Immunotherapy/Chemo Combinations Show Potential in NSCLC

Shirish Gadgeel, MD

Pembrolizumab (Keytruda) and nivolumab (Opdivo) have both made a significant difference for a high number of patients with advanced non—small cell lung cancer (NSCLC). However, there is still a great deal to learn about the optimal use of PD-1 inhibitors in the disease, says Shirish Gadgeel, MD.

“Both pembrolizumab and nivolumab are approved for the management of NSCLC and have shown activity,” says Gadgeel, medical oncologist, leader of the Thoracic Oncology Multidisciplinary Team at Karmanos Cancer Center, Wayne State University. “When these agents do work, the benefit is for a prolonged period of time. However, these agents are only efficacious in a minority of patients—probably in the range of 20%.”

To increase the number of patients who benefit from PD-1 inhibitors, researchers are investigating combination treatments that include pembrolizumab or nivolumab.

OncLive: What were the significant findings from the KEYNOTE-021 study?

In an interview with OncLive, Gadgeel discusses the KEYNOTE-021 and KEYNOTE-189 studies, which are both examining pembrolizumab with chemotherapy. He also discusses the role of PD-L1 testing and potential future best practices for the use of PD-1 agents in NSCLC.Gadgeel: KEYNOTE-021 was a phase I multicenter trial evaluating the feasibility of combining pembrolizumab with a variety of agents. The first 3 cohorts—A, B, and C—combined it with cytotoxic chemotherapy in patients with advanced NSCLC. In cohort A, pembrolizumab was combined with carboplatin and paclitaxel. In cohort B, it was added to carboplatin, paclitaxel, and bevacizumab (Avastin). Finally, in cohort 3, pembrolizumab was combined with carboplatin and pemetrexed.

The primary objective was safety, but there was also a secondary objective of efficacy when combining it with chemotherapy. The combination was found to be fairly tolerable in all 3 cohorts. Approximately 25 patients were enrolled in each cohort. There was no dose-limiting toxicity observed except in 1 patient in cohort C who developed a skin reaction called toxic epidermal necrolysis.

The combination showed that the response rate ranged, overall, from 48% to 71% in cohort C. The median progression-free survival (PFS) was about 10.5 months in each of the 3 cohorts and the median OS was not observed after the median follow-up, which ranged from about 9 months to 16 months in each of the cohorts.

Are there other trials exploring pembrolizumab in NSCLC that you find exciting?

The conclusions were that the addition of pembrolizumab with these cytotoxic chemotherapy agents was possible in patients with NSCLC, and that—at least in cohort C—efficacy results were promising enough that this combination is going to be further evaluated in a phase III study.There is also KEYNOTE-189, which is a trial in progress that was presented in a poster at the 2016 ASCO Annual Meeting. In this study, patients with advanced NSCLC who are treatment-naïve were randomized to chemotherapy alone or chemotherapy plus pembrolizumab.

How do you see the use of immunotherapies evolving in NSCLC?

With both pembrolizumab and nivolumab available, how do you determine which is the best option for your patients?

However, the randomization was 2:1, where out of every 3 patients, 2 patients did receive pembrolizumab with chemotherapy. The endpoint of this study, which is currently enrolling, is PFS.In the future, we need to learn how to recognize which patients are going to benefit from these agents and how we can provide benefit for the patients that do not benefit from single-agent therapy. Do we combine these PD-1 agents with chemotherapy similar to how we are doing in these 2 trials? Do we combine it with other immunotherapy drugs? The hope is that we can expand the amount of patients who can benefit from these agents.Basically, both agents are very similar in terms of efficacy and toxicity in the management of NSCLC. However, the one difference in the approval process is, for nivolumab, you don’t have to have a PD-L1 test. With pembrolizumab, the patient’s tumor must be positive for PD-L1 in order to use the drug.

How do you think the use of immunotherapies in NSCLC will change in the future?

From my interpretation of the data, PD-L1—positivity does predict for a higher possibility of benefit, but the lack of PD-L1 expression does not eliminate the possibility of benefit. In general, I don’t get PD-L1 testing done. Therefore, if a patient does not have a PD-L1 result, I am much more likely to use nivolumab. If for whatever reason I do know the PD-L1 status and they are PD-L1–positive, I would likely use pembrolizumab because, from clinical trials, I have more experience with it. I feel very comfortable using either agent, and I don’t think there is really any difference.It is possible that in the future, either with PD-L1 or some other marker, we may start managing these patients differently. If a patient’s tumor is biomarker positive—maybe it is PD-L1—they will only get single-agent nivolumab or pembrolizumab. However, if the patient’s tumor is biomarker negative or below a certain threshold for a certain biomarker, in those patients perhaps we will combine nivolumab or pembrolizumab with another immunotherapy or chemotherapy and provide a greater benefit. We need to be more selective in how we manage these patients instead of just giving everyone pembrolizumab or pembrolizumab combined with chemotherapy.