Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer

Abstract

Purpose: Neoadjuvant immune checkpoint blockade with nivolumab plus ipilimumab improves overall survival (OS) in non-small cell lung cancer (NSCLC); however, randomized data for resectable lung cancer are limited. We report results from the exploratory concurrently randomized nivolumab plus ipilimumab and chemotherapy arms of the international phase III CheckMate 816 trial.

Methods: Adults with stage IB-IIIA (American Joint Committee on Cancer seventh edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery. Analyses included event-free survival (EFS), OS, pathologic response, surgical outcomes, biomarker analyses, and safety.

Results: A total of 221 patients were concurrently randomly assigned to nivolumab plus ipilimumab (n = 113) or chemotherapy (n = 108). At a median follow-up of 49.2 months, the median EFS was 54.8 months (95% CI, 24.4 to not reached [NR]) with nivolumab plus ipilimumab versus 20.9 months (95% CI, 14.2 to NR) with chemotherapy (HR, 0.77 [95% CI, 0.51 to 1.15]); 3-year EFS rates were 56% versus 44%. Higher rates of EFS events were initially seen, with later benefit favoring nivolumab plus ipilimumab; 3-year OS rates were 73% versus 61% (HR, 0.73 [95% CI, 0.47 to 1.14]); pathologic complete response rates were 20.4% versus 4.6%, respectively. In the respective arms, 83 (74%) and 82 patients (76%) underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 14% and 36% of patients, respectively.

Conclusion: Neoadjuvant nivolumab plus ipilimumab showed potential long-term clinical benefit versus chemotherapy, despite early crossing of EFS curves in the preoperative phase and a lower rate of high-grade toxicity.

Trial registration: ClinicalTrials.gov NCT02998528.

FIG 1.

CONSORT diagram of patient disposition. ^aIncludes patients randomly assigned to receive nivolumab plus chemotherapy (n = 179) and chemotherapy (n = 105; these patients were not concurrently randomly assigned to the nivolumab plus ipilimumab arm and are not included in this analysis) in the revised protocol. ^bOne patient randomly assigned to the nivolumab plus ipilimumab arm incorrectly received chemotherapy (this patient is counted in the nivolumab plus ipilimumab arm for baseline and efficacy analyses and in the chemotherapy arm for exposure and safety analyses). ^cIncludes grade 2 pneumonitis, grade 3 pulmonary thromboembolism, and grade 3 diarrhea (n = 1 each). ^dIncludes refusal of surgery or withdrawal of consent (n = 4 per arm), unresectable tumor (n = 1 per arm), patient who was randomly assigned but never treated (n = 1 per arm), patient who was unfit for surgery (nivolumab plus ipilimumab, n = 2; chemotherapy, n = 5), and patient who achieved a complete response (chemotherapy, n = 1).

FIG 2.

(A) EFS, (B) pCR, (C) MPR, and (D) EFS in patients with or without a pCR and (E) OS with nivolumab plus ipilimumab versus chemotherapy. EFS per BICR was determined among concurrently randomly assigned patients; patients who received subsequent therapy were censored at the last evaluable tumor assessment on or before the date of subsequent therapy. pCR (0% RVT) and MPR (≤10% RVT) postsurgery in both primary tumor (lung) and sampled lymph nodes per BIPR; patients who did not undergo surgery were classified as nonresponders. The OR was calculated using the stratified Cochran-Mantel-Haenszel method. ^aNot computed because of the low number of patients with a pCR (n = 5). BICR, blinded independent central review; BIPR, blinded independent pathologic review; EFS, event-free survival; HR, hazard ratio; MPR, major pathologic response; NR, not reached; OR, odds ratio; OS, overall survival; pCR, pathologic complete response; RVT, residual viable tumor.

FIG 3.

Baseline four-gene inflammatory signature score by (A) pCR, (B) MPR, and (C) EFS in the nivolumab plus ipilimumab arm and (D) EFS in the chemotherapy arm. The four-gene inflammatory signature comprised CD8A, STAT1, LAG3, and CD274 (encoding PD-L1) and was assessed by RNA sequencing of evaluable tumor samples at baseline; scores were grouped as high or low relative to the median z-score across the data set. pCR (0% RVT) and MPR (≤10% RVT) postsurgery in both primary tumor (lung) and sampled lymph nodes per BIPR. EFS was per BICR. Patients who received subsequent therapy were censored at the last evaluable tumor assessment on or before the date of subsequent therapy. BICR, blinded independent central review; BIPR, blinded independent pathologic review; EFS, event-free survival; HR, hazard ratio; MPR, major pathologic response; NR, not reached; pCR, pathologic complete response; RVT, residual viable tumor.