Clinical Cases in Lung Cancer - Episode 4

Case 1: CASPIAN Trial in Extensive-Stage Small Cell Lung Cancer

Edward Kim, MD: Another study that’s been reported is CASPIAN. This is a platinum-etoposide doublet, and what was unique about this study is it was 3 different arms. You had a combination of durvalumab and tremelimumab—so it’s CTLA4 with the PD-L1, with chemotherapy. That was given for 4 cycles, so the 4-drug regimen, followed by a maintenance durvalumab schedule every 4 weeks. That’s different from every 3 weeks that was given with the concurrent. Then you had the triplet; again, every 3 weeks for 4 cycles, and then the every-4-week maintenance. Then you had the control arm, which was the chemotherapy given up to 6 cycles. You could give more chemotherapy therapy there and again get optional PCI. The primary end point here was again overall. It was a randomized trial with very interesting results. No PD-L1 or anything that you can see was done ahead of time. The survival curve was 12.9 versus 10.5 months. That’s a little more than 2 months that was shown; very similar numbers. As you can see, the control arm did very well, and that’s the thing that’s been highlighted across all these trials. The control arm has behaved as we would expect to see in our daily practice. The PFS also was a little—you could see the curves overlap and then separate, so there was some link separation there. That raised some eyebrows from some folks. But it was still beneficial and clearly small cell is a tough disease early on. Maybe there’s an effective maintenance here or maybe it was the fact that you were able to take 6 cycles of chemotherapy in a control arm. There are many reasons, but the comparison here is that the durvalumab with chemotherapy is what showed the benefit. There was not the same benefit by adding the additional CTLA4 with tremelimumab, that 4-drug regimen, so it was a 3-drug regimen in the comparison that was the best. As you see, updated data, this duration of response here. The response rate is very high. There was certainly an additive effect with durvalumab with the chemotherapy regimen. The brain metastases are very interesting. We know this is a tough area with small patients with small cell, and there was a benefit throughout. They allowed patients on the study with asymptomatic brain metastases, and they showed a benefit in OS as you can see in the Figure 3, Panel A and B, with the addition of durvalumab. There was an effect that they were able to demonstrate.

The adverse effects—it was very well tolerated. You’ll see this as a recurring theme across grade 3 and 4. We’re very good about looking for these adverse effects that can occur both early and later in the course of therapy.

Then we have everyone’s popular drug, pembrolizumab. This is the KEYNOTE-604 study: platinum-etoposide with the combination. Everybody expected this to be something that was going to hold out as positive. Here was the early event, but it missed its cutoff. It was just barely, not significant. It was close but not statistically significant. Although the PFS early on for this study was pretty impressive, the overall survival did not hit. So pembrolizumab, as you saw the NCCN Guidelines is not FDA approved for small cell.

Mark Socinski, MD: What about the issues of patient quality of life? There was some patient-reported outcome [PRO] data from the CASPIAN trial. Can you comment on that?

Edward Kim, MD: Yeah. PROs are a very important area, and so is quality of life. We’re seeing that immunotherapy is very well tolerated and that, in fact, we see the benefits of adding this drug. What we see is not necessarily an improvement, but we see a lack of deterioration in quality of life in PROs. If we can hold the line and not make people feel sick but also add another drug on top of things that are going to improve efficacy, then that’s a win.

Mark Socinski, MD: The older literature you can go way back to in the early days of treatment, and there were actually a number of studies that suggested that you do palliate symptoms when you shrink a tumor. I would prefer for quality of life and PROs to tell us how many times they got better vs worse later. It’s interesting that that’s the path that they took in the CASPIAN trial.

Edward Kim, MD: Yeah, and the age increase can always be a little clearer. It was 1 of those mandates where they said, “OK, we want to see quality-of-life data, so you should measure it.” Then they’ve been very slow to approve drugs based on that indication.

Transcript edited for clarity.