Yesterday at the ECC meeting, BMS (BMY) and Exelixis (EXEL) presented data for their respective drugs ,Opdivo (nivolumab or nivo) and cabozantinib (cabo) in renal cancer (RCC). Before delving into the inevitable comparison, it is important to note that cross-trial comparisons are tricky and it’s impossible to definitively say which drug is better without a direct comparison in the same study. Nevertheless, the studies were very similar in terms of patient population, control arm and prior treatment lines so as far as cross-trial comparison goes, this is as good as it gets.
Overall survival – Opdivo improves overall survival and cabo is very likely to do so as the data mature. The magnitude of benefit appears similar with a numerical advantage for cabo (needs to be validated)
Opdivo demonstrated a 5.4-month survival benefit (25 vs. 19.6 months) over Afinitor with a hazard ratio of 0.73 that was statistically significant (p=0.002). Cabozantinib’s data set was immature so median survival values are not available but there was a strong trend favoring cabo with a hazard ratio of 0.67 on the verge of statistical significance (p=0.002). This is also clear from the survival curves which already start to separate after 4 months (see below). Given the strong signal, cabozantinib has a high likelihood of demonstrating a statistically significant survival benefit at the next analysis (expected in 2016).
Source: Choueiri TK, NEJM 2015
Progression-free survival – Cabo wins but what matters is overall survival
Cabo improved PFS whereas Opdivo did not but given the strong survival benefit for both drugs, the relevance of PFS is unclear. As I previously discussed, PFS has been regarded as the basis for approving most RCC drugs to date as it was viewed as a surrogate endpoint for overall survival. In Opdivo’s case, this hypothesis proved incorrect.
Safety profile – Opdivo is clearly a safer drug but dose reductions should allow physicians to keep patients on cabo until progression
Safety and tolerability is going to be a major topic going forward, as the two agents have very distinguished profiles. The way the studies reported adverse events makes it challenging to compare the two agents but it is clear that cabo has more tolerability issues. Compared to Afinitor, cabo had led to a higher incidence of most toxicities (GI, appetite, Palmar-Plantar, hypertension etc.). In contrast, Opdivo had a lower incidence of adverse events almost across the board compared to Afinitor.
Surprisingly, treatment-related discontinuation appears only slightly more common with cabo than with Opdivo. This is explained by physicians’ ability to reduce or interrupt dosing while keeping patients on the drug. Although dose reductions occurred in 60% of patients who got cabo, only 9% discontinued, demonstrating that with a daily oral pill it is possible to find an optimal dose without stopping treatment.
Market positioning – Opdivo will dominate 2nd line RCC but virtually all patients will require 3rd line options, where cabo is ideally positioned
From a clinical perspective, both drugs should be viewed as major breakthroughs. Opdivo is the first drug to demonstrate a survival benefit in the general RCC population. Hopefully, cabozantinib will be the second agent to have a survival benefit in its label with more follow up. Consequently, both agents are likely to be used sequentially in the 2nd/3rd line setting after Sutent /Votrient. Going forward both agents may be used in combination although previous experience with Opdivo and other kinase inhibitors revealed a problematic safety profile.
As can be seen in the summary table below, the two drugs are quite similar in terms of most clinical endpoints (survival, response rate, treatment discontinuation). At the end of the day, Opdivo is better positioned because it has a confirmed survival benefit (based on a more mature data set) whereas cabozantinib has a strong survival trend with a better hazard ratio that requires validation. Opdivo has a superior safety profile even though cabozantinib-related toxicities can be managed with dose reductions that minimize discontinuations. Lastly, Opdivo has the advantage of being branded as “immunotherapy” whereas cabozantinib belongs to an old class of drugs (kinase inhibitors) with many approved drugs.
Portfolio holdings – September 27, 2015