Yesterday was a weird day for Bristol-Myers Squibb. The company announced the results of a highly anticipated clinical trial, one combining Opdivo (nivolumab) and Yervoy (ipilimumab) in lung cancer patients. As those who follow this area know, BMS has been losing ground to Merck for the last year or two, as Merck’s Keytruda (pembrolizumab) makes gains in this area (a situation that goes back to the earlier clinical trials). This is a big result in the Big Immuno-oncology Hoedown, as everyone tries to figure out which types of cancer are best treated by these agents, how to identify such patients up front, and what kinds of combinations (IO and non-IO) work better than others. There are a huge number of possibilities, there are very large potential medical rewards, and many of the key questions are unanswered, so it’s a pretty fraught business.
Opdivo and Keytruda are both antibodies to the PD-1 receptor (as opposed to others that block its ligand, PD-L1), and Yervoy is an antibody to CTLA-4. There’s certainly room to think that simultaneous attack on these targets could be beneficial, but this was the first big controlled test of that idea. Matthew Herper has a good summary of what’s actually happened, though:
This study, called CK-227, was important because it aimed to establish that two immunotherapies are better than one. It was actually two different trials: one in patients who tested positive for PD-L1, and one in patients who tested negative. PD-L1 positive patients would receive one of three treatments: the combination of Opdivo and Yervoy, Opdivo alone, or chemotherapy. PD-L1 negative patients would receive the combination of Opdivo and Yervoy, Opdivo plus chemo, or chemo alone. Investors expected to find out whether the Opdivo and Yervoy beat chemo or Opdivo alone.
But Bristol decided to change the main measure of success. The company had already increased the size of the study – there were now 1200 PD-L1 positive patients, and 700 PD-L1 negative ones – and pooled the results. And it had changed the goal: instead of looking at PD-L1, the study would pool patients in both groups and pool them by another measure, tumor mutation burden, or TMB.
One problem is that no one knew about these changes until yesterday’s announcement. So the reaction was initially cheers for the successful trial, followed (in case of the sharper observers, followed within a minute or two) by “Wait, what?” The changes to the trial were one issue, the lack of transparency about how the trial had changed was another, and just the fact that a company this large, with such an important readout, would have done something like this was a third. The general feeling set in that you don’t mess around with a trial’s design lightly, and the fact that the company had done so in this case (and without saying a word) raised suspicions that the whole thing was an attempt to produce more positive results.
That may or may not be a fair criticism, but Bristol-Myers Squibb must have known that it was coming their way. One big problem is that tumor mutation burden has not (so far) been shown to be a predictor of overall survival in this area, so making that the big headline of your trial is going to raise unanswerable questions. And sure enough, the company got plenty of them. The press release was followed by a conference call with analysts, which was followed by a general press conference, but no one still knows the answer to “Is the Opdivo/Yervoy combination better than Opdivo alone?” The high PD-L1 portion of the trial is continuing to report on overall survival, but until that reads out (and more data are released in general), everyone watching the field is going to be somewhat more confused than they were last week. Which is not what you want your big clinical trial announcement to do for you, presumably.
The company’s stock jumped in the premarket and opened higher. But by 10 AM it was back to the previous close, and it spent the rest of the day down, with pretty much everything else. It’s sheer bad luck to have a big announcement on a day that the Dow drops over 1100, of course. But a lot of the other stuff was, perhaps, avoidable. (I’m writing this, as usual, well before the market opens on Tuesday, and won’t today be fun!) So the immuno-oncology field is (at least for now) as wide open as ever. Clarity will come – but not soon, and as is often the case, it will arrive in pieces. Some assembly required.