Neoadjuvant Nivolumab Plus Chemotherapy Retains EFS Advantage in Resectable NSCLC

Neoadjuvant therapy with nivolumab (Opdivo) plus chemotherapy produced a long-term event-free survival (EFS) benefit vs chemotherapy alone in patients with resectable non–small cell lung cancer (NSCLC), independent of whether patients underwent minimally invasive surgery or thoracotomy or complete or partial resection of the lung, according to updated data from the phase 3 CheckMate 816 trial (NCT02998528).¹

Data presented during the 2023 European Lung Cancer Congress showed that at a median follow-up of 41.4 months, the median EFS was not yet reached (95% CI, 31.6-not reached [NR]) with nivolumab plus chemotherapy (n = 179) vs 21.1 months (95% CI, 14.8-42.1) with chemotherapy alone (n = 179; HR, 0.68; 95% CI, 0.49-0.93). The 3-year EFS rates reported with nivolumab plus chemotherapy and chemotherapy alone were 57% vs 43%, respectively.

“These results from CheckMate 816 further support the use of nivolumab plus chemotherapy as a standard neoadjuvant treatment for patients with resectable NSCLC,” Nicolas Girard, MD, PhD, study author and head of the Thorax Institute Curie-Montsouris, and professor of respiratory medicine and thoracic oncology at the Paris Saclay University in Paris, France, said in a presentation of the data.

On March 4, 2022, the FDA approved nivolumab plus platinum-doublet chemotherapy for adult patients with resectable (tumors ≥ 4 cm or node positive) NSCLC in the neoadjuvant setting. The decision was supported by earlier data from CheckMate 816. Prior findings from the trial demonstrated that nivolumab plus chemotherapy led to a significant improvement in EFS and pathologic complete response (pCR) vs chemotherapy alone.^2,3

The median EFS with nivolumab plus chemotherapy was 31.6 months (95% CI, 30.2-NR) vs 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (HR, 0.63; 95% CI, 0.45-0.87; P =.0052). The pCR rates were 24% (95% CI, 18.0%-31.0%) and 2.2% (95% CI, 0.6%-5.6%), respectively (estimated treatment difference, 21.6; 95% CI, 15.1-28.2; P < .0001).³ Moreover, the combination had a tolerable safety profile and did not affect the feasibility of surgery, Girard noted.

The trial enrolled patients with newly diagnosed, resectable, stage IB (≥ 4 cm) to IIIA NSCLC per the American Joint Committee on Cancer tumor node metastasis 7th edition criteria. Patients were required to have an ECOG performance status of 0 or 1 and no known sensitizing EGFR mutations or ALK alterations.¹

Eligible patients were randomly assigned 1:1 to 360 mg of nivolumab plus chemotherapy every 3 weeks for 3 cycles (n = 179) or chemotherapy alone (n = 179) at the same dose and schedule. Following treatment completion, patients underwent radiologic restaging and proceeded to surgery within 6 weeks of completing therapy. Subsequent adjuvant chemotherapy and/or radiation therapy was given at the treating physician’s discretion.

Presented in the analysis were updated data regarding the coprimary end point of EFS by blinded independent central review, and secondary end points of overall survival (OS) and time to distant metastasis (TTDM). EFS by surgical outcomes, and pCR and EFS by 4-gene inflammatory signature score were also presented as exploratory findings.

Additional results from the trial indicated that EFS was also improved with nivolumab regardless of whether patients underwent minimally invasive surgery, or thoracotomy or conversion. In the minimally invasive group, median EFS was NR (95% CI, 30.8-NR) with nivolumab plus chemotherapy (n = 44) or chemotherapy alone (n = 29; 95% CI, 9.5-NR; HR, 0.61; 95% CI, 0.28-1.29). The 3-year EFS