The treatment of non-small cell lung cancer (NSCLC) is evolving, with immune checkpoint inhibitors (ICIs) like nivolumab and ipilimumab playing a crucial role. Recent data from the CheckMate 77T, NEOSTAR, and CA209-159 trials, presented at the European Society for Medical Oncology (ESMO) Congress 2024, highlight the potential of perioperative and neoadjuvant immunotherapy to improve outcomes in resectable NSCLC.
CheckMate 77T: Perioperative Nivolumab Benefits
The CheckMate 77T trial (NCT04025879), a phase 3 study, evaluated neoadjuvant chemotherapy plus nivolumab versus neoadjuvant chemotherapy plus placebo, followed by surgery and adjuvant nivolumab or placebo in patients with resectable early-stage NSCLC. The primary endpoint, event-free survival (EFS), showed significant improvement with the addition of nivolumab. After a median follow-up of 33 months, patients treated with perioperative nivolumab experienced a notable extension in median EFS from 17.0 months to 40.1 months (Hazard Ratio not provided in source).
Jonathan D. Spicer, from the Research Institute of the McGill University Health Centre (RI-MUHC), noted that the benefit of perioperative nivolumab was consistent across both PCR and non-PCR patient subgroups. Patients who achieved PCR trended toward better overall outcomes, but those who did not achieve PCR also derived benefit from nivolumab. Swimmer plots indicated a larger proportion of patients with PD-L1 positive (PD-L1+) tumors in the PCR population, but those with PD-L1 negative tumors exhibited comparable survival outcomes, suggesting nivolumab's applicability beyond PD-L1+ disease.
ctDNA Clearance and Molecular Recurrence
An important finding from the CheckMate 77T trial was the evaluation of circulating tumor DNA (ctDNA) clearance as a biomarker. Patients receiving nivolumab with chemotherapy demonstrated significantly higher rates of ctDNA clearance during the neoadjuvant period (66% vs 38% in the placebo group). Furthermore, those who achieved ctDNA clearance were more likely to achieve PCR, while patients who did not clear ctDNA showed residual disease upon surgery. Perioperative nivolumab also appeared to suppress molecular recurrence, with a lower rate of ctDNA recurrence in the nivolumab cohort (8%) compared to the placebo cohort (20%).
The safety profile of nivolumab in the perioperative setting was consistent with previous reports of ICIs. Adverse events (AEs) were slightly more common in patients who achieved PCR, though these events were generally low-grade and manageable.
NEOSTAR and CA209-159: Neoadjuvant Nivolumab and Ipilimumab
Joshua E. Reuss, from MedStar Georgetown University Hospital, presented 5-year outcomes from a combined analysis of the NEOSTAR (CA209-926;NCT03158129) and CA209-159(NCT02259621) trials, which explored neoadjuvant nivolumab and nivolumab plus ipilimumab in resectable NSCLC.
The combined analysis included 90 patients, with 60 treated with nivolumab monotherapy and 30 with nivolumab plus ipilimumab. At a median follow-up of 5 years, the median EFS and overall survival (OS) had not yet been reached in either cohort. The landmark 5-year EFS rates were 57.7% for the nivolumab cohort and 50.3% for the nivolumab plus ipilimumab cohort, while the 5-year OS rates were 70.0% and 66.9%, respectively.
Major pathological response (MPR), defined as ≤10% viable tumor cells, was observed in 30% of patients, while PCR was achieved in 13.5%, with higher rates in the nivolumab plus ipilimumab group (26.7%). Patients who achieved MPR or PCR had significantly improved long-term outcomes, with 5-year EFS rates of 74.0% for MPR and 77.5% for PCR, and OS rates of 81.7% for MPR and 85.5% for PCR.
Biomarker Insights: PD-L1 and KRAS Mutations
In the nivolumab cohort, PD-L1 positivity was associated with improved EFS, though this correlation was not seen in the nivolumab plus ipilimumab group. Additionally, the presence of KRAS co-mutations (including STK11, KEAP1, and/or SMARCA4 mutations) was linked to worse outcomes in patients treated with nivolumab alone, but this effect was mitigated in the combination therapy group. These findings suggest that biomarker-driven approaches could help identify patients who are most likely to benefit from neoadjuvant regimens. For example, patients with KRAS co-mutations may respond better to the nivolumab plus ipilimumab combination therapy, while those with PD-L1+ tumors may benefit more from nivolumab monotherapy.
The results from these trials highlight significant advances in the use of ICIs for resectable NSCLC, underscoring the importance of integrating immunotherapy into early-stage lung cancer treatment and paving the way for more personalized, biomarker-driven investigations in the future.
