Simon Shares Insight on Emerging Immunotherapy Regimens in NSCLC

George R. Simon, MD

Following the success of single-agent immunotherapy, multiple studies are investigating immunotherapy combination strategies for patients with non—small cell lung cancer (NSCLC), according to George R. Simon, MD.

In a trial combining immunotherapy with chemotherapy, the phase III KEYNOTE-189 study—the confirmatory trial for the May 2017 FDA approval of pembrolizumab (Keytruda) with carboplatin/pemetrexed—demonstrated improved survival in the frontline treatment of patients with nonsquamous NSCLC. Participants received pembrolizumab or placebo in combination with pemetrexed and either cisplatin or carboplatin. The study met both primary endpoints of progression-free survival (PFS) and overall survival (OS).

It was also recently reported that the dual immunotherapy regimen of nivolumab (Opdivo) and ipilimumab (Yervoy) improved PFS compared with chemotherapy in treatment-naïve patients with high tumor mutation burden NSCLC, according to preliminary findings from part 1a of the phase III CheckMate-227 trial.

OncLive: Please provide an overview of your presentation on frontline combination strategies in NSCLC.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Simon, a professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed emerging advancements with immunotherapy combination strategies for patients with NSCLC.Simon: I discussed immunotherapy combinations in the first-line setting for the treatment of patients with NSCLC. These consist of combining immunotherapy with chemotherapy or combining immunotherapy with another immunotherapy agent.

The principal studies that are farthest along in development are the KEYNOTE studies. Principally, cohort G of the KEYNOTE-021 trial, which has already reported out, suggested a significant advantage for combining carboplatin and pemetrexed with pembrolizumab. As a follow-up to that study, there is a larger phase III study called KEYNOTE-189, for which a recent press release suggested that it met its coprimary endpoints of PFS and OS. We have not seen the data yet; I believe that will be presented soon.

Other combination studies are exploring chemotherapy and immunotherapy options. The principal combination of that strategy is atezolizumab (Tecentriq) with various chemotherapy drugs, including carboplatin and nab-paclitaxel (Abraxane). A press release suggested that it met 1 of its primary endpoints of PFS. Those data were presented briefly at the 2017 ESMO Congress, where they looked at carboplatin and paclitaxel with atezolizumab and bevacizumab (Avastin) versus carboplatin, paclitaxel, and bevacizumab.

What trials are focusing on the immunotherapy with chemotherapy combinations?

Radiation therapy also shows promise. Can you speak to its potential in combination with immunotherapy?

Can you highlight safety data with chemotherapy and immunotherapy combinations?

Looking to the future, what steps should community physicians take with these types of regimens for their patients?

Other immunotherapy combination studies include CheckMate-227, which is investigating the combination of nivolumab and ipilimumab versus nivolumab by itself. A third study, called MYSTIC, is combining durvalumab (Imfinzi) and tremelimumab. A recent press release suggested that it did not meet its first primary endpoint of PFS, but we are waiting to see the results of the other primary endpoint of OS.KEYNOTE-024 looked at using immunotherapy alone versus chemotherapy, and that showed an OS benefit when immunotherapy was used alone in a population of patients with high PD-L1 expression. You could argue that patients with high levels of PD-L1 could receive immunotherapy by itself. However, KEYNOTE-189 might help answer some of those questions once those data are reported. More recently, there have been reports suggesting that after you complete concurrent radiation for locally advanced NSCLC, giving durvalumab (Imfinzi) for maintenance therapy for 1 year improved PFS. The OS data are still pending, but those are significant improvements in PFS. Other studies are looking at other immunotherapy agents. We have a study looking at atezolizumab in that setting. This is the first significant advance in stage III disease that we have seen in a while where an intervention has improved survival over concurrent radiation alone.Thus far, no serious safety signals have been identified either in cohort G of KEYNOTE-021 or in the PACIFIC trial. Durvalumab was found to be safe in the consolidation setting. One is worried about pneumonitis, particularly with durvalumab in the post-concurrent chemoradiation setting, but no signal was seen in the PACIFIC trial. Even in the chemotherapy plus immunotherapy combination studies, no specific safety signal has risen so far. I would like physicians to take home the importance of selecting patients carefully. There has to be an algorithm, and in my talk, I outlined this algorithm. Targeted therapy is still the best option for patients, particularly for EGFR-mutant and ALK-translocated patients. Those patients might not see much benefit with immunotherapy initially. They could potentially use immunotherapy down the road, but it is a distant choice. We need to choose between using immunotherapy by itself or combining immunotherapy plus chemotherapy.