We may have to rethink what we think about the recent trial in which Bristol-Myers Squibb’s Opdivo was ineffective in non-small cell lung cancer. The arguing has been about the status of the patients, specifically how much PD-L1 protein they were expressing. But writing in BioCentury, Stephen Hansen points out that comparing the various trials is difficult, and maybe even impossible:
The reaction to the CheckMate-026 data appeared to suggest some investors believe patients don’t benefit from PD-1inhibitor monotherapy when PD-L1 expression is as low as 5% ; however, Opdivo and Keytruda are being used with companion or complementary diagnostics in a setting that’s proving difficult to parse for companies and physicians alike.
Part of the challenge is that positive PD-L1 status has not consistently predicted patient benefit across cancer types, with PD-L1 negative patients also deriving benefit from anti-PD-1 mAbs, albeit typically in smaller numbers.
Compounding the issue, however, is that each of the five mAbs against PD-1 or PD-L1 in Phase III testing or beyond has its own assay to determine PD-L1 expression, with each assay possessing its own scoring algorithm and method of measuring cells.
Given these differences, according to one assay developer who spoke to BioCentury, it is unlikely that a generic cutoff for PD-L1 expression to predict patient benefit can be determined without a prospective trial involving all the therapies and assays.
Now that’s a mess! The article (for subscribers) has a great deal more detail on this problem, but my first thought is “Welcome to immunoassays”, because that’s where this variation is coming from. Everyone has different antibodies and different protocols, and unless you run the same samples through the different assays, there’s really no way to tell how things correlate. Or if they do at all.
The one bright spot is the Blueprint Project, which is trying to resolve these questions. Most of the companies involved in this area are part of it, along with several diagnostics companies, societies like the AACR, agencies like the FDA, etc. A great big notable absence from the group, though, is the Merck KGaA/Pfizer partnership, who are going their own way. Some results from the effort are already coming in, and they mostly highlight the need for more results.
So it’s early, very early, to try to draw head-to-head comparisons between Opdivo and Keytruda (Merck’s antibody), or the other players in this field, based on their individual clinical trial data. Everyone’s brining their own facts, which are valid only in their own trials. A separate question is if you’re a physician, and you use some particular PD-L1 assay (such as Merck’s): can you then turn around and give either their antibody or Opdivo? You’d sort of think so, but “sort of think so” is not a very good rationale on which to base one’s oncology practice. Not even the Blueprint folks are trying to go all the way to figuring out clinical equivalence, so that may be an open question for some time to come. . .