Neoadjuvant Nivolumab plus Chemotherapy Increased Pathological Complete Response Rate in CheckMate-816 Lung Cancer Trial

PHILADELPHIA – Adding nivolumab (Opdivo) to chemotherapy as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC) produced significant improvement of pathological complete response (pCR, primary endpoint) rate to 24 percent, compared with 2.2 percent in the chemotherapy alone arm, with the combination treatment leading to no increase in overall toxicity or delays to surgery, according to data from the phase III trial CheckMate-816, presented during Week 1 of the virtual AACR Annual Meeting 2021, held April 10-15.

“The standard treatment for resectable lung cancer is surgery to remove the tumor. Despite this, many patients experience recurrence of their lung cancer and when this happens, it is usually incurable,” said Patrick Forde, MBBCh, associate professor at Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University. “Platinum-based chemotherapy given either before (neoadjuvant) or after (adjuvant) surgery improves survival of patients by only 5 percent at five years.

“For the first time in a phase III trial, we see the potential for an anti-PD-1 immunotherapy to improve outcomes in earlier-stage NSCLC. We are highly encouraged by the marked improvement in pCR, the overall good tolerability, and the absence of impact on surgery feasibility when nivolumab is added to neoadjuvant chemotherapy,” Forde said. “Data accumulated to date from several retrospective studies show a clear trend that patients who achieve a pCR with neoadjuvant chemotherapy live longer than those who do not.”

In CheckMate-816, adults with stage 1b-3a resectable NSCLC and no known activating alterations in the EGFR or ALK genes were randomly assigned to receive either nivolumab plus platinum-doublet chemotherapy (179 patients) or chemotherapy alone (179 patients), followed by surgery. pCR was defined as no residual viable tumor when the resected lung specimen and the sampled lymph nodes were examined after surgery.

The trial met its first primary endpoint, with nivolumab plus chemotherapy increasing the pCR rate to 24 percent, compared with 2.2 percent with chemotherapy alone. This improvement was consistent across all subgroups, including disease stage, NSCLC subtype, PD-L1 status, tumor mutational burden status, and for both men and women.

The nivolumab-chemotherapy combination also significantly increased the major pathological response rate (defined as 10 percent or less viable tumor in lung and lymph nodes) to 36.9 percent, compared with 8.9 percent in the chemotherapy alone arm. Pre-surgery objective response rate on imaging in the nivolumab-chemotherapy arm was 54 percent, versus 37 percent in the chemotherapy arm.

“pCR was assessed in both lung and lymph nodes by pathology central review and the pathologist was blinded as to which arm of the study the specimen came from. Therefore, this provides a unique and more stringent assessment of pCR, as compared to other early trials evaluating immunotherapy in the neoadjuvant setting,” Forde noted.

In the nivolumab-chemotherapy arm, 83 percent of patients went on to receive definitive surgery, compared with 75 percent of patients in the chemotherapy arm. “Remarkably, despite the addition of nivolumab to neoadjuvant chemotherapy, there was no associated increase in treatment-related adverse events, and rates of adverse events leading to surgery delay or cancellation were low. This provides reassurance that side effects from the combination will not adversely impact patients’ ability to have curative surgery,” Forde said.

“The significant improvement in pCR and absence of any meaningful increase in toxicity or decrease in the feasibility for surgery suggest that neoadjuvant nivolumab plus chemotherapy is a viable option for patients with resectable NSCLC at high risk of recurrence,” Forde said. “While neoadjuvant therapy has historically been less commonly used than adjuvant therapy for this patient population, I believe that CheckMate-816 has the potential to change that treatment paradigm.”

Forde cautioned that although the results for the primary endpoint of pCR for CheckMate-816 are encouraging, the study continues to mature for the second primary endpoint of event-free survival.

This study was sponsored by Bristol Myers Squibb. Forde has served as an uncompensated consultant for Bristol Myers Squibb in the past and the company has provided research funding to his institution. Forde has served as a consultant for Amgen, AstraZeneca, Janssen, Daichii Sankyo, and Novartis. AstraZeneca, Novartis, and Kyowa have provided research funding to his institution.