Insights From: Stephen Liu, MD, Georgetown University; Benjamin P. Levy, MD, John Hopkins Sidney Kimmel Cancer Center
Benjamin P. Levy, MD: The CASPIAN trial was yet another trial, very similar to IMpower133, adding a checkpoint inhibitor, durvalumab, in combination with platinum-etoposide. There were a few differences in CASPIAN that were not in IMpower133. You had the option of using either cisplatin or carboplatin in the induction regimen in the CASPIAN trial. You also, in the experimental arm, were allowed to receive prophylactic cranial irradiation, and patients could also get 4 to 6 cycles of induction chemotherapy with immunotherapy. It was very similar to IMpower133. This was a trial randomized to platinum-etoposide versus platinum-etoposide plus durvalumab with maintenance durvalumab.
It was very similar to what we saw, almost identical outcomes, when compared with IMpower133. We saw an improvement in median overall survival, roughly 13 months versus 10 months, and we saw improvements in the landmark survival points as well. This is yet another option for our patients. I haven’t used durvalumab yet in combination with platinum-etoposide. Given how similar the results with CASPIAN are to IMpower133, of course I will try it at some point. But because IMpower133 was first, this is the regimen I think most physicians are using in their patients with small-cell lung cancer.
Stephen Liu, MD: The safety of durvalumab in the CASPIAN trial was very similar to what we saw with atezolizumab in the IMpower133 trial. In the CASPIAN study, the addition of durvalumab to chemotherapy improved overall survival. The toxicity profile is very similar to the control arm. Most of the grade 3/4 adverse events were hematologic in nature, attributed to the chemotherapy backbone. These are typically reversible, larger paper toxicities, which don’t negatively impact the patient in most cases.
Durvalumab certainly was associated with an increased risk of immune-related adverse events compared with the control arm with no immunotherapy. However, these were primarily low-grade adverse events, and the risk of severe grade 3 or higher adverse events that were immunologically mediated was quite low. Whether this translates into a low incidence in real-world practice remains to be seen. We do know from several real-world studies that the risk of immune-related adverse events can be a little higher in the general clinic population, but overall this is a very safe regimen, very well tolerated, and the risk of severe toxicity is quite low.
Benjamin P. Levy, MD: The CASPIAN trial has another arm that has not been reported on, which is adding a CTLA4 inhibitor to a PD-L1 [programmed death-ligand 1] drug, so platinum-etoposide-durvalumab-tremelimumab. The questions are how will that look, and what are the toxicities of these drugs? I don’t think we know. My guess is the addition of a CTLA4 inhibitor to a PD-L1 drug will probably enhance the toxicity in that arm. Giving those 2 drugs together, dual checkpoint blockade, appears to be more toxic in every single study we look at when we compare with single-agent checkpoint inhibitors. I imagine that dual checkpoint blockade may improve outcomes but also may lead to more toxicity. I guess we’ll find out soon enough.
Stephen Liu, MD: The KEYNOTE-604 study, we’ve learned from a press release, did not meet its survival end point. This is a randomized phase III trial that looked at chemotherapy alone versus chemotherapy with pembrolizumab. We have not seen the data for this trial. The press release tells us the PFS [progression-free survival] was improved with the addition of pembrolizumab; however, overall survival was not statistically significant. Based on the numbers that were released, there did still seem to be an effect with a hazard ratio of 0.80.
However, the statistical significance of these results unfortunately was not high enough to result in a positive trial. We still do need to see those data to identify the specific differences in those patient populations. The trials are somewhat different. They were separated in time. The KEYNOTE-604 study was a bit later, so the crossover rate may be a bit higher. Subtle differences in trial conduct may account for these differences, but again it is possible that it is the result of a different drug.
Does the difference between PD-1 [programmed cell death protein 1] and PD-L1 matter? Are the crossover rates different? Are the chemotherapy backbones, the use of cisplatin versus carboplatin, different between those 2 populations? We don’t really have enough data to really know why 1 study was negative and the other 2 were positive. But as it stands, the positive trials with the PD-L1 inhibitors, durvalumab and atezolizumab, and the PD-1 inhibitor, pembrolizumab, did not obtain a statistically significant result. And so we eagerly await those data.