Bladder Cancer Update & Renal Cell Cancer Update, 2017 (Video Program)Response of smokers versus never smokers to pembrolizumab on the Phase III KEYNOTE-045 trial
3:16 minutes.
TRANSCRIPTION:
DR LOVE: What do we know in terms of smokers versus nonsmokers both in terms of mutational load as well as response to checkpoint inhibitors? DR PLIMACK: That’s a great question, and very timely. So we just saw the results of the KEYNOTE-045 study, which is the first randomized study that looked at pembrolizumab versus chemotherapy second line after platinum. So the chemo was primarily taxane or vinflunine in Europe. And when they created the forest plots, right, to see who responded better, the interesting one was smokers. So current smokers actually did better with pembrolizumab than never smokers. And that was the one thing — again, now, all smoking groups did better with pembrolizumab than with chemotherapy, but the difference was really most pronounced in patients who were current smokers. And so a lot have hypothesized that smoking leads to DNA damage, which leads to accumulation of these alterations, which then leads to this responsive phenotype. I know we’ve looked across smoking status at neoadjuvant chemotherapy and chemotherapy. And there may be some trends towards better response, but really nothing definitive in terms of smoking. These data that we saw at SITC were really interesting, I thought, in that regard. DR LOVE: And of course that’s been seen with lung cancer. What about actual mutational load? Has that been looked at in bladder cancer patients, smokers versus nonsmokers? DR PLIMACK: Right. So mutational load has been looked at in bladder cancer patients. The atezolizumab trials did incorporate that analysis. And it’s been presented both in the paper and was presented at ASCO. Higher mutational load does portend a better response to atezolizumab. I don’t believe I’ve seen the correlation between smoking status and mutational load directly, to see if one begets the other. DR LOVE: What about PD-1 levels? DR PLIMACK: Right. Great question. So we’ve been looking at PD-1 in bladder cancer and PD-L1 expression extensively. Part of that was the initial atezolizumab trials looked at that from the get-go in terms of their analyses and presented response rates always in terms of PD-L1 high versus PD-L1 low. And what’s interesting is that the first time any company looks with their drug and develops the assay, right — so for atezolizumab is the Phase I basket study, that cohort. They looked at it. They developed the assay. And it discriminated pretty well between responders and nonresponders. But when you take that same assay and apply it to another data set, it didn’t perform as well. And by the time it was applied to the front-line data there was really almost no discriminatory ability in terms of response and nonresponse. So it’s useful in the beginning, because it looks good in the set it was developed in, and then subsequent ones it doesn’t. That same pattern has been shown with pembrolizumab now. So that biomarker was really best developed in their front-line data set. Then, when they took that same — it’s called the CPS score for pembrolizumab — and applied it to their randomized trial, which was presented at SITC, really, same response rate with CPS-high versus overall. Right? So I think that what we’re seeing is that in the discovery set, these tests might look good. They aren’t being validated in subsequent sets, and they aren’t useful for treatment selection. |