Neoadjuvant Nivolumab/Ipilimumab Vs Chemotherapy in Resectable NSCLC

1. Median event-free survival was 54.8 months with immunotherapy vs 20.9 months with chemotherapy, with HR 0.77 (non-significant).

2. Grade 3-4 treatment-related adverse events were reported in 14% in the immunotherapy arm vs 36% in the chemotherapy arm.

Evidence Rating Level: 1 (Excellent)

Study Rundown: PD-L1 immune checkpoint inhibitor in combination with chemotherapy has expanded neoadjuvant treatment options for resectable non–small cell lung cancer (NSCLC). Some early research shows the potential of combining a PD-L1 inhibitor (nivolumab) with a CTLA-4 inhibitor (ipilimumab) in this population. This phase 3 trial further explored this immunotherapy couplet and compared it to standard chemotherapy in resectable NSCLC. The endpoints assessed included event-free survival (EFS), EFS with next line of treatment (EFS2), pathological complete response (pCR), major pathologic response (MPR), overall survival (OS), time to death or distant metastases (TTDM), and safety. Surgical rates were 73% in immunotherapy arm and 76% in chemotherapy arm. R0 resection was achieved in 80% and 71% of patients in the immunotherapy and chemotherapy arms, respectively. The median follow-up time was 49.2 months. Median EFS was 54.8 months with immunotherapy vs 20.9 months with chemotherapy, with HR 0.77 (non-significant), and 3-year EFS rates were 56% and 44%, respectively. EFS2 HR 0.70 (non-significant). Among the PD-L1 <1% subgroup, EFS and surgical rates seemed to favour chemotherapy, although the sample size in this subgroup was small. The pCR rate was 20.4% in the immunotherapy arm vs 4.6% in the chemotherapy arm with OR 5.14 (significant), and MPR rates being 28.3% versus 14.8%, respectively. Recurrence rates after definitive surgery in the immunotherapy and chemotherapy arms were 23% and 44%, respectively, with TTDM HR 0.61 (significant). OS data was immature at the time of analysis, the median OS was not reached but the HR was 0.73 (non-significant), and 3-year OS rates were 73% vs 61%, respectively. For safety, grade 3-4 treatment-related adverse events were reported in 14% in the immunotherapy arm vs 36% in the chemotherapy arm, with the most common grade 3-4 immune-related adverse event was diarrhea/colitis (3%). The strengths of this study included its methodology, and the limitations included the small sample size. Overall, this study found doublet immunotherapy improves some endpoints and has a lower rate of high-grade toxicity when compared to doublet chemotherapy in resectable NSCLC.

Click to read the study in JCO

Relevant Reading: Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial

In-Depth [randomized controlled trial]: This open-label, international phase 3 trial enrolled adults with newly diagnosed stage IB-IIIA NSCLC with no known mutations and randomized them (1:1) to neoadjuvant treatment with either nivolumab/ipilimumab (3/1, n=113) vs platinum-doublet chemotherapy (n=108). Surgery was planned for 6 weeks after the last neoadjuvant treatment and patients were eligible for optional adjuvant therapy with chemotherapy and/or radiotherapy per the investigator’s discretion (34% in the immunotherapy arm and 32% in the chemotherapy arm). Surgical rates were 73% in the immunotherapy arm and 76% in the chemotherapy arm and reasons for surgery cancellation included disease progression (16% vs 8%), adverse events (3% vs 0%), and other reasons (7% vs 11%). R0 resection was achieved in 80% and 71% of patients in the immunotherapy and chemotherapy arms, respectively. The median follow-up time was 49.2 months (37.1-65.2). Median EFS was 54.8 months (95%CI, 24.4-not reached (NR)) with immunotherapy vs 20.9 months (14.2-NR) with chemotherapy, with HR 0.77 (95%CI, 0.51-1.15), and 3-year EFS rates were 56% and 44%, respectively. EFS2 HR 0.70 (95%CI, 0.45-1.08). Among the PD-L1 <1% subgroup, EFS and surgical rates seemed to favour chemotherapy, although the sample size in this subgroup was small. The pCR rate was 20.4% (95%CI, 13.4-29.0) in the immunotherapy arm vs 4.6% (95%CI, 1.5-10.5) in the chemotherapy arm with OR 5.14 (95%CI, 1.91-13.80), and MPR rates being 28.3% versus 14.8%, respectively. With respect to safety, grade 3-4 treatment-related adverse events were reported in 14% in the immunotherapy arm vs 36% in the chemotherapy arm, with the most common grade 3-4 immune-related adverse event was diarrhea/colitis (3%). Overall this study found doublet immunotherapy improves some endpoints and has a lower rate of high-grade toxicity when compared to doublet chemotherapy in resectable NSCLC.

Image: PD

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