Immunotherapy in Relapsed-Refractory SCLC



Jacob Sands, MD: At the time of progression, unfortunately the prognosis is just very poor. There really isn’t a situation where there’s a good prognosis in this patient population when there’s progression of small cell lung cancer. In the refractory setting, when it’s grown in less than 3 months from having completed the platinum-etoposide or on treatment, this is a particularly difficult situation—survival tends to be a very limited number of months. Even in the greater-than-6-months range, we do see people who have responses to chemotherapy again in that setting, but the majority of these patients also have significant clinical decline over a handful of months. And so the historical numbers at the time of progression have really been pretty abysmal, and there is a low bar upon which to grow. I’ll say it’s a low bar upon which to grow, but it’s such a complicated and difficult disease that to overcome that bar has also been very difficult.

As far as trying to determine subsequent therapy after progression, I think the biggest thing is whether there was progression after 6 months from having finished the platinum-etoposide. In that setting, you can consider using it again. I have seen people who really have had responses again when it has been used as second-line therapy. The other thing ends up being their functional status. People often decline so quickly that it becomes harder to give them toxic therapies that are harder to tolerate. Irinotecan is certainly a regimen that’s reasonable to use. Topotecan is an FDA-approved next-line therapy option. But these are also things that require people to still have a little bit of energy for—to be able to tolerate those treatments. Although topotecan is approved, I think there’s some resistance to using it because we just don’t see such tremendous outcomes. Certainly, there are people who benefit from topotecan and irinotecan, but the toxicities can be significant, and the durability of these responses is also very limited.

Immunotherapy has really changed the landscape within small cell lung cancer, and we initially saw this in the third-line setting and beyond. KEYNOTE-028 and KEYNOTE-158 together, presented, showed a response rate of about 19%. So the majority of people were not really benefiting from the drug. But among those who responded, we saw 13% with ongoing disease control at 2 years. That’s 13% from 19%, which means more than 60% of people who had a response to therapy had ongoing disease control at 2 years. This is astonishing considering that we’re talking about a clinical scenario, where people often really decline very rapidly.

Similarly, in the CheckMate-032 study, the response rate to nivolumab was about 11%, 12%, and the median progression-free survival among those responders was about 18 months. Again, in both we see a fraction of patients [who] get responses to therapy, but among those who have a response, there’s really some impressive durability within a clinical setting that generally experiences pretty rapid decline.

In the setting of CheckMate331, though, this was nivolumab versus chemotherapy. Unfortunately, the nivolumab group actually did not perform as well in median progression-free survival and overall survival. I will say that within that, though, we did see that in those who had a response, there was a more consistent durability to those responses. We still see that hint of those who benefit from the drug really tend to benefit significantly, but the number is low. I think it speaks to the fact that when looking at these checkpoint inhibitors, maybe using median progression-free survival and overall survival is not necessarily the way to really capture the efficacy of these drugs. And really, looking at time points and durability of responses is a better way of trying to capture that. Either way, within that study, it was a disappointing result from what we expected with nivolumab versus chemotherapy.

Now, in CheckMate 451, this was looking at maintenance therapy after having received chemotherapy in the frontline setting of small cell lung cancer. This was nivolumab versus nivolumab-ipilimumab versus placebo. And what we see in that is, again, a negative study. To me, 1 of the more interesting things to take away from this was the nivolumab versus nivolumab-ipilimumab arms. The statistics of this was set up in a hierarchy, so technically this was not a direct evaluation where the stats are being done for this. But when we at least just look at those numbers, we do not see a substantial difference between those numbers. In fact, if anything, we see a little bit of a trend of improvement in the nivolumab arm. These are essentially very similar in outcomes. But at a minimum, the nivolumab numbers are actually slightly better. When we’re talking about ipilimumab, which does have a real adverse-effect profile to it, there doesn’t seem to be a hint of justification for that, at least within this clinical setting.

So to summarize those, essentially what we’re seeing from these checkpoint inhibitor studies, from the KEYNOTE and CheckMate studies, is that most patients don’t really benefit from the treatment. However, those who do really have a median durable response to these. And we see some who really benefit tremendously from these drugs.

I think what we’re generally seeing is that the majority of patients don’t benefit from these checkpoint inhibitors, but those who do can really have very durable, impressive benefits from these drugs.

Transcript Edited for Clarity

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