A perioperative regimen of neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab achieved a statistically significant and clinically meaningful improvement in event-free survival compared with neoadjuvant chemotherapy plus placebo followed by surgery and adjuvant placebo in patients with resectable stage IIA to IIIB non–small cell lung cancer (NSCLC). This first interim prespecified analysis of event-free survival from the phase III CheckMate 77T trial was presented during the first Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2023 by lead author Tina Cascone, MD, PhD, Associate Professor of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.¹

Tina Cascone, MD, PhD

At a median follow-up of 25.4 months, the risk of disease recurrence, disease progression, or death was reduced by 42% with the perioperative regimen of nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab compared with neoadjuvant placebo/chemotherapy followed by surgery and adjuvant placebo (P = .00025). Secondary endpoints were also improved with the perioperative immunotherapy/chemotherapy combination regimen. Specifically, the rate of pathologic complete response was 25.3% with nivolumab/chemotherapy vs 4.7% with placebo and chemotherapy. The rate of major pathologic response was 35.4% vs 12.1%, respectively. Overall survival was not yet formally tested and continues to mature.

“CheckMate 77T met its primary endpoint. Neoadjuvant nivolumab plus chemotherapy, followed by surgery and adjuvant nivolumab, demonstrated a statistically significant and clinically meaningful event-free survival benefit vs neoadjuvant chemotherapy and placebo followed by surgery and adjuvant placebo in patients with resectable NSCLC,” stated Dr. Cascone.

“CheckMate 77T is the first phase III perioperative study that builds on the current standard of care neoadjuvant nivolumab plus chemotherapy. The results from the CheckMate 77T study are very encouraging and support this option for our patients with resectable NSCLC,” Dr. Cascone said.

While this perioperative regimen represents a new therapeutic option for our patients with resectable NSCLC, several questions remain. “The next steps will focus on identifying patient and disease characteristics for those most likely to benefit from neoadjuvant chemoimmunotherapy alone, as well as those who instead require a more intensified approach, including the strategy used in CheckMate 77T with periopertive nivolumab added to neoadjuvant chemotherapy, or a change in therapy in the adjuvant setting,” she stated.

Study Details

The phase III randomized, double-blind, placebo-controlled, multicenter CheckMate 77T trial randomly assigned 461 patients with resectable stage IIA to IIIB (per the American Joint Committee on Cancer staging manual, 8th edition) NSCLC in a 1:1 ratio to the nivolumab/chemotherapy arm (nivolumab at 360 mg every 3 weeks plus four cycles of chemotherapy every 3 weeks followed by surgery and nivolumab at 480 mg every 4 weeks for 1 year) or the placebo/chemotherapy arm (placebo plus four cycles of chemotherapy every 3 weeks followed by placebo every 4 weeks for 1 year). At enrollment, patients had no prior systemic anticancer treatment and no EGFR mutations or known ALK alterations. Patients were stratified according to histology, disease stage, and tumor PD-L1 expression (< 1% vs ≥ 1%). Surgery was performed within 6 weeks following the last dose of neoadjuvant therapy and radiologic restaging.

The primary endpoint of the trial was event-free survival according to blinded independent central review. Secondary endpoints included overall survival, pathologic complete response, major pathologic response, and safety.

At baseline, patient characteristics were well balanced between the two treatment arms. The median patient age was about 66 years. More than 50% of patients were from Europe and about 20% from Asia. Approximately two-thirds had stage III disease, and approximately 90% were current or former smokers. More than half the patients had tumor PD-L1 expression of 1% or more, and about 40% of patients had PD-L1 expression < 1%. The majority of patients (75%) received carboplatin-based chemotherapy.

Study Results

Almost all patients received at least one dose of neoadjuvant treatment, with at least 85% completing four treatment cycles. Drug toxicity was the most common reason for discontinuing neoadjuvant therapy in both arms.

Definitive surgery was performed in 78% of the nivolumab/chemotherapy arm and 77% of the placebo/chemotherapy arm. Disease progression was the most common reason for cancellation of surgery in both arms. Only 3% and 2%, in the nivolumab and placebo arms, respectively, canceled surgery because of adverse events. Drug toxicity was the most common reason for not receiving adjuvant therapy in the nivolumab-containing arm, whereas disease progression was the most common reason in the placebo/chemotherapy arm.

“Surgical outcomes were overall similar in both arms to what we have seen in other studies,” Dr. Cascone noted.

Lobectomy was the most common type of surgery, performed in 80% of the nivolumab/chemotherapy arm and 72% of the placebo/chemotherapy arm. Pneumonectomy was performed in 9% and 14% of patients, respectively. About 90% of patients had a complete resection.

Median event-free survival was not reached in the nivolumab/chemotherapy arm compared with 18.4 months in the placebo/chemotherapy arm, representing a 42% improvement in the experimental arm (P = .00025). The 12-month event-free survival rate was 73% vs 59%, respectively; the 18-month event-free survival rate was 70% vs 50%. “These data suggest a greater benefit over time for nivolumab [increased magnitude of benefit for event-free survival at 18 months vs 12 months],” Dr. Cascone told the audience. Investigator assessment of event-free survival also favored nivolumab over chemotherapy with a hazard ratio of 0.56.

Benefit With Nivolumab

The event-free survival benefit of nivolu-mab/chemotherapy was evident across most subgroups, regardless of disease stage, tumor histology, and level of PD-L1 expression. However, the benefit was more pronounced in patients with stage III disease, those with squamous histology, and those whose tumors expressed PD-L1 at 1% or more. Event-free survival was also improved with nivolumab/chemotherapy in current and former smokers.

In exploratory analyses, both the rates of pathologic complete response and major pathologic response were higher with the nivolumab/chemotherapy perioperative regimen vs chemotherapy/placebo. As expected, event-free survival rates were improved in patients with a pathologic complete response.

“These analyses are exploratory, and we have to interpret these results with caution,” she said.

No new safety signals were identified. The incidence of all-cause adverse events and treatment-related adverse events, including grade 3 and higher, was similar between patients in the two arms. Any-grade treatment-related adverse events were reported in 50% of those treated with adjuvant nivolumab/chemotherapy and 30% of those who received adjuvant placebo/chemotherapy. Any-grade surgery-related adverse events occurred in 41% and 39%, respectively. 

DISCLOSURE: Dr. Cascone has received honoraria from AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and the Society for Immunotherapy of Cancer; has served as an advisor or consultant for Arrowhead Pharmaceuticals, Bristol Myers Squibb, Genentech, MedImmune/AstraZeneca, Merck, Pfizer, Regeneron; has received research funding from Bristol Myers Squibb, EMD Serono, MedImmune/AstraZeneca; has received travel expenses from AstraZeneca, Bristol Myers Squibb, Dava Oncology, Genentech, IDEOlogy Health, International Association for the Study of Lung Cancer, OncLive, Parker Institute for Cancer Immunotherapy, Physicians’ Education Resource, and the Society for Immunotherapy of Cancer.

REFERENCE

1. Cascone T, Awad M, Spicer J, et al: CheckMate 77T: Phase III study comparing neoadjuvant nivolumab plus chemotherapy vs neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II-IIIb NSCLC. ESMO Congress 2023. Abstract LBA1. Presented October 21, 2023.