Immunotherapy Research Continues to Improve Patient Selection in NSCLC

Roy Herbst, MD, PhD

Nivolumab (Opdivo) plus ipilimumab (Yervoy) in the frontline setting for patients with advanced non—small cell lung cancer (NSCLC) led to an improvement in overall survival (OS) over chemotherapy, regardless of PD-L1 expression, according to data from the phase III CheckMate-227 trial, explained Roy S. Herbst, MD, PhD.

In CheckMate-227, patients with PD-L1 expression ≥1% showed a median OS of 17.1 months with nivolumab/ipilimumab compared with 14.9 months with chemotherapy (HR, 0.79; 97.72% CI, 0.65-0.96; P = .007). Further, the median OS was 17.1 months with the combination compared with 13.9 months with chemotherapy (HR, 0.73; 95% CI, 0.64-0.84) in all randomized patients, regardless of PD-L1 expression. Based on these findings, the FDA granted a priority review designation to a supplemental biologics license application for the combination of nivolumab and ipilimumab for the first-line treatment of patients with metastatic or recurrent NSCLC that does not have EGFR or ALK genomic tumor aberrations.

PD-L1 expression currently serves as the only biomarker used to help determine patient response to immunotherapy versus chemoimmunotherapy, said Herbst. Current standard practice, he added, is single-agent pembrolizumab for patients with PD-L1 expression ≥50%, and immunotherapy plus chemotherapy for patients with PD-L1 <50%. The efficacy seen with immunotherapy/immunotherapy combinations will likely impact clinical practice, Herbst said.

Looking forward, research efforts are focused on other biomarkers for NSCLC, including tumor mutational burden (TMB) and gene signatures.

“There's so much that we have done to benefit patients, but there is so much that we have to learn regarding the best drugs and combinations,” said Herbst, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital. “That will take a little bit of time.”

In an interview with OncLive, Herbst, who is also the Ensign Professor of Medicine and professor of pharmacology, and the associate cancer center director for Translational Research at Yale Cancer Center, discussed research regarding immunotherapy and accompanying biomarkers in NSCLC.

OncLive: What research would you like to highlight from the 2019 ESMO Congress?

Herbst: The major presentation at the 2019 ESMO Congress would be the CheckMate-227 trial, which looked at ipilimumab plus nivolumab versus chemotherapy as frontline therapy for patients with NSCLC. [Ipilimumab/nivolumab] showed a significant improvement in survival in patients who have high PD-L1 expression. There was also an improvement in survival in patients who have low PD-L1 expression, but it was not significant because of the statistical plan and the way the trial was designed.

The trial shows that ipilimumab/nivolumab, 2 immunotherapies without chemotherapy, improve survival versus chemotherapy. The big question [now] is how [does ipilimumab/nivolumab] compare with chemotherapy plus immunotherapy, such as with pembrolizumab (Keytruda). It is hard to make an cross-trial comparison, but it does suggest that we will possibly find a niche for ipilimumab/nivolumab in the future.

Are there any attempts to compare immunotherapy alone versus chemoimmunotherapy?

Ultimately, we will need to do a trial in which we take dual-immunotherapy combinations and compare them with immunotherapy/chemotherapy combinations, but that might be up to the cooperative groups [that conduct these trials].

How is immunotherapy currently being used in the lung cancer space? How has it evolved over the past few years?

Right now, almost every patient with NSCLC is getting immunotherapy. Most are getting immunotherapy combined with chemotherapy. Patients with PD-L1 expression greater than 50%, which is about 20% of patients, will get single-agent immunotherapy—mostly with pembrolizumab. There were recent data presented at the 2019 ESMO Congress with atezolizumab (Tecentriq), which will hopefully lead to a single-agent approval in patients with high PD-L1 expression.

Has there been work with biomarkers to determine whether a patient should receive immunotherapy alone or in combination?

Interestingly, the only biomarker we really have right now is PD-L1. Someday, we might use TMB, gene signature, or some sort of quality measure of the T cells and their potency. Right now, PD-L1 [is what is mostly being used].

What are the immunotherapy combinations currently available to patients?

There are a number of combinations. There is carboplatin, paclitaxel, bevacizumab (Avastin), and atezolizumab, which is a 4-drug combination that was compared to chemotherapy [and showed] a positive result. There is also carboplatin, pemetrexed, and pembrolizumab from the KEYNOTE-189 study, as well as carboplatin, either with paclitaxel or nab-paclitaxel, plus pembrolizumab in the KEYNOTE-407 study.

I always tell my group at Yale Cancer Center that it depends on the chemotherapy and the amount of chemotherapy to enhance the immune system without having an effect on the long-term outcomes. We have a lot to learn.

Peters S, Ramalingam SS, Paz-Ares L, et al. Nivolumab + low-dose ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non—small cell lung cancer: CheckMate-227 part 1 final analysis. Ann Oncol. 2019;30(suppl_5). doi: 10.1093/annonc/mdz394.075.