The PDL Wars
By now even those living under the rock know that there is a major war underway among PD1-PDL1 makers for market leadership. Big players involved - Bristol-Myers Squibb (BMS) the front runner, Merck the challenger, Roche/Genentech, Pfizer and Astra Zeneca the hopeful, are all jockeying for leadership, trying to carve out a space for themselves which would lead to scientific and financial glory. Clear leader thus far is BMS, my alma mater, but that leadership is quickly being challenged by the new comers.
The latest salvo in this war comes from Merck, which just yesterday secured its position as the "first" among challengers by adding the first line indication in non-small cell lung cancer (NSCLC) to the Keytruda® label. Merck's stock was up on the news and has many analysts crowing how this win establishes superiority of Keytruda over the other PD-1/PDL1 inhibitors. But caution needs to be applied here. It is foolhardy to think that any one PD1 inhibitor is better than others based on one clinical trial, let alone the fact that the trial was not even a comparative trial between two checkpoint inhibitors.
There is no doubt that Keytruda's new indication in first line NSCLC is a major milestone for Merck and this win is significantly magnified by the fact that BMS' Opdivo® failed in first line setting some months ago, ceding the frontline space to Merck. However, savvy strategists at Bristol had already thought of this possibility and prepared a contingency plan - a plan that calls for studying a combination of Opdivo and Yervoy in first line. If this combination study data turns out to be as good as expected, oncologists will have two choices in front line - Opdivo + Yervoy or Keytruda + Chemo. Of course, there are differences in patient populations and the opportunities are not mutually exclusive, and the two immunotherapy combination will likely come with its own liabilities, but a positive Opdivo + Yervoy trial will bring BMS quickly back into the front line space in NSCLC.
Bristol is not the only company that has suffered a setback. Just days ago Roche/Genentech announced a negative Bladder cancer trial for Tecentriq® that has people wondering what went wrong; after all, Tecentriq received the indication for advanced Bladder cancer only recently in April 2017.
This goes to show just how difficult it is to design trials that are guaranteed to yield a predicted outcome. Although we know a lot more about cancer immunotherapies today than we did ten years ago, there is a lot more to be learned before we can confidently predict if a particular trial design will definitely yield a positive outcome. There are so many unknown elements beyond PDL1 biomarker - the role of complex stromal elements like cytokines, other immune cells, structural barriers like hyaluronic acid etc. etc. - that may influence the clinical benefit of a check point inhibitor to a patient. The complexity is mind boggling and it will be a long while before any one is able to come up with an algorithm that confidently predict success with a check point inhibitor. A good strategist always takes these uncertainties into account and develops a contingency plan to reduce the risk of failure, as has been done by BMS strategists.
It bears to be reminded that it was the brilliant scientists and strategists at Medarex and Bristol-Myers Squibb who started this immuno-oncology revolution in the first place by finding a creative way to develop and register Yervoy, an anti CTLA-4 antibody, in melanoma, so let's not count them out just yet. For that matter, let's not count out Roche or Pfizer or Astra Zeneca either. Many of the scientists who led the IO revolution at BMS have found new homes in these companies and are leading creative thinking there. We are in early phases of these PDL wars with a lot of great work being done in the IO space.
While arm chair drug developers may think that the game is already over, in reality the game has only just begun and it is way too early to crown any company as the ultimate winner.
Opdivo® is the registered trademark of Bristol-Myers Squibb Company, Keytruda® is the registered trademark of Merck, Tecentriq® is the registered trademark of Genentech