Naiyer Rizvi, MD: Small-cell lung cancer has been an incredibly recalcitrant disease, especially if you have extensive stage disease. You know, we've had no advances beyond chemotherapy forever. And IMpower133 was I think the first positive, phase III trial in small cell. It was published in the New England Journal of Medicine. Leora was the first author. So, Leora, tell us about IMpower133 since it's your trial.

Leora Horn, MD, MSc: Sure. There are a lot of people out there saying it's only a 2-month benefit. But it is a positive study. So it was a randomized, phase III trial looking at carboplatin and etoposide. Importantly, it didn't have cisplatinum, which is a big difference between the IMpower133 study and CASPIAN, with or without atezolizumab. And while response rate was not improved—it's hard to improve on an almost 70% response rate—there was an improvement in progression-free survival, and more importantly, an improvement in overall survival for patients treated with the carbo [carboplatin]/etoposide and atezolizumab. And last year we had a study that pretty much mirrored that: a PD-L1 [programmed death-ligand 1] inhibitor, durvalumab, the CASPIAN trial, that looked at carbo/etoposide, or cis [cisplatin]/etoposide with or without durvalumab. And, again, another positive study significant for extensive stage small-cell lung cancer.

Naiyer Rizvi, MD: And, Jacob, what do you think? Is it great, or is it so-so?

Jacob Sands, MD: Well, I mean there's widespread enthusiasm about this, and it's been hailed as really the first advance in decades in small-cell lung cancer. This is the new first-line therapy. I have a little bit of a different impression as to why. I'll point out that in both trials very few patients who were in the control arm ever got a checkpoint inhibitor. So in some ways, this really showed us that the checkpoint inhibitors work for a portion of these patients, which I think we already knew. I will also point out that, although people say that the median progression-free survival was only a month and the overall survival only 2 months, that's kind of not the point. When you look out at the tail, there is a percentage of patients who are really having long-term, durable responses, and that is incredibly meaningful.

So, again, to my analogy earlier, these checkpoint inhibitors are swinging for the fences. It really is swinging for a homerun, and when you connect, we see amazing responses, and durable responses in this very difficult-to-treat population. My impression on using it first-line is a little different in that the most patients don't really tend to get a great response from the checkpoint inhibitors alone. And if you're saving it only for second-line, you're now having the majority of patients getting a drug that ends up not really being effective to try and catch those from whom it is very effective, and in doing so you lose the opportunity for other treatment options. So I do think it's very important. It's meaningful to use it in a frontline setting. These drugs do work for probably more like 10% to 20% of patients, who really get very meaningful benefit from these drugs. It's a huge advance for those individuals over what was previously available in small-cell lung cancer.

Joshua Bauml, MD: But I don't think that it's only that. I think that there must be some synergy because if you look at the second-line studies that have been done, particularly, there was a study that randomized patients who had completed platinum/etoposide for extensive stage small-cell to nivolumab, nivolumab/ipilimumab, or placebo, and nivolumab/ipilimumab didn't beat placebo. So I think that these drugs do have some benefit. We don't know for whom it is, but the fact that we're seeing now 2 large phase III studies showing that the addition of a PD-L1 inhibitor, notably not a PD1 inhibitor, not pembrolizumab, 2 chemotherapy in extensive stage small-cell lung cancer led to an improvement in overall survival. The improvement is modest, but as everyone said, this is the only improvement we’ve had for over 20 years. So I think that this is a very meaningful improvement, and I think that it's important for us to incorporate it front-line and I do suspect here that there is more synergy going on than it is from just exposure to the drug.

Leora Horn, MD, MSc: That same study that you were referring to, Josh, CHECKMATE-451 [NCT02538666], also showed that patients who got nivolumab less than 5 weeks after completing chemotherapy had a median overall survival of 12 months, compared to 9 months for the patients getting nivo/ipi [nivolumab/ipilimumab], or placebo. So it's not that I would advocate doing chemotherapy followed by nivo less than 5 weeks later, but it does point to that synergy giving the checkpoint inhibitor upfront with chemotherapy early.

Tim Kruser, MD: At the same time, we do see differences in the tail of those curves, speaking to the fact that it probably is a subset of patients. And when you're talking about median for a drug that affects a subset, you may lose that in that median versus the subset that's really benefitting. And, you know, for the checkpoint inhibitors, it's probably more meaningful to look at the 1-year progression-free survival as opposed to the median progression-free survival.

Naiyer Rizvi, MD: Leora, we have IMpower133, and we have CASPIAN. How you kind of compare the 2 trials as you go forward?

Leora Horn, MD, MSc: The 1 difference with CASPIAN is that patients could have had 6 cycles of chemo if they were in the chemo alone arm, whereas in the IMpower133 study both arms had 4 cycles. There was a bit of an argument, maybe that was the difference, but clearly it's not the difference. Also, in CASPIAN, patients did not necessarily have whole brain radiation if they were getting checkpoint inhibitor therapy. Now, many of us have moved away from that practice anyway, in patients with extensive stage disease, where we're observing their brains rather than going on to doing whole brain or PCI [prophylactic cranial irradiation], as these patients weren't with brain mets [metastases]. So those were sort of the main differences. I stop at 4 cycles of chemo. You know, I used to give 6 if patients were still responding, and the CASPIAN data shows me that I think that that's fine to do, because those patients did stop at four cycles in the durvalumab arm. And the CNS [central nervous system] surveillance is something that we're doing more, where we're just scanning patients’ CNS every 3 to 6 months in patients where we're not treating their brain.

Transcript Edited for Clarity