Combination of Nivolumab and Chemotherapy in Nonmetastatic Resectable NSCLC (CheckMate-816)

Combining nivolumab with a limited course of chemotherapy in resectable non–small-cell lung cancer (NSCLC) enhances rates of pathologic complete response compared with chemotherapy alone.

In patients with nonmetastatic non–small-cell lung cancer (NSCLC), surgery can be curative. However, 30% to 80% of patients who undergo resection experience disease recurrence.1 Neoadjuvant or adjuvant chemotherapy is currently recommended for patients who are at high risk of recurrence, but its benefits are modest and the rate of pathologic complete response (pCR) is low.1

Immunotherapy that targets the PD-1 pathway has demonstrated survival benefits in metastatic NSCLC, but robust data in resectable disease have not yet been shared. Recently, neoadjuvant nivolumab (NIVO), alone or in combination with chemotherapy, has shown encouraging rates of pCR in single-arm phase 2 studies.1 In April 2021 at the American Association of Cancer Research Annual Meeting 2021, researchers reported the final analysis of pCR rates in the CheckMate-816 study, a randomized, phase 3, open-label study comparing NIVO plus chemotherapy with chemotherapy alone as neoadjuvant therapy for resectable NSCLC.1

CheckMate-816 enrolled adults with clinical stage IB (≥4 cm) to stage IIIA resectable NSCLC, good performance status (Eastern Cooperative Oncology Group performance status 0 or 1), and no known EGFR or ALK alterations. Patients were randomized to either intravenous (IV) NIVO at a dose of 360 mg plus platinum-doublet chemotherapy every 3 weeks or chemotherapy alone every 3 weeks for 3 cycles followed by surgery. Stratification parameters included disease stage (IB/II vs IIIA), PD-L1 status (≥1% or <1%), and sex.1

Primary end points of the study include pCR by blinded independent pathological review (BIPR) and event-free survival by blinded independent central review (BICR). The definition of pCR was 0% viable tumor cells in resected lung and lymph nodes. Patients who did not undergo surgery were counted as nonresponders. Overall survival, major pathologic response (MPR; ≤10% viable tumor in both lung and lymph nodes) per BIPR, and time to death or distant metastases are secondary end points of the CheckMate-816 trial. Exploratory end points include objective response rate (ORR) per BICR and potential predictive biomarkers including PD-L1 and tumor mutational burden (TMB).1

Researchers reported that characteristics of patients were balanced between the study arms at baseline; there were 179 patients in each arm. The study met its pCR end point: neoadjuvant NIVO + chemotherapy significantly increased pCR rates compared with chemotherapy in the intent-to-treat (ITT) population: 24.0% versus 2.2%. The odds ratio was 13.94 (99% confidence interval, 3.49-55.75); P <.0001.1

The improvement in rate of pCR with NIVO + chemotherapy compared with chemotherapy was consistent across key subgroups, including disease stage (IB/II [26% vs 5%]; ≥IIIA [23% vs 1%]), PD-L1 status (<1% [17% vs 3%]; ≥1% [33% vs 2%]), and TMB (low [22% vs 2%]; high [31% vs 3%]).1

In the ITT population, use of neoadjuvant NIVO + chemotherapy also improved MPR rates compared with chemotherapy (37% vs 9%), as well as ORR (54% vs 37%) and radiographic downstaging rates (31% vs 24%).1 Definitive surgery occurred in 83% of patients treated with NIVO + chemotherapy and 75% with chemotherapy alone.1 Surgery was canceled rarely due to adverse events (AEs; 2 patients per arm) and due to disease progression in 12 and 17 patients, respectively.1

Grade 3 and 4 therapy-related AEs and grade 3 and 4 surgery-related AEs were reported in 34% and 37% and 11% versus 15% of patients in the NIVO + chemotherapy versus chemotherapy arms, respectively.1

The CheckMate-816 investigators concluded that the trial met its first primary end point with a statistically significant improvement in the rate of pCR with neoadjuvant NIVO + chemotherapy compared with chemotherapy alone based on independent review. They also noted that the safety profile of NIVO + chemotherapy was consistent with known information about this combination regimen and that the addition of NIVO did not affect the ability to perform surgery. CheckMate-816 is the first phase 3 trial to demonstrate a significant improvement in the rate of pathologic response with neoadjuvant immunotherapy plus chemotherapy in resectable NSCLC.1


1. Forde PM, Spicer J, Lu S, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. Presented at: American Association of Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT003.

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