The combination of nivolumab plus ipilimumab was at least as effective as chemotherapy in front-line therapy for patients with advanced non–small cell lung cancer (NSCLC) and brain metastases at baseline, according to the results of a post hoc analysis from part 1 of the phase III CheckMate 227 trial, presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.¹

Nivolumab plus ipilimumab improved overall survival, progression-free survival, objective response rates, and duration of response vs chemotherapy in patients with and without brain metastases at baseline. The analysis also showed that patients with PD-L1 expression of 1% or greater had better outcomes on the immunotherapy combination.

“Hazard ratios for overall survival and progression-free survival favor the combination of nivolumab and ipilimumab. Also, systemic overall responses and duration of responses with the combination were similar in patients with and without brain metastases,” said lead author Hossein Borghaei, DO, MS, Chief of Thoracic Medical Oncology and Professor in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia.

Hossein Borghaei, DO, MS

Part 1 of the randomized, open-label, phase III CheckMate 227 trial enrolled patients with stage IV or recurrent NSCLC with no known mutations in EGFR or ALK who were previously untreated. Brain metastases were allowed if they were stable or treated. Stratification was based on histology (nonsquamous vs squamous). Dr. Borghaei presented the results of a post hoc analysis of 134 patients from study parts 1A and 1B with baseline brain metastases and 1,032 patients without baseline metastases.

In part 1A of the trial, 1,189 patients with PD-L1 expression of 1% or higher were randomly assigned 1:1:1 to nivolumab/ipilimumab (n = 396), chemotherapy (n = 397), or nivolumab alone (n = 396). In part 1B of the trial, 550 patients with PD-L1 expression less than 1% were randomly assigned 1:1:1 to receive the combination (n = 187), chemotherapy (n = 186), or nivolumab plus chemotherapy (n = 177). Since this was a post hoc analysis and brain lesions were considered to be nontarget lesions, there were no data on intracranial response.

Key Findings

Median overall survival in patients with baseline brain metastases (treated or stable) was 17.4 months with nivolumab/ipilimumab vs 13.7 months with chemotherapy, for a 40% improvement favoring the combination. Median overall survival in patients with no brain metastases at baseline was 17.1 months for the immunotherapy combination vs 13.9 months with chemotherapy, a 33% improvement favoring nivolumab/ipilimumab. The 3-year survival rate, with and without brain metastases, was 33%.

Median treatment duration with nivolumab/ipilimumab was 4.2 months among patients with brain metastases at baseline vs 4.2 months in patients without baseline brain metastases. Median duration of chemotherapy was 3.6 months in patients with baseline brain metastases vs 2.6 months in patients without baseline brain metastases, respectively.

In the overall part 1 population, fewer patients treated with nivolumab/ipilimumab had subsequent treatment compared with those who received chemotherapy. Among patients with brain metastases, 42.6% on the combination arm received subsequent treatment vs 66.7% in the control arm. In the group without baseline brain metastases, 47.4% on the combination arm were given subsequent therapy vs 61.1% on the control arm.

Among all patients in part 1 with PD-L1 expression of 1% or higher, those receiving nivolumab/ipilimumab had improved overall survival vs those on chemotherapy. Median overall survival in patients with baseline brain metastases and PD-L1 expression of 1% or higher was 20.6 months for the nivolumab/ipilimumab group vs 13.7 months for the chemotherapy group and 12.0 months with nivolumab alone. In patients without baseline brain metastases and PD-L1 expression of 1% or higher, median overall survival was 16.7 months for nivolumab/ipilimumab recipients vs 15.0 months with chemotherapy and 16.1 months with nivolumab monotherapy.

No new safety signals were found with the immunotherapy combination. Treatment-related central nervous system disorders occurred in 15.6% of patients with brain metastases who received nivolumab/ipilimumab vs 16.7% of those who received -chemotherapy.

The nivolumab/ipilimumab combination was approved by the U.S. Food and Drug Administration in May 2020 as a first-line therapy in metastatic NSCLC without EGFR or ALK aberrations and PD-L1 expression of 1% or higher, based on primary findings from part 1 of CheckMate 227.

