC patients. No updates have been released since, so it is unclear whether activity was corroborated in additional patients. Interestingly, the clinical trial was recently expanded to include patients with other rare mutations (Trk, Ros1, Axl). It is unclear whether the decision to pursue additional subsets is a result of preclinical experiments or anecdotal signs of evidence in patients.
Renal cancer – A phase III vs. Afinitor will read out in 2015. Although there is no randomized phase II data set to support this program, good activity was observed in a single- arm study. In contrast to prostate cancer, where the activity was documented in an unvalidated endpoint (bone scan resolution), the renal cancer data set includes response rate and PFS as the major efficacy endpoints.