Stephen Liu, MD: I think one of the important things to keep in mind with extensive stage small cell lung cancer is this is a disease that moves quickly, and we really need to minimize delays. We know from early placebo-controlled trials in the 1970s that without treatment the average survival would only be a few months. So we really need to institute systemic therapy as quickly as we can. As a result, a lot of the patients who we are treating for small cell lung cancer don’t perfectly fit the clinical trial population. Patients may not have a perfect performance status. They may not have treated brain metastases. But we need to move forward, or we lose the opportunity to institute therapy.
With platinum doublet chemotherapy, we see fairly high response rates. At times, we even see complete responses. The problem has been that these responses are transient. And as much as we expect a response and we expect patients to feel better, we also expect relapse. Small cell lung cancer responds to any number of agents up front, but that response is transient. When the cancer relapses, it is highly refractory to most of our standard treatments.
Our standard since the 1980s has been platinum/etoposide chemotherapy for small cell lung cancer. We have not been able to improve upon that regimen, but it’s not for lack of trying. There have been many failed phase III trials for small cell lung cancer. You can name up to 40 different trials. Over 60 different drugs have failed to improve the standard of care. We’ve tried many different strategies—alternating back and forth between regimens, high doses of chemotherapy, novel combinations, antiangiogenesis. The list is very long. What we are sometimes able to do is increase the response rate, improve progression-free survival, but not really impact the history of the disease. We haven’t been able to improve survival.
My approach for extensive stage small cell lung cancer is a combination of carboplatin, etoposide and atezolizumab, an anti—PD-L1 [anti–programmed death-ligand 1] antibody. And that is concurrent use from the beginning followed by maintenance atezolizumab until progression or a loss of benefit. This is based on the IMpower133 trial. This is a randomized, phase III, double-blind, placebo-controlled trial where all patients received standard carboplatin, AUC [area under the curve] 5, plus etoposide at 100 mg/m2 days 1 through 3. They were randomized 1:1 to receive concurrent atezolizumab or placebo during chemotherapy; after 4 cycles, then maintenance atezolizumab or placebo.
What the study showed, for the first time in decades, was that the addition of atezolizumab, this intervention, this addition of upfront immunotherapy, improved survival. We had a median survival of 12.3 months versus 10.3, which is a hazard ratio of 0.70—a 30% reduction in the risk of death. Importantly, that survival benefit did not come with the cost of significant toxicity. The rate of grade 3/4 adverse events were similar between both arms. Most patients were able to complete 4 cycles of chemotherapy. The survival benefit didn’t compromise our ability to complete chemotherapy. And with that improvement in survival, we finally advanced the field. So that’s really been my approach.
What we’ve seen in other trials is that the use of second-line immunotherapy, nivolumab versus topotecan, did not improve survival—CheckMate 331. We saw maintenance therapy with nivolumab/ipilimumab right after chemotherapy, not waiting until progression. That maintenance strategy also did not improve survival versus placebo. The only strategy that’s been shown to improve survival is the upfront addition of an anti—PD-L1 inhibitor with first-line chemotherapy. And so these delays run the risk of forfeiting that survival benefit.
Some of our first experiences with immunotherapy in extensive stage small cell lung cancer were in the relapsed and refractory setting. What we saw was that previously treated patients with small cell lung cancer who received nivolumab monotherapy had a response rate of about 10%. When you add the CTLA-4 [cytotoxic T-lymphocyte—associated protein 4] antibody, ipilimumab, it doubled the response rate to about 20%. You also increased toxicity. We see comparable response rates with pembrolizumab monotherapy in the third-line setting, about 19%. These response rates are modest. If you look at median progression-free survival, they’re quite poor, somewhere between 1.5 and 2.5 months with any of those regimens.
But what we see with those treatment options with immunotherapy in the third-line setting: Our durable benefit, our extended survival, our landmark survival rates that are much higher than we would expect with nivolumab and ipilimumab. In CheckMate 032, we saw a 2-year survival rate of over 25%. And so, while the medians are not too impressive, the landmark survival rates are quite impressive. In the third-line setting, to have more patients alive at 18 months, at 2 years, really is quite remarkable. That led to the approval of nivolumab and pembrolizumab in the third-line setting, and accelerated approval based on the durability of that benefit in the extended landmark survival.
Moving those drugs to the second-line setting, though, has proved challenging. Nivolumab versus topotecan in CheckMate 331 did not prove to be superior, so we don’t have a viable option over chemotherapy in the second-line setting. In the maintenance setting, nivolumab/ipilimumab versus placebo did not improve survival. And so, we have drugs approved in the third-line setting, really filling an unmet need. In the second-line setting, our standard of care would remain chemotherapy, and the only FDA-approved agent there is topotecan. But certainly, an unmet need for more novel agents there. And as we move immunotherapy into the frontline setting, the second-line option has to change, and that space is still evolving.
Transcript Edited for Clarity