The treatment of non-small cell lung cancer (NSCLC) is evolving, with immune checkpoint inhibitors (ICIs) like nivolumab and ipilimumab playing an increasingly important role. Recent data from the CheckMate 77T trial and a combined analysis of the 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 Improves EFS
The phase 3 CheckMate 77T trial (NCT04025879) 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. This highlights the clinical significance of this regimen in the perioperative setting. Further analyses of pathological complete response (PCR) status and circulating tumor DNA (ctDNA) clearance provided insights into the mechanisms underlying these observed benefits.
PCR and EFS Benefits Across Subgroups
An important finding from the CheckMate 77T trial was the consistent benefit of perioperative nivolumab across both PCR and non-PCR patient subgroups. While patients who achieved PCR trended toward better overall outcomes, those who did not achieve PCR also derived benefit from the addition of nivolumab. The hazard ratios were proportional to the degree of pathological response, emphasizing the efficacy of nivolumab in a wide range of patient subgroups.
Swimmer plots of the PCR population demonstrated a larger proportion of patients with PD-L1 positive tumors, but those with PD-L1 negative tumors exhibited comparable survival outcomes. These results highlight the broader applicability of nivolumab beyond PD-L1 positive disease, suggesting a potential role in diverse NSCLC populations.
ctDNA Clearance and Molecular Recurrence
The CheckMate 77T trial also evaluated ctDNA clearance as a biomarker. Patients who received nivolumab in combination with chemotherapy demonstrated significantly higher rates of ctDNA clearance during the neoadjuvant period—66% in the nivolumab group compared to 38% in the placebo group. Furthermore, those who achieved ctDNA clearance were more likely to achieve PCR, whereas patients who did not clear ctDNA showed residual disease upon surgery.
Perioperative nivolumab appeared to suppress molecular recurrence, as demonstrated by the lower rate of ctDNA recurrence in the nivolumab cohort (8%) compared to the placebo cohort (20%). Patients who did not achieve PCR also benefitted from this molecular suppression, with fewer developing recurrences compared to the placebo group. These findings suggest that ctDNA could serve as a valuable marker to guide perioperative treatment decisions.
Safety Profile of Perioperative Nivolumab
The CheckMate 77T trial showed that the safety 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. Overall, the safety data support the use of perioperative nivolumab as a feasible and well-tolerated treatment option for patients with resectable NSCLC.
NEOSTAR and CA209-159: Neoadjuvant Nivolumab and Ipilimumab
A combined analysis of the NEOSTAR (CA209-926;NCT03158129) and CA209-159 (NCT02259621) trials explored the use of neoadjuvant nivolumab and nivolumab plus ipilimumab in resectable NSCLC. The NEOSTAR trial investigated nivolumab with or without ipilimumab or chemotherapy in patients with previously untreated stage I to IIIA NSCLC. The CA209-159 trial assessed neoadjuvant nivolumab, or nivolumab in combination with ipilimumab, in resectable NSCLC.
Long-Term Efficacy and Survival
The combined analysis included 90 patients, 60 of whom were treated with nivolumab monotherapy and 30 of whom were treated with the combination of nivolumab and ipilimumab. At a median follow-up of 5 years, the median EFS and overall survival (OS) had not yet been reached in either cohort, underscoring the durable benefit of immune checkpoint blockade. 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.
Pathological Response and Long-Term Outcomes
One of the key outcomes assessed in the analysis was pathological response, with major pathological response (MPR) defined as 10% or less of viable tumor cells, and PCR defined as the absence of viable tumor cells. MPR was observed in 30% of patients, while PCR was achieved in 13.5% of the cohort, with higher rates of PCR in the nivolumab plus ipilimumab group (26.7%). Importantly, 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
The analysis also highlighted the role of biomarkers in predicting response to therapy. 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 positive tumors may benefit more from nivolumab monotherapy.
