FDA Approves Neoadjuvant Nivolumab/Chemo for Resectable NSCLC

The FDA has approved nivolumab plus platinum-doublet chemotherapy for adult patients with resectable non–small cell lung cancer in the neoadjuvant setting.

The FDA has approved nivolumab (Opdivo) plus platinum-doublet chemotherapy for adult patients with resectable non–small cell lung cancer (NSCLC) in the neoadjuvant setting.1

The regulatory decision is based on findings from the phase 3 CheckMate-816 trial (NCT02998528), which found that the combination (n = 179) resulted in a significant improvement in event-free survival (EFS) vs chemotherapy alone (n = 179). The median EFS with nivolumab plus chemotherapy was 31.6 months (95% CI, 30.2–not reached) vs 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (hazard ratio [HR], 0.63; 95% CI, 0.45-0.87; P =.0052).

Moreover, nivolumab plus chemotherapy also resulted in a pathologic complete response (pCR) of 24% (95% CI, 18.0%-31.0%) vs 2.2% (95% CI, 0.6%-5.6%) with chemotherapy alone (estimated treatment difference 21.6; 95% CI, 15.1-28.2; P < .0001). Results from a prespecified interim analysis for overall survival (OS) resulted in a HR of 0.57 (95% CI, 0.38-0.87), which did not cross the boundary for statistical significance.

“Given the rates of disease recurrence in patients with resectable NSCLC, additional treatment options are needed that can be given before surgery to help improve the chance of successful surgical treatment and support the goal of reducing the risk of cancer returning,” Mark Awad, MD, PhD, CheckMate-816 study investigator and clinical director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, stated in a press release. “The approval of nivolumab with platinum-doublet chemotherapy marks a turning point in how we treat resectable NSCLC and it enables us to use immunotherapy and chemotherapy as neoadjuvant treatment for patients before surgery. Today’s announcement reinforces the need to increase the rates of NSCLC screening and early detection, and for patients to discuss treatment options with their providers.”

The open-label, multicenter, phase 3 CheckMate-816 trial enrolled patients with newly diagnosed, resectable, stage IB to IIIA NSCLC who had an ECOG performance status of 0 or 1 and no known sensitizing EGFR mutations or ALK alterations.

A total of 358 participants were randomized 1:1 to receive nivolumab at a dose of 360 mg every 3 weeks plus platinum-doublet chemotherapy every 3 weeks for 3 doses or chemotherapy alone. Patients then underwent radiologic restaging, went on to undergo surgery within 6 weeks after treatment, went on to receive optional adjuvant chemotherapy with or without radiotherapy, and then entered follow-up.

Patients were stratified by disease stage (IB/II vs IIIA), PD-L1 expression (1% or higher vs less than 1%), and sex (male vs female).

The primary end points of the trial were pCR by blinded independent pathological review (BIPR), and EFS by blinded independent central review (BICR). Key secondary end points included major pathological response by BIPR, overall survival, and time to death or distant metastases. Key exploratory end points included by objective response rate by BICR, and feasibility of surgery as well as peri- and post-operative surgery–related toxicities.

At a database lock of September 16, 2020, and a minimum follow-up of 7.6 months for both treatment arms, 179 patients were randomized to nivolumab/chemotherapy and 179 were randomized to chemotherapy alone; 98% of patients in both arms received neoadjuvant treatment. Of those in the investigative arm, 94% completed 3 cycles of the neoadjuvant treatment; 85% completed neoadjuvant treatment in the control arm.

Additionally, 16% of patients in the investigative arm cancelled surgery because of progressive disease (7%), toxicity (1%), or another reason not specified (8%). Twenty-one percent of patients on the control arm cancelled their surgery; 10% did so because of disease progression, 1% did so because of an adverse effect, and 11% did so because of another reason. Eighty-three percent of patients on the investigative arm received surgery vs 75% of those on the control arm; the median duration of surgery in these groups was 184 minutes and 217 minutes, respectively.

The median age of patients on the nivolumab/chemotherapy arm was 64 years (range, 41-82) vs 65 years (range, 34-84) in the chemotherapy-alone arm; 28% and 29% of patients, respectively, were female, and 69% and 65% of patients, respectively, had an ECOG performance status of 0. In the nivolumab/chemotherapy arm, 49% had squamous disease and 51% had nonsquamous disease; in the chemotherapy-alone arm, these rates were 53% and 47%, respectively. Most patients were current or former smokers.

Earlier findings showed that when broken down by disease stage at baseline, the pCR with nivolumab/chemotherapy (n = 10) among those with stage IB disease was 40% vs 0% with chemotherapy alone (n = 8).2,3 In those with stage IIA disease at baseline, the pCR in the investigative arm (n = 30) was 23% vs 3% in the control arm (n = 32); within those with stage IIB disease, these rates were 24% (n = 25) and 9% (n = 23), respectively. Finally, in those with stage IIIA disease, with pCR with nivolumab plus chemotherapy (n = 113) was 23% vs 1% with chemotherapy alone (n = 115). The pCR improvement observed with nivolumab/chemotherapy vs chemotherapy alone was noted irrespective of radiologic downstaging.

Additional data presented during the 2021 ASCO Annual Meeting showed that the median residual viable tumor percentages in patients with stage IB/II disease (n = 52) and those with stage IIIA disease (n = 89) with nivolumab plus chemotherapy were 28% and 8%, respectively. In those with stage IB/II disease (n = 49) and those with stage IIIA disease (n = 77) who received chemotherapy alone, these rates were 79% and 70%, respectively.

R0, R1, and R2 rates of resection were comparable irrespective of baseline disease stage in both treatment arms. The median number of lymph nodes dissected was similar between the nivolumab/chemotherapy and chemotherapy-alone arms, at 19.0 (IQR, 12-25) and 18.5 (IQR, 10-26), respectively. The length of hospital stays was similar irrespective of disease stage at baseline in both treatment arms, at 10.0 days.

Nivolumab is linked with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis with renal dysfunction, other immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.

Increased mortality in patients with multiple myeloma when nivolumab is combined with a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

“At Bristol Myers Squibb, we are leading innovative science in the use of immunotherapy in earlier stages of cancer and are committed to bringing these options to patients,” Adam Lenkowsky, senior vice president and general manager, US Cardiovascular, Immunology and Oncology at Bristol Myers Squibb, added in the press release. “Today’s approval builds on that commitment and expands the role of nivolumab-based treatment in NSCLC, the most common form of lung cancer, so patients may benefit earlier in the course of their disease.”

The EFS data from the phase 3 trial will be presented at the 2022 AACR Annual Meeting in April 2022.


  1. US Food and Drug Administration approves Opdivo (nivolumab) with chemotherapy as neoadjuvant treatment for certain adult patients with resectable non-small cell lung cancer. News release. Bristol Myers Squibb; March 4, 2022. Accessed March 4, 2022. https://bit.ly/3sG3zQA
  2. Neoadjuvant Opdivo (nivolumab) plus chemotherapy significantly improves pathologic complete response in patients with resectable non-small cell lung cancer in phase 3 CheckMate -816 trial. News release. Bristol Myers Squibb; April 10, 2021. Accessed February 28, 2022. https://bit.ly/3HrBxw7
  3. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503