FDA Grants Priority Review to Neoadjuvant Nivolumab/Chemo for Resectable NSCLC

The FDA has granted priority review to a supplemental biologics license application for the combination of nivolumab and chemotherapy in the neoadjuvant treatment of patients with resectable non–small cell lung cancer.

The FDA has granted priority review to a supplemental biologics license application (sBLA) for the combination of nivolumab (Opdivo) and chemotherapy in the neoadjuvant treatment of patients with resectable non–small cell lung cancer (NSCLC).1

The application is supported by data from the phase 3 CheckMate-816 trial (NCT02998528), which showed that the addition of nivolumab to chemotherapy, when administered prior to surgery, resulted in a significant improvement in pathologic complete response (pCR) and event-free survival (EFS) compared with chemotherapy alone.2,3

Overall, 24% of patients who received nivolumab plus chemotherapy achieved a pCR with treatment vs 2.2% of those who were given chemotherapy alone (odds ratio, 13.94; 99% CI, 3.49-55.75; P < .0001), meeting a primary end point of the trial.2

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).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.

Under the Prescription Drug User Fee Act, the FDA will decide on the sBLA by July 13, 2022.

“The FDA’s acceptance of our application marks an important step in our effort to offer patients and physicians the first immunotherapy-based option that can be given before surgery to extend the time patients can continue living without disease progression or recurrence,” Abderrahim Oukessou, MD, vice president of thoracic cancers and development lead at Bristol Myers Squibb, stated in a press release. “We look forward to working with the FDA to potentially bring this regimen to patients in the United States, where lung cancer is the leading cause of cancer deaths.”

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.

In the nivolumab/chemotherapy arm, 36% of patients had stage IB/II disease, 6% had IB disease, 17% had IIA disease, 14% had IIB disease, and 63% had IIIA disease. In the chemotherapy-alone arm, 35% had stage IB/II disease, 4% had IB disease, 18% had IIB disease, and 64% had IIIA disease. Regarding PD-L1 expression in the investigative arm, 50% had an expression of 1% or higher, 44% had an expression of less than 1%, and 7% were not evaluable. In the control arm, 50% had a PD-L1 expression of 1% or higher, 43% had an expression of less than 1%, and 7% were not evaluable.

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.

Regarding safety, neoadjuvant nivolumab plus chemotherapy was found to be tolerable, and the addition of the immunotherapy to chemotherapy was not found to result in more post-surgical complications. Moreover, grade 5 surgery-related toxicities were experienced by 2 patients who received nivolumab/chemotherapy, but they were not determined to be associated with study drug per investigator assessment; these effects were pulmonary embolism and aortic rupture.

The pharmaceutical company is working with study investigators to present EFS data from the trial at an upcoming medical meeting.


  1. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Opdivo (nivolumab) plus chemotherapy as neoadjuvant treatment for resectable non-small cell lung cancer. News release. Bristol Myers Squibb; February 28, 2022. Accessed February 28, 2022. https://bit.ly/3HofJ4x
  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