CheckMate 816: Neoadjuvant Nivolumab Plus Chemotherapy Boosts Pathologic Complete Response in Resectable NSCLC

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Neoadjuvant chemotherapy with nivolumab plus platinum-doublet chemotherapy significantly improved pathologic complete response rates compared with chemotherapy alone in patients with resectable stage IB to IIIA non–small cell lung cancer (NSCLC), according to the results of the CheckMate 816 study presented at the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021.1 The pathologic complete response rate was 24% with nivolumab plus chemotherapy vs 2.2% with chemotherapy. In the trial, pathologic complete response was the primary endpoint, and pathologic complete response to neoadjuvant therapy has been associated with improved survival in retrospective studies.

“The standard treatment of resectable lung cancer is surgery to remove the tumor. Despite this, many patients experience recurrence of their lung cancer, and when it happens, it is usually incurable,” explained lead author ­Patrick M. Forde, MBBCh, Associate Professor at the Sidney Kimmel Comprehensive Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, Baltimore.

Patrick M. Forde, MBBCh

Patrick M. Forde, MBBCh

“For the first time in a phase III trial, we see the potential for an anti–PD-L1 immunotherapy to improve outcomes in earlier-stage NSCLC. We are highly encouraged by the marked improvement in pathologic complete response, the good overall tolerability, and the absence of impact on the feasibility of surgery when nivolumab is added to neoadjuvant chemotherapy,” stated Dr. Forde.

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

Study Description

Platinum-based neoadjuvant or adjuvant chemotherapy for resectable NSCLC improves survival by just 5% at 5 years. “Several studies suggest a clear association between pathologic complete response and overall survival. Of note, patients with resectable NSCLC treated with neoadjuvant chemotherapy have had low rates of pathologic complete response, a median of 4%, ranging from 0% to 16%,” Dr. Forde said. More recently, single-arm phase II studies of immunotherapy as monotherapy or in combination have yielded encouraging results, leading to the phase III CheckMate 816 trial.

Dr. Forde presented the final analysis of pathologic complete response and key secondary endpoints in the randomized, open-label CheckMate 816 trial; this study evaluated nivolumab plus chemotherapy vs chemotherapy alone as neoadjuvant treatment in 358 newly diagnosed patients with resectable stage IB to IIIA NSCLC. No sensitizing EGFR or ALK mutations were allowed. Patients were stratified by cancer stage, PD-L1 status, and gender.

Baseline characteristics were well balanced between the two treatment arms. About two-thirds had stage IIIA disease, and participants were evenly split between squamous and nonsquamous histologies. Tumor mutational burden results were available for 50%.

Patients were randomly assigned 2:1 to receive nivolumab at 360 mg every 3 weeks plus chemotherapy every 3 weeks (three cycles) vs the same chemotherapy schedule. Then, patients underwent radiologic staging and surgery within 6 weeks of neoadjuvant therapy. They had the option of adjuvant therapy with or without radiation therapy. An exploratory arm of nivolumab plus ipilimumab was closed early.

The primary endpoint was pathologic complete response by blinded independent review, defined as no residual viable tumor in resected primary tumor and lymph nodes after surgery. Event-free survival was a co-primary endpoint but was not presented at the AACR meeting.

A total of 98% of all patients enrolled in the trial received neoadjuvant therapy; 94% of the nivolumab-containing arm and 84% of the chemotherapy arm completed treatment, and 83% and 75%, respectively, completed surgery. Lung-sparing surgery (lobectomy) was performed in 77% vs 61%, respectively.

Key Results

Nivolumab added to chemotherapy improved the pathologic complete response rate from 2.2% in the chemotherapy arm to 24%, according to an intent-to-treat analysis, representing a highly significant 86% improvement favoring the addition of nivolumab (P < .0001), with an absolute difference of 21.6%.

“Surgery was rarely cancelled due to toxicity,” Dr. Forde noted.


  • CheckMate 816 is the first phase III trial to show a benefit for neoadjuvant immunotherapy (nivolumab) plus platinum-doublet chemotherapy for resectable NSCLC.
  • This therapy did not seem to compromise the ability to have surgery.
  • A higher percentage of patients treated with nivolumab plus chemotherapy were able to undergo lung-sparing surgery compared with chemotherapy alone.

