David R. Gandara, MD: Well, maybe let’s switch gears a little bit and talk about squamous cell lung cancer, which for immunotherapy I think some oncologists would say, “Well, you know, there’s not really that much in terms of histologic differentiation.” Some companies, of course, have done trials that included all histologies. Others have been very specific about when they have a nonsquamous trial, and when they have a squamous trial. My own impression, looking at the data for tumor mutational burden [TMB] is—even going back to the TCGA [The Cancer Genome Atlas] data where the squamous cell is a different beast—you might expect it to be because it has more smokers, they’re exposed to the tobacco carcinogens. The kind of mutations in their cancers are more likely to be transversions rather than transitions. Those are the ones that are neoantigenic, and how much that plays out in the trials I don’t know. What’s your thinking? If we took the same scenario about patients with very high PD-L1 [programmed death-ligand 1] expression, or intermediate, or 0, how would you approach those patients with squamous cell?
Everett E. Vokes, MD: I’m not so sure how I can differentiate them based on biomarkers yet. To me, there was KEYNOTE-407 earlier this year that established CarboTaxol [carboplatin plus paclitaxel] and pemetrexed [Alimta] as a new standard of care I think across PD-L1 groups, but PD-L1—positive, if I recall correctly. So, I think the same dichotomy and principle applies—very high expression, single agent; lower expression, chemotherapy combination. To then apply TMB, I have not examined carefully enough to know how different that is. Intuitively, you’re right, it’s a group of patients with larger tumor masses. The prognosis hasn’t been good. The development over time, in terms of changing therapy has not been very fast. But here and in small cell finally, we now have inklings of improved outcomes. But do you use TMB differentially in squamous?
David R. Gandara, MD: No, but I’m just saying I think if you look at the studies, there’s what’s called a mutational density. And the mutational density is much more homogenous in squamous cell, where for adenocarcinomas, of course, we have a larger component of patients that are never-smokers, we have patients with oncogene driven cancers, and the spread of TMB is much, much greater. And I think that plays out in some of the results of the studies.
What about the new data that have just been recently presented on squamous cell lung cancer?
Everett E. Vokes, MD: So squamous, the other trial that’s come out is IMpower-131; one more empowerment that also looked at the addition of atezolizumab [Tecentriq] with CarboTaxol in the squamous population. It too is positive, although interestingly at this point only for progression-free survival. And we’ve seen updates of that that show a trend in overall survival but not statistical significance. So that, at this point I think in squamous cell tumors, we have a clear winner with pembrolizumab [Keytruda], and we have a suggested winner and potentially future winner with additional follow-up with atezolizumab.
David R. Gandara, MD: Right. Well, maybe actually an aside I can ask you because I debate this myself is, do we think all these drugs are the same or do they have some differences?
Everett E. Vokes, MD: It’s a loaded question because conceptually, certainly you could say one is a PD-1 [programmed cell death protein 1], the other is a PD-L1 group of inhibitors. The toxicities look very similar. And, if you look at second-line treatment, I think the results were kind of overlapping in many, many ways. That said, you can’t help but observe a trend that the majority of pembrolizumab trials are a little bit more positive than the alternative drugs in this setting. So, as I looked at standard of care, over 50, it’s single-agent pembrolizumab. Under 50 for PD-L1, you can make a very clear case with KEYNOTE-189. You can arguably do that with IMpower-150 for the arm that has 4 drugs; I think arm A. But you then have to use 4 drugs as opposed to 3 drugs in the trade-off.
Transcript Edited for Clarity