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