Here is how I order the trials based on my confidence in a positive outcome.
1. Comet 2 "Shooting fish in a barrel" Even if you shoot like a girl (or MiningPHD)
3. HCC Just discussed
4. Comet 1 Based on the Scher abstract I see it 65-35.
Correct me if I'm off, but the FDA didn't indicate they wouldn't approve Cabo for CRPC based upon pain palliation, they just wanted to set the bar higher than EXEL was comfortable with in the Comet trial. Thus if Comet 2 achieves a much higher pain palliation rate than set in the trial design, which sounds plausible if the trial design is like "shooting fish in a barrel", EXEL has a pretty good shot at NCCN compendium for pain. Wouldn't that be a fairly significant revenue opportunity? And wouldn't that also come much sooner than any other trial?
Sentiment: Strong Buy
"Correct me if I'm off, but the FDA didn't indicate they wouldn't approve Cabo for CRPC based upon pain palliation, they just wanted to set the bar higher than EXEL was comfortable with in the Comet trial."
Yes. What is approvable is a moving target, but FDA has definitely not said that pain is no longer an approvable endpoint. Rejection of the SPA was not a wholesale rejection of the endpoint. There were concerns with the Comet 2 trial design, including problems with inadvertent unmasking of the treatment assignment and a relatively low level of requisite effectiveness. An actual show of overwhelming efficacy could overcome those concerns. However, with an OS trial underway, the politically expedient course would be to wait for those results.
"if the trial design is like "shooting fish in a barrel" EXEL has a pretty good shot at NCCN compendium for pain."
If Cabo achieves only half the pain response rates seen so far, the trial will attain its primary endpoint by a wide margin. Each indication has its own NCCN committee. The prostate committee has not recommended any off label drugs of which I am aware and the CRPC indication has been hit with an embarrassment of riches regarding new drug approvals. I think they will also see that Comet 1 is underway and wait for the FDA. I think EMA might actually be a more likely source for an early approval. At the same time EXEL was negotiating for the SPA, EMA provided positive guidance regarding the trial design.
"Wouldn't that be a fairly significant revenue opportunity?"
EXEL has previously listed the post-chemo symptomatic metastatic CRPC U.S. population as 4,000. Requiring significant pain would pare that down a bit.
"And wouldn't that also come much sooner than any other trial?"
I think so. RET NSCLC could also read out fairly quickly, but Comet 2 has a head start. Even if Comet 2 does not directly lead to a supplemental approval, the impact of a positive outcome on the EXEL pps would be appreciable.
The dream team/tablet for mCRPC.
Abi plus Cabo (with small dose) will be my best bet for EXEL If this combined tablet for mCRPC can pan out, PPS will move much higher than the results from successful Comet 1 and 2 trials together.
Sentiment: Strong Buy
?The dream team/tablet for mCRPC.
Abi plus Cabo (with small dose) will be my best bet for EXEL If this combined tablet for mCRPC can pan out, PPS will move much higher than the results from successful Comet 1 and 2 trials together."
Or maybe Cabo/MDV (aka enzalutamide or Xtandi). I'm also beginning to consider that it might be better to wait until patients are refractory to Abi and then retreat with an Abi/Cabo combination. Cabo has a very broad and initially very deep activity. Maybe it is because it is being tested in such heavily pretreated populations, but I am beginning to think that in the nonRET indications, tumors seem to develop Cabo resistance relatively quickly (less than 12 months, perhaps as little as 6 months). Abi and MDV maintain monotherapy efficacy for a much longer time. It makes me wonder if it might be better to let the tumor develop AA resistance and then retreat with the combo. We'll see what results they are having in the current trial and have the opportunity to reassess then.
Let's expand on RCC. The upcoming pivotal trial will be Cabo vs Afinitor (Everolimus) in sunitinib or sorafenib pretreated patients. That is the population for which Afinitor is approved and we have its phase 3 results for comparison. Afinitor had OS of 14.8 months, PFS of 4.9 months and ORR of 2%.
Based on a sample size of only 25, here are the comparable stats for Cabo. OS is indetermined (not reached), PFS of 14.7 months and ORR of 28%.
The only caveat here is that 25 is a relatively small sample size, but the efficacy statistics consistently favor Cabo.
It could be that Exelixis decided not to pursue RCC first because of AVEO's presence in this space. In light of Tivozanib's recent results and their failure to secure an SPA for prostate, they didn't pick the best possible path toward revenues in terms of indication pursued, but hindsight is always 20/20. In terms of ORR and OS, Cabo looks unchallenged here; compare that to Nivolumab's 2 out of 17 ORR (12%) from NEJMoa1200694.
I agree that it's likely when compared against other agents, Cabo will exhibit similar benefit numbers like OS for instance. However, its ace in the hole for approval is that Cabo will stack with the other agents because of its orthogonal MOA. On the other hand, because it's being tested in such refractory populations, the revenues coming in for approved indications may be much smaller than for first-line treatments.