Insights From: Stephen Liu, MD, Georgetown University; Benjamin P. Levy, MD, John Hopkins Sidney Kimmel Cancer Center
Stephen Liu, MD: Chemotherapy with a PD-L1 [programmed death-ligand 1] inhibitor is the current standard of care for the treatment of extensive-stage small-cell lung cancer. This is based on 2 randomized phase III trials, IMpower133 and CASPIAN, which both showed that the addition of a PD-L1 inhibitor to a platinum/etoposide backbone improved overall survival without a significant increase in toxicity.
Benjamin P. Levy, MD: The IMpower133 trial was a welcome change. This was a trial evaluating the role of adding immunotherapy with a PD-L1 drug to chemotherapy in extensive-stage small-cell lung cancer. It randomized patients between carboplatin-etoposide for 4 cycles versus carboplatin-etoposide with the addition of atezolizumab. Patients in both arms received 4 cycles of either 2 or 3 drugs. In the experimental arm, if patients had at least stable disease after 4 cycles, they were allowed to go on maintenance atezolizumab, which I think is important.
What we saw from this study was the first survival advantage in extensive-stage small-cell lung cancer in over 30 years. There was an improvement in median overall survival of roughly 2 months. The experimental arm was around 12.2, 12.3 months versus 10 months in the control arm. We also saw improvements in landmark analyses at both 12 and 18 months of a roughly 12% difference in overall survival between the 2 arms in the study.
Importantly, there was a biomarker search to see, who were the patients that really garnered a benefit with this regimen? But it didn’t seem that PD-L1 predicted outcomes for these patients, so it didn’t matter what your PD-L1 status was. I don’t think we could look at PD-L1 to inform treatment decisions. I think every patient should be considered for carboplatin-etoposide and atezolizumab. They also looked at TMB, tumor mutational burden, in the plasma to see if levels of TMB in the plasma were predictive of outcome for the triplet regimen. And we didn’t see that.
The biomarker search is important because we’re trying to understand who those patients are who garnered the most benefit from this regimen. Importantly, we know right now that every patient who doesn’t have a contraindication to immunotherapy, every patient with extensive-stage small-cell lung cancer, should be considered for triplet therapy with platinum-etoposide and atezolizumab.
With the publication and the presentation of IMpower133 and its results, I’ve shifted my practice pattern, and I think it’s important. This is the first trial to show survival advantage in over 30 years, and so for all my patients with extensive-stage small-cell lung cancer, I do offer platinum-etoposide with atezolizumab every 3 weeks for 4 cycles. And then if the scan shows response or at least stable disease, I continue them on atezolizumab every 3 weeks until 1 of 2 things: disease progression or toxicity.
My clinical experience with this regimen mirrors what we’ve seen in the data. Patients do garner a benefit from it, and patients do end up going on maintenance atezolizumab. It’s a little bit of a different story from non–small-cell lung cancer, where you see this very large tail of the curve or an unprecedented tail of the curve. We’re not necessarily seeing that in small-cell lung cancer, so I don’t have many patients who remain on atezolizumab for years. I haven’t given it enough, or I’m still too early on in giving it, to know what the long-term outcomes are for these patients. Basically, my experience is mirroring what we’re seeing in the data.
Recognizing immune-related adverse events is important, and we see these whether we’re giving checkpoint inhibitors as single agents or they’re being given in combination with chemotherapy. I think what we’ve learned is that when we give these agents in combination with chemotherapy, we don’t see increased rates of immune-related adverse events when we compare with just giving single-agent immunotherapy. You just have to be mindful of all the things you would be if you were giving it as a single agent.
We have to be mindful of pneumonitis, we have to be mindful of colitis, we have to be mindful of liver function abnormalities, and of course we have to be mindful of endocrine problems, specifically with thyroid function. Monitoring their thyroid function is important. I think fatigue is 1 thing that’s underrepresented. It’s reported in the literature. These drugs can cause fatigue, and as a single agent can cause fatigue. We need to be mindful of that. But overall, compared with what we’ve seen before in other agents we’ve looked at, this is a fairly well-tolerated regimen and a fairly well-tolerated drug, which is a welcome change. Yes, we’re improving outcomes on the order of 8 to 10 weeks. But at the same time, the drugs are exceptionally well tolerated and don’t lead to deterioration in quality of life.