Treatment of Relapsed/Refractory SCLC

Transcript: Stephen Liu, MD: Unfortunately, the prognosis for relapsed/refractory small-cell lung cancer remains quite poor, and this is a pressing unmet need. For patients who progress on first-line chemotherapy, the standard second-line treatment is topotecan. Topotecan does have a fair amount of toxicities. It’s quite myelosuppressive, and there is a lot of fatigue. It’s a difficult regimen to administer and to receive at the currently approved doses.

However, it remains our standard of care after a randomized trial showed a response rate of about 24%, PFS [progression-free survival] of about 6 months, and an improved quality of life compared with CAP [cyclophosphamide, doxorubicin, cisplatin]. However, if patients relapse fairly shortly after completing platinum doublet chemotherapy for a platinum-refractory or resistant small-cell lung cancer, topotecan, though approved in that setting, is really not an effective treatment. And there have been few if any options that have shown efficacy in that particular setting.

Benjamin P. Levy, MD: Currently, for patients who have extensive-stage small-cell lung cancer, obviously we’re offering them chemotherapy with immunotherapy as first-line treatment. Based on the data from IMpower133 and CASPIAN, we have a new treatment paradigm. I think the question becomes, what do you do next? When patients experience relapse or progression, what are the options on the table? The 1 FDA-approved option currently is topotecan, and topotecan unfortunately has a response rate of 15% to 20% in this setting and is not extremely well tolerated by patients. Really, that’s where we are right now. Until we have newer drugs—and we have some that are coming out soon—usually topotecan is the standard of care.

Now, topotecan is the board answer. Is that what I do for my patients? I usually don’t. These patients either go on to clinical trials or I offer other types of chemotherapy regimens, like a taxane or gemcitabine. Those drugs are a little better tolerated in this setting than topotecan and have similar efficacy. I’ve been swaying away from topotecan and have really been trying these—off a clinical trial—other chemotherapy drugs, which may elicit more meaningful responses in these patients.

Stephen Liu, MD: Immunotherapy is approved for the treatment of relapsed/refractory small-cell lung cancer. This is based on several studies that explored the efficacy of nivolumab and pembrolizumab in this setting. Nivolumab was explored in the phase I/II CheckMate032 study. This is a large-basket trial that explored the efficacy of nivolumab, a PD-1 [programmed cell death protein 1] inhibitor, alone or with ipilimumab, a CTLA4. One of the cohorts was in patients with previously treated small-cell lung cancer. Most patients were quite heavily pretreated. In that study, which was nonrandomized, we saw that nivolumab alone offered a response rate of about 10%. When we added ipilimumab, we doubled the response rate to about 20%. We also significantly increased the toxicity with a grade 3/4 adverse-event rate of around 30%.

The median progression-free survival was quite poor, about 1.4 months, with nivolumab alone at the time of the first scan, telling us that most patients don’t see a significant progression-free survival. However, the landmark survival rates were quite high. If you looked at nivolumab and ipilimumab in heavily pretreated patients, the 18-month survival rate exceeding 20% was quite remarkable. While that number may seem low, with any standard therapy it would be quite close to 0; to see 1 of 5 or 1 of 4 patients alive 2 years later is quite remarkable and tells us there is certainly activity.

In the third-line setting, nivolumab monotherapy in CheckMate 032 was not associated with a high response rate, about 12%, but the responses were high quality, quite durable. And with the lack of other third-line options, the FDA granted accelerated approval to nivolumab in the third-line setting. This was followed by the approval of pembrolizumab. This was based on 2 separate phase II trials. In both studies, we saw very similar trends to nivolumab: modest response rates, very high landmark survival rates. In the third-line setting, monotherapy with pembrolizumab is associated with a response rate of about 19% but fairly durable responses, with again impressive landmark survival. With comparable efficacy across trials to nivolumab, pembrolizumab was also granted accelerated approval by the FDA as third-line monotherapy for extensive-stage small-cell lung cancer.

Unfortunately, very few patients received third-line treatment. In a fairly large single-institution experience, out of patients who receive frontline chemotherapy, only about 1 of 5 receive third-line treatment. It’s hard to reconcile that because these are potentially transformative drugs, some patients living for years with treatment. How do we ensure those patients have the opportunity to receive immunotherapy? How do we maximize the impact of those drugs? We try to move those earlier. Unfortunately, those efforts have been somewhat disappointing.

In the second-line setting, nivolumab versus topotecan was examined in the CheckMate331 study. In this trial, despite topotecan being a fairly low bar, nivolumab did not improve overall survival compared with topotecan in this unselected population. A maintenance study of nivolumab alone or nivolumab with ipilimumab versus placebo for patients who had small-cell lung cancer, completed chemotherapy and did not progress, also was negative. Patients who hadn’t progressed finished chemotherapy then received nivolumab and ipilimumab, and that did not have a survival impact over placebo. In fact, the only strategy that has improved survival has been the first-line incorporation of immunotherapy. And while pembrolizumab and nivolumab are approved as third-line monotherapy, these approvals were for patients who had not received immunotherapy before. And in an era where we are using PD-L1 [programmed death-ligand 1] inhibitors in the first-line setting, their impact is probably going to be quite low.

Transcript Edited for Clarity