In patients who completed resection, the addition of nivolumab to chemotherapy increased from 3.2% in the chemotherapy arm to 30.5%. In an intent-to-treat analysis of the primary tumor alone, nivolumab increased the pathologic complete response from 2.8% to 25.7%, respectively. The magnitude of pathologic complete response benefit with nivolumab was similar in patients with stage IB and IIIA disease, in squamous and nonsquamous histologies, regardless of PD-L1 status and tumor mutational burden.

The major pathologic response rate in patients who went on to surgery was 46.8% in the nivolumab-containing arm vs 12.7% for chemotherapy alone. The radiographic objective response rate based on scans was 54% with nivolumab plus chemotherapy vs 37% with chemotherapy alone.

In a subset of 87 patients with available samples, circulating tumor DNA (ctDNA) was more likely to clear when nivolumab was given: 56% vs 34% for chemotherapy alone. The pathologic complete response was more likely to be achieved with clearance of ctDNA: The pathologic complete response was 46% in patients with ctDNA clearance vs 13% in those without it.

“Patients with pathologic complete response and clearance of ctDNA were more likely to have surgical resection,” Dr. Forde said.


“The addition of nivolumab did not appear to increase all-cause adverse events,” continued Dr. Forde.

Adverse events were relatively similar between the two treatment arms. The rate of grade 3 and 4 adverse events was 34% in the nivolumab-plus-chemotherapy arm vs 37% in the chemotherapy-alone arm. Grade 5 surgery-related adverse events were reported in two patients in the chemotherapy arm unrelated to the study drugs. No treatment-related deaths were reported. Treatment-related adverse events occurred in 15% of patients treated with nivolumab.

Additional Commentary

Formal discussant of the CheckMate 816 trial, Charles Swanton, MBPhD, FRCP, FMedSci, FRS, FAACR, of the Francis Crick Institute and UCL Cancer Research; Chief Clinician, Cancer Research UK, London; and Program Chair of the virtual AACR Annual Meeting 2021, was encouraged by these results.

“CheckMate 816 is the first phase III trial to show a benefit for neoadjuvant immunotherapy plus chemotherapy for resectable NSCLC. This therapy did not impact the ability to undergo
surgery. There was a higher percentage of lung-sparing surgery in the nivolumab arm,” Dr. Swanton said. 


DISCLOSURE: Dr. Forde has served as a consultant or advisor to AbbVie, Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, and Janssen; has received research funding from Corvus Pharmaceuticals; and has received institutional research funding from AstraZeneca/MedImmune, Bristol Myers Squibb, Kyowa Kirin, and Novartis. Dr. Swanton holds stock or other ownership interests in Achilles Therapeutics, Apogen Biotechnologies, Epic Sciences, and GRAIL; has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Illumina, Lilly, MSD Oncology, Novartis, Ono Pharmaceutical, Pfizer, and Roche; has served as a consultant or advisor to Bicycle Therapeutics, Genentech/Roche, Medicxi, and Sarah Cannon Research Institute; has received research funding from Archer Dx, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Ono Pharmaceutical, Pfizer, and Roche-Ventana; holds intellectual property in Achilles Therapeutics, “immune checkpoint intervention in cancer,” “method for determining whether an HLA allele is lost in a tumor,” “method for identifying responders to cancer treatment,” “method for treating cancer,” “method for treating cancer based on identification of clonal neoantigens,” “method of detecting tumor recurrence,” “method of identifying insertion/deletion mutation targets,” “method of predicting survival rates for cancer patients,” “method of treating cancer by targeting insertion/deletion mutations,” and “methods for lung cancer detection”; and has held uncompensated relationships with AstraZeneca.


1. Forde PM, Spicer J, Lu S, et al: Nivolumab + platinum-doublet chemotherapy vs chemotherapy as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer in the phase 3 CheckMate 816 trial. AACR Annual Meeting 2021. Abstract CT003. Presented April 10, 2021.


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