Perspectives on Study Results

“The results of CheckMate 227 add nivolumab/ipilimumab as an additional option for first-line treatment of NSCLC without a known driver mutation. Prior to the approval of nivolumab/ipilimumab, single-agent immunotherapy or immunotherapy plus chemotherapy was the standard,” explained Jhanelle Gray, MD, Chair of the Department of Thoracic Oncology at Moffitt Cancer Center, Tampa, Florida.

Jhanelle Gray, MD

“The data in this analysis support what has been demonstrated previously in patients with melanoma—that immunotherapy can have benefit in patients with central nervous system metastatic disease,” she continued. Regarding value, Dr. Gray noted that one would have to compare the cost and toxicities of chemotherapy plus immunotherapy vs combination immunotherapy. “Nivolumab/ipilimumab can be considered in patients whose tumors have a PD-L1 score of 1% to 49% using the 22C3 antibody, as well as patients who may have a contraindication to chemotherapy,” she said.

Also weighing in, Tawee Tanvetyanon, MD, MPH, of Moffitt Cancer Center, said: “Because this was a post hoc, unplanned subgroup analysis [and only 66 patients with brain metastases were treated with the combination], I would not say this is a new standard of care yet. But it is safe to be used in this setting, provided that the PD-L1 expression level is at least 1%.”

Ravi Salgia, MD, PhD, a medical oncologist at City of Hope, Duarte, California, said: “It’s a great finding. Nivolumab plus ipilimumab is already approved for adenocarcinoma and squamous cell NSCLC. To have this finding about brain metastases is phenomenal.”

Tawee Tanvetyanon, MD, MPH

Ravi Salgia, MD, PhD. Photo: City of Hope.

Dr. Salgia continued: “These findings do change the treatment paradigm. If a patient has small brain metastases, we can use this combination to control and resolve them. The caveats are that large brain lesions may need resection, edema needs to be controlled, and if EGFR or ALK mutations are present, the patient needs targeted therapy. There is precision medicine with targeted therapy or immunotherapy, and ultimately personalized therapy. I also treat according to the number of brain metastases, the presence of edema, and the presence of neurologic complications.”

In addition, Dr. Salgia said, “It is not clear if chemotherapy still has a role in the upfront treatment of advanced NSCLC. The question to ask is whether chemotherapy plus immunotherapy is better than nivolumab plus ipilimumab. Other trials will answer this question. Also, patients with PD‑L1 expression less than 1% may benefit from chemotherapy,” he said. 

DISCLOSURE: Dr. Borghaei has received honoraria from Axiom Biotechnologies, Bristol-Myers Squibb, Celgene, and Pfizer; has served in a consulting or advisory role for AbbVie, Amgen, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia AB, Celgene, EMD Serono, Genentech, Genmab, HUYA Bioscience International, Lilly, Merck, Novartis, Pfizer, PharmaMar, Regeneron, Rgenix, Sonnet Biotherapeutics, Takeda, and Trovagene; has received institutional research funding from Bristol-Myers Squibb, Celgene, Lilly, Merck, and Millennium; has been reimbursed for travel, accommodations, or other expenses by Amgen, Bristol-Myers Squibb, Celgene, Clovis Oncology, Genentech, Lilly, Merck, and Novartis; and has had other relationships with Incyte, Takeda, and the University of Pennsylvania. Dr. Gray has received research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GI Therapeutics, Novartis, Pfizer, and the Ludwig Institute of Cancer Research; and has served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, Blueprint Medicines, EMD Serono/Merck KGaA, Inivata, Merck, and Novartis. Dr. Tanvetyanon reported no conflicts of interest. Dr. Salgia has served in a consulting or advisory role for AbbVie, Ariad, Iovance Biotherapeutics, and Novartis, and Octimet; and has participated in speakers bureaus for AstraZeneca and Merck.

REFERENCE

1. Borghaei H, Pluzanski A, Caro RB, et al: Nivolumab + ipilimumab as first-line treatment for patients with advanced non-small cell lung cancer with brain metastases: Results from CheckMate 227. 2020 AACR Virtual Annual Meeting II. Abstract CT221.