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Medicine Matters oncology

Keynote 604 is a phase 3, randomized, placebo-controlled trial looking at the addition of pembrolizumab versus placebo control to first-line platinum-etoposide chemotherapy for the first-line treatment of extensive-stage small-cell lung cancer. The trial was designed with co-primary endpoints of progression-free survival and overall survival. The study was designed to be considered positive if either one of those two endpoints were statistically significant. The trial involved 453 participants that were randomly allocated one-to-one to either platinum etoposide, the platinum being carboplatin, or cisplatin at the investigator's choice together, with either placebo or pembrolizumab at 200 milligrams every three weeks.



The arms were well balanced. The bottom-line outcome data-- progression-free survival was statistically significantly positive in favor of pembrolizumab with a hazard ratio is 0.75, 95% confidence intervals between 0.61 and 0.91 - that read out with p-value of 0.0023. The overall survival appeared to favor pembrolizumab but did not meet the statistical significance threshold. The hazard ratio for overall survival was 0.80, and the p-value was 0.0164. But actually the statistical threshold for positivity was slightly lower at 0.0128. So this did not quite meet the overall survival threshold.



The PFS is statistically significant, but is it clinical significant?

Well, I think it fits in the context of other studies that have shown a benefit for immunotherapy in the context of first-line chemotherapy for small-cell lung cancer. The curves are actually very similar to the prior CASPIAN trial and the IMpower133 trial, both of which added a PD-L1 antibody to first-line platinum-etoposide chemotherapy. So I think it further reinforces the data from those two studies that there is a benefit for immunotherapy in this context.



How will physicians choose between the available options?

It's difficult to know how physicians will choose between the various options of adding a checkpoint inhibitor to first-line chemotherapy for extensive-stage small-cell lung cancer. The atezolizumab trial was the first to be reported. And I think people have become comfortable with administering that as part of a first-line regimen, at least in the United States and in other countries around the world where this is now approved.



The CASPIAN result was a little bit later. It's very similar, a very similar drug. It has one advantage in-- potential advantage in having every four week dosing as opposed to every three week dosing. So it'll be interesting to see whether that increases the use. Currently, those are the two drugs that are approved for use in this context.



What questions remain unanswered?

Well, I think one of the interesting features of these trials is that there is a tail on the curve for the patients on the immunotherapy arm. If we look at duration of response on the study today, we see that almost 20% of the patients who are responders on pembrolizumab are progression free at one year whereas only 3% of patients on the control arm are progression free.



So there is that tail. And I think it'll be really important going forward to try to define, who are the patients that make up that tail? Are there biomarkers that would predict the patients that derive long-term benefit from the immunotherapy in this context? And can we better understand the reasons for immunotherapy failure in the patients for whom this treatment really didn't work as well as it did in the small subset?