Neoadjuvant nivolumab plus platinum-doublet chemotherapy significantly improved pathologic complete response (pCR) rates compared with chemotherapy alone in patients with resectable stage IB to IIIA non–small cell lung cancer (NSCLC), according to results of the randomized, phase III, open-label CheckMate 816 trial presented by Patrick M. Forde, MBBCh, at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract CT003).

The pCR rate was 24% with nivolumab plus chemotherapy vs 2.2% in the chemotherapy-alone arm. In the trial, pCR was selected as the primary endpoint, since pCR achieved on neoadjuvant therapy is associated with improved survival in retrospective studies.

“The standard treatment for resectable lung cancer is surgery to remove the tumor. Despite this, many patients experience recurrence of their lung cancer, and when it happens, it is usually incurable,” explained lead author Dr. Forde, Associate Professor at the Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University.

For the first time in a phase III trial, we see the potential for an anti–PD-L1 immunotherapy to improve outcomes in earlier-stage NSCLC. We are highly encouraged by the marked improvement in pCR, the good overall tolerability, and the absence of impact on feasibility of surgery when nivolumab is added to neoadjuvant chemotherapy.

— Patrick M. Forde, MBBCh

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“For the first time in a phase III trial, we see the potential for an anti–PD-L1 immunotherapy to improve outcomes in earlier-stage NSCLC. We are highly encouraged by the marked improvement in pCR, the good overall tolerability, and the absence of impact on feasibility of surgery when nivolumab is added to neoadjuvant chemotherapy,” Dr. Forde told listeners.

“The significant improvement in pCR and absence of any meaningful increase in toxicity or decrease in the feasibility of surgery suggest that neoadjuvant nivolumab plus chemotherapy is a viable option for patients with NSCLC at high risk of recurrence. While neoadjuvant chemotherapy has historically been less commonly used than adjuvant chemotherapy for this patient population, I believe that CheckMate 816 has the potential to change that treatment paradigm,” he added.

More on CheckMate 816

Platinum-based neoadjuvant or adjuvant chemotherapy for resectable NSCLC improves survival by only 5% at 5 years. “Several studies suggest a clear association between pCR and overall survival. Of note, resectable NSCLC treated with neoadjuvant chemotherapy shows low rates of pCR—a median of 4% and range of 0% to 16%,” Dr. Forde said. More recently, single-arm phase II studies of immunotherapy as monotherapy or in combination have had encouraging results, leading to the CheckMate 816 randomized phase III trial.

Dr. Forde presented the final analysis of pCR in CheckMate 816. The study evaluated nivolumab plus chemotherapy vs chemotherapy alone as neoadjuvant treatment in 358 newly diagnosed patients with resectable stage IB to IIIA NSCLC. No sensitizing EGFR or ALK mutations were allowed. Patients were stratified by stage, PD-L1 status, and sex.

Patients were randomly assigned to receive nivolumab at 360 mg every 3 weeks plus chemotherapy every 3 weeks (3 cycles) vs the same chemotherapy alone. Then, patients underwent radiologic staging and surgery within 6 weeks of neoadjuvant therapy.

The primary endpoint was pCR by blinded independent review, defined as no residual viable tumor in the resected primary tumor and lymph nodes after surgery. Event-free survival was a co-primary endpoint, which will be presented in the future when data mature, along with other key secondary endpoints.

Ninety-eight percent of all patients enrolled in the trial received neoadjuvant therapy; 94% of patients in the nivolumab-containing arm and 84% in the chemotherapy-alone arm completed treatment, and 83% and 75%, respectively, completed surgery. Lung-sparing surgery (lobectomy) was performed in 77% vs 61%, respectively.

Improvements in pCR

Nivolumab added to chemotherapy improved the pCR rate from 2.2% in the chemotherapy arm to 24%, according to an intent-to-treat (ITT) analysis, representing a highly significant 86% improvement favoring the addition of nivolumab (P < .0001), with an absolute difference of 21.6%. In patients who underwent complete surgical resection, the addition of nivolumab to chemotherapy increased the pCR rate from 3.2% in the chemotherapy arm to 30.5%. In an ITT analysis of the primary tumor only, nivolumab increased pCR rate from 2.8% to 25.7%, respectively.

Among subgroups, the benefit in pCR with nivolumab plus chemotherapy was sustained by stage, histology, PD-L1 status, and tumor mutational burden. In a subset of samples that were available for analysis, circulating tumor (ct)DNA was more likely to clear when nivolumab was given: 56% vs 34% for chemotherapy alone. pCR was more likely to be achieved with clearance of ctDNA: pCR was 46% in patients with ctDNA clearance vs 13% in those without it.

The rates of adverse events were relatively similar; the rates of grades 3 and 4 adverse events were 34% in the nivolumab plus chemotherapy arm vs 37% in the chemotherapy-alone arm. Grade 5 surgery-related adverse events were reported in two patients in the chemotherapy arm and were determined to be unrelated to study drugs.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.