Bunn Discusses Future of Immunotherapy in SCLC

Paul A. Bunn Jr, MD

For the first time in decades, physicians treating small cell lung cancer (SCLC) are getting new tools in their armamentarium, said Paul A. Bunn Jr, MD.

Bunn, the James Dudley Chair in Lung Cancer Research at the University of Colorado Cancer Center, said that the research on immunotherapy, alone and in combination, may provide new treatment options for this long-overlooked disease.

“In SCLC, we're not going to use etoposide and platinum [-based therapy] 10 years from now as we have been for the past 30 years, and that's a good thing,” he said. “Immunotherapy is going to be a part of the treatment and there is going to be a resurgence of interest and, hopefully, more people going on trials.”

In August 2018, the FDA granted an accelerated approval to single-agent nivolumab (Opdivo) for the treatment of patients with SCLC with disease progression following platinum-based chemotherapy and 1 other line of therapy, based on data from the phase I/II CheckMate-032 trial.

In the open-label study, the objective response rate (ORR) was 12% (95% CI, 6.5-19.5) for nivolumab after platinum-based chemotherapy and 1 other prior line of therapy in 109 patients, according to the new label. This response rate consisted of partial responses (11%) and a complete response (0.9%). The median duration of response (DOR) was 17.9 months (95% CI, 7.9-42.1).^1,2

The combination of nivolumab and ipilimumab (Yervoy) is also being evaluated in SCLC, as well as single-agent checkpoint inhibitors pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Results of the phase III IMpower133 trial showed that combining frontline atezolizumab with chemotherapy improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy alone in patients with extensive-stage SCLC.

OncLive: Could you provide an overview on the current state of research in SCLC?

In an interview with OncLive^® just prior to the FDA approval of nivolumab in SCLC, Bunn, who is also a 2014 Giant of Cancer Care^® in Lung Cancer, discussed the potential for new agents to treat SCLC, the challenges involved in treating this population, and the ongoing search for biomarkers to guide treatment decisions.Bunn: The main immunotherapeutic agents being studied now are checkpoint inhibitors—antibodies that bond to either PD-1 or PD-L1. Since they bind to that interaction, one of the biomarkers that has been explored is PD-L1 expression. In some cancers, such as non—small cell lung cancer (NSCLC), that's been a decent biomarker. One of the issues in SCLC is that these tumors tend to have pretty low PD-L1 expression. Therefore, one of the major issues is, just like in NSCLC, is there a better biomarker?

One that has been suggested is tumor mutation burden (TMB). Small cell cancers, since they're all in smokers, have a higher TMB in general. There's some evidence that TMB might be a good biomarker, especially for the addition of CTLA-4 inhibitors.

But going back to the original studies, there was a study of pembrolizumab alone that showed a response rate in about 30% of patients. The progression-free survival was not very long, but there is a tail on the curve. Among the patients who responded, those responses last a long time. There was about 30% of patients who were alive at 1 and 2 years, which is much higher than chemotherapy. This was in second-line treatment. The response rate, of 20% to 30%, is not outstanding but the long-term survival was very impressive.

There is also a study comparing nivolumab alone versus nivolumab and ipilimumab (Yervoy). Again, between 20% to 30% of patients responded, which is mostly not related to PD-L1 expression. However, the patients who received nivolumab plus ipilimumab seemed to do a little bit better— but if they had high TMB, they did much better with the combination.

Those are small trials that have led to randomized trials. Looking at the randomized trials, let's take extensive-stage disease. Just like in NSCLC, there could be several ways to do this. One would be to add to chemotherapy itself—chemotherapy plus a checkpoint inhibitor versus chemotherapy alone. One of those trials with atezolizumab announced a positive result. No one other than the Data and Safety Monitoring Board and the company [Genentech] have seen the results, but we're really looking forward to them.

The other ongoing trials with pembrolizumab doing the same thing—randomizing patients to chemotherapy or chemotherapy plus immunotherapy. However, another approach is to give 4 cycles of chemotherapy, then maintenance immunotherapy and Bristol-Myers Squibb just did a study like that. At maintenance, people are randomized to either nivolumab alone or nivolumab plus ipilimumab.

We also know that in limited-stage NSCLC, the addition of durvalumab (Imfinzi) after chemotherapy improved PFS and OS. Now there are trials in limited-stage ongoing, also after chemoradiation, to see if immunotherapy will improve survival outcomes after standard induction therapy.

How would an approval of nivolumab affect patients with SCLC?

It's likely that immunotherapy will be used in the first-line setting. It may be that we need to measure TMB and consider combinations of immunotherapies, but that remains to be determined. I'm very optimistic that checkpoint inhibitors will improve survival in SCLC to the same extent that they do in NSCLC.Right now, according to the NCCN guidelines, you can give nivolumab, nivolumab and ipilimumab, or pembrolizumab after chemotherapy. Once again, while only 20% or 30% of patients have a response, the majority of those responses last for a long time. Most people, myself included, we're giving immunotherapy after patients relapse on induction chemotherapy. We know from NSCLC that it's probably better to do it in the first-line rather than second-line setting. If these first-line trials turn out to be positive, we are probably not going to be giving these agents in the second-line setting, we'll be giving them in the first-line setting.

Will other classes of immunotherapies become more prominent in SCLC?

What emerging agents—immunotherapy or targeted—are you excited about in SCLC?

That said, many people don't benefit. We need better biomarkers and we need combinations to increase the fraction of patients who benefit.Undoubtedly, yes. There are many more patients who have NSCLC, so some of these things tend to be done first [in that space], and many are done without preclinical data. Undoubtedly, if some of those have a positive signal that something is adding to a checkpoint inhibitor, you'll see that rapidly translated to SCLC. Most of those combinations are not being done primarily in SCLC. This is because there are fewer patients and we don't have the final results of the first-line randomized trials, other than a recent press release about the atezolizumab trial.Lurbinectedin is an interesting one. Rovalpituzumab tesirine (ROVA-T), despite some less-than-expected results in the third-line setting, still has a second-line trial ongoing and several first-line trials. There are certainly responses even in that third-line trial, though not as high as what was expected.

What are the treatment challenges unique to SCLC?

There is activity with PARP inhibitors, but we're still looking for a biomarker; there are a number of biologically based treatments in SCLC.First, all patients with SCLC are heavy smokers so they have a lot of comorbid diseases, so anything with toxicity will be [of higher grade] in SCLC. Second, since smoking has been declining in the United States over the past 20 years, the number of SCLC cases has been declining. Third, because we haven't had any treatment advances and the same chemotherapy has been standard, many people in the community keep these patients and don't refer them to clinical trials. Finally, after 20 or 30 years, that's beginning to change, albeit slowly.

References

1. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstr 100).
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5.