Findings from a phase III study show that neoadjuvant nivolumab plus chemotherapy had a significant benefit over chemotherapy alone with respect to event-free survival (EFS) and pathological complete response (pCR) and had no adverse effect on surgical feasibility or surgical outcomes in patients with resectable stage IB (≥4 cm) to IIIA non-small cell lung cancer (NSCLC) and ECOG performance status of 0 or 1. The results are published on 11 April 2022 by Prof. Patrick Forde of the Johns Hopkins Kimmel Cancer Center in Baltimore, MD, US and CheckMate 816 colleagues in The New England Journal of Medicine.

The authors wrote in the study background that neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable NSCLC. In the neoadjuvant context, immunotherapy provides an early opportunity to treat micrometastatic disease and enhances the immune response when bulk tumour and tumour antigens are still present during the treatment. In early-phase studies, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase III studies are needed to confirm these findings.

In an open-label, phase III, CheckMate 816 study, the investigators randomly assigned in a 1:1 ratio patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy (three cycles) or platinum-based chemotherapy alone (three cycles), followed by resection. The primary endpoints were EFS and pCR, defined as 0% viable tumour in resected lung and lymph nodes, both evaluated by blinded independent review. Overall survival (OS) was a key secondary endpoint. Safety was assessed in all treated patients.

Patients had to have measurable disease according to the RECIST version 1.1, and pretreatment tumour tissue available to assess the expression of PD-L1. Patients with known ALK translocations or EGFR mutations were excluded.

The median EFS was 31.6 months (95% confidence interval [CI] 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI 14.0 to 26.7) with chemotherapy alone (hazard ratio [HR] for disease progression, disease recurrence, or death 0.63; 97.38% CI 0.43 to 0.91; p = 0.005).

The percentage of patients with a pCR was 24.0% (95% CI 18.0 to 31.0) and 2.2% (95% CI 0.6 to 5.6), respectively (odds ratio 13.94; 99% CI 3.49 to 55.75; p < 0.001).

Results for EFS and pCR across most subgroups favoured nivolumab plus chemotherapy over chemotherapy alone.

At the first prespecified interim analysis, the HR for death was 0.57 (99.67% CI 0.30 to 1.07) and did not meet the criterion for significance.

In terms of other key outcomes, including OS, time to death or distant metastases, major pathological response, EFS2, objective response, and radiographic downstaging, also favoured nivolumab plus chemotherapy.

An exploratory analysis involving a subgroup of patients suggested that ctDNA clearance before surgery was more common among patients receiving nivolumab plus chemotherapy than among those receiving chemotherapy alone.

Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus chemotherapy arm and in 36.9% of those in the chemotherapy-alone arm. Safety was consistent with that in previous reports.

Of the patients who underwent randomisation, 83.2% of those in the nivolumab plus chemotherapy arm and 75.4% of those in the chemotherapy alone arm underwent surgery. The addition of nivolumab to neoadjuvant chemotherapy did not increase surgery-related adverse events or impede the feasibility of surgery.

The authors commented that CheckMate 816 builds on a strong biologic rationale for nivolumab use in resectable NSCLC, especially in the neoadjuvant context. On the basis of this study, nivolumab in combination with chemotherapy has been approved in the US as neoadjuvant treatment for adult patients with resectable NSCLC (tumours ≥4 cm or node positive).

In accompanied editorial, Dr. Christine M. Lovely of the Vanderbilt–Ingram Cancer Center in Nashville, TN, US wrote that the results from this study are expected to be practice changing, but several issues remain to be addressed. First, she questioned if a pCR is predictive of EFS and can EFS be used as a surrogate endpoint for OS. Second, is adjuvant therapy necessary and what criteria should be used to select patients to receive adjuvant therapy. Third, protocols must be put in place to ensure successful tissue handling, avoiding the potential for delays in obtaining biomarker results needed to plan preoperative therapy. Fourth, neoadjuvant therapy requires a disease management team made up of experts in different disciplines challenging implementation broadly, regardless of location, to prevent widening the survival gaps that already exist for lung cancer. Despite challenges, neoadjuvant therapy is expected to herald a new era for early lung cancer.

The study was funded by Bristol Myers Squibb.