The treatment landscape for non-small cell lung cancer (NSCLC) is evolving with the emergence of novel immunotherapy combinations and optimized perioperative strategies. Recent studies presented at major oncology conferences highlight the potential of these approaches to improve patient outcomes in both advanced and resectable disease settings.
LAG-3 Inhibition Enhances Anti-PD-1 Therapy in Advanced NSCLC
The phase 2 RELATIVITY-104 study (NCT04623775), presented at the 2024 ESMO Congress, investigated the addition of relatlimab to nivolumab and platinum-doublet chemotherapy in patients with stage IV or recurrent NSCLC. Relatlimab, a human LAG-3-blocking antibody, aims to restore effector T-cell function, potentially enhancing the anti-tumor immune response when combined with the PD-1 inhibitor nivolumab.
The study randomized 309 treatment-naive patients with stage IV/recurrent NSCLC, no driver alterations, and an ECOG performance status of 0 or 1 to receive either nivolumab, relatlimab, and chemotherapy or nivolumab and chemotherapy alone. Patients were stratified by tumor PD-L1 expression, histology, and ECOG performance score.
After a median follow-up of 10.7 months, the combination arm showed a slight improvement in progression-free survival (PFS) compared to nivolumab plus chemotherapy (HR, 0.88; 90% CI, 0.71-1.11), with median PFS of 6.7 months and 6.0 months, respectively. The overall response rate (ORR) was also moderately improved with the relatlimab combination (51.3% vs 43.7%).
Notably, in stratified patient subgroups, those with PD-L1 expression of 1% or higher experienced improved PFS and response rates with the relatlimab-based treatment. The median PFS was 9.8 months in the relatlimab group versus 6.1 months in the nivolumab plus chemotherapy group (HR, 0.63; 90% CI, 0.45-0.88). This benefit was further enhanced in patients with non-squamous cell histology, with a median PFS of 8.3 months versus 6.0 months (HR, 0.86; 90% CI, 0.64-1.13).
Nicolas Girard, MD, PhD, head of the Curie-Montsouris Thorax Institute, stated that the RELATIVITY-104 study is the first to demonstrate improved clinical benefit from LAG-3 inhibition combined with anti-PD-1 therapy and chemotherapy in PD-L1-positive NSCLC, particularly those with non-squamous cell histology. He also noted that the safety profile of the combination was consistent with the known profiles of the individual components.
Perioperative Nivolumab Improves Outcomes in Resectable NSCLC
An analysis of patient-level data from the phase 3 CheckMate 77T (NCT04025879) and CheckMate 816 (NCT02998528) trials, presented at the 2024 IASLC World Conference on Lung Cancer, suggests that perioperative nivolumab may offer a survival advantage over neoadjuvant nivolumab plus chemotherapy alone in patients with resectable NSCLC.
The analysis compared event-free survival (EFS) from the time of surgery among patients from CheckMate 77T, who received neoadjuvant nivolumab plus chemotherapy followed by definitive surgery and at least one dose of adjuvant nivolumab, with patients from CheckMate 816, who also received neoadjuvant nivolumab plus chemotherapy followed by definitive surgery but without adjuvant nivolumab.
After applying propensity score weights to account for differences in baseline characteristics, perioperative nivolumab (n = 139) showed improved EFS compared to neoadjuvant nivolumab plus chemotherapy only (n = 147). The hazard ratio for EFS was 0.61 (95% CI, 0.39-0.97).
Notably, EFS benefit was observed regardless of pathologic complete response (pCR) status, although the benefit was more pronounced in patients without pCR who received additional adjuvant nivolumab treatment after surgery. Benefit was also seen regardless of baseline disease stage, with a greater magnitude of benefit in patients with tumor PD-L1 < 1%.
Patrick Forde, MBBCH, codirector of the Division of Upper Aerodigestive Malignancies at Johns Hopkins Medicine, highlighted that this analysis represents the only comparison of perioperative versus neoadjuvant-only immunotherapy treatments for resectable NSCLC using individual patient-level data from two randomized phase 3 trials.
Local Consolidative Therapy in Oligometastatic NSCLC
A single-arm phase 2 study (UMIN000022431) published in Radiation Oncology explored the role of aggressive local consolidative therapy (LCT) in combination with systemic chemotherapy for stage IV NSCLC with oligometastases. The study enrolled 19 patients who received platinum-doublet chemotherapy and radiotherapy for thoracic disease, followed by LCT for distant disease within 8 weeks of thoracic radiotherapy initiation or conclusion.
At a median follow-up of 42.1 months, the 2-year survival rate was 68.4% (80% CI, 52.6%-79.9%). The median overall survival (OS) was 42.1 months (95% CI, 13.6-NR), and median progression-free survival (PFS) was 8.6 months (95% CI, 7.0-10.2). The response rate was 57.9% (95% CI, 33.5%-79.9%).
Takaaki Tokito, MD, PhD, professor at Kurume University School of Medicine, concluded that aggressive LCT in combination with systemic chemotherapy for stage IV NSCLC with oligometastases demonstrated tolerability and possible efficacy, warranting further studies incorporating immune checkpoint inhibitors.
