Advances in the Treatment of Resectable NSCLC: Key Insights From CheckMate 77T, NEOSTAR, and CA209-159 Trials

The treatment landscape for non–small cell lung cancer (NSCLC) has evolved significantly over the past decade, with immune checkpoint inhibitors (ICIs), such as nivolumab (Opdivo; Bristol Myers Squibb) and ipilimumab (Yervoy; Bristol Myers Squibb), playing a key role. In presentations at European Society for Medical Oncology (ESMO) Congress 2024, Jonathan D. Spicer, BSc (Hon), MD, PhD, FRCS, and Joshua E. Reuss, MD, discuss the results of pivotal trials investigating the perioperative and neoadjuvant use of these therapies in resectable NSCLC, with the goal of improving event-free survival (EFS), pathological complete response (PCR), and long-term outcomes. These findings provide further evidence for the integration of immunotherapy in early-stage lung cancer and offer insights into the biomarkers that could drive more personalized treatment approaches.

CheckMate 77T: Nivolumab in Perioperative Therapy

Spicer, scientist, Research Institute of the McGill University Health Centre (RI-MUHC) and associate professor, Department of Surgery, McGill University, discussed the exploratory outcomes from the CheckMate 77T trial (NCT04025879), a phase 3 study evaluating neoadjuvant chemotherapy plus nivolumab vs neoadjuvant chemotherapy plus placebo, followed by surgical removal and adjuvant treatment with nivolumab or placebo in patients with resectable early stage non–small cell lung cancer. The study's primary end point, EFS, demonstrated significant improvement with the addition of nivolumab.

After a median follow-up of 33 months, patients with NSCLC who were treated with perioperative nivolumab experienced a notable extension in median EFS. Image Credit: © Rabil - stock.adobe.com

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, highlighting both the statistical and clinical significance of the findings regarding the use of this regimen in the perioperative setting. These data were reinforced by further analyses of PCR status and circulating tumor DNA (ctDNA) clearance, providing insights into the mechanisms underlying these observed benefits.

PCR and EFS

A key finding from the CheckMate 77T trial, according to Spicer, was the consistent benefit of perioperative nivolumab across both PCR and non-PCR patient subgroups. Although 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 corresponding to these 2 groups were proportional to the degree of pathological response, emphasizing the efficacy of nivolumab in a wide range of patient subgroups.

The 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. According to Spicer, these results highlight the broader applicability of nivolumab beyond PD-L1 positive disease, suggesting a potential role in diverse NSCLC populations.

Circulating Tumor DNA Clearance and Molecular Recurrence

Spicer noted that an important finding from the CheckMate 77T trial relates to the evaluation of 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.

Additionally, 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. According to Spicer, these findings suggest that ctDNA could serve as a valuable marker to guide perioperative treatment decisions.

Safety Profile

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.

Neoadjuvant Nivolumab and Nivolumab Plus Ipilimumab: NEOSTAR and CA209-159

Reuss, thoracic medical oncologist at MedStar Georgetown University Hospital and assistant professor at Georgetown University, presented the 5-year outcomes from a combined analysis of 2 trials—NEOSTAR (CA209-926;NCT03158129) and CA209-159(NCT02259621)—which explored the use of neoadjuvant nivolumab and nivolumab plus ipilimumab in resectable NSCLC.

In the NEOSTAR trial, investigators at MD Anderson Cancer Center investigated nivolumab with or without ipilimumab or chemotherapy in patients with previously untreated stage I to IIIA NSCLC. In theCA209-159 trial, investigators at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins assessed neoadjuvant nivolumab, or nivolumab in combination with ipilimumab, in resectable NSCLC.

Long-Term Efficacy and Survival

The combined analysis of the 2 trials 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 AE 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.

Conclusion

The results from the CheckMate 77T trial and the NEOSTAR and CA209-159 combined trial analysis highlight significant advances in the use of ICIs for resectable NSCLC. Based on the findings, perioperative nivolumab was shown to improve EFS and reduce molecular recurrence, particularly in patients who achieved ctDNA clearance. Meanwhile, neoadjuvant nivolumab, either alone or in combination with ipilimumab, provided durable long-term survival benefits, especially for patients who achieved pathological response. These findings underscore the importance of integrating immunotherapy into early-stage lung cancer treatment and pave the way for more personalized, biomarker-driven investigations in the future.

REFERENCE

Spicer JD, Reuss JE. Mini oral session 1: Non-metastatic NSCLC. ESMO Congress 2024; Barcelona, Spain; September 13-17, 2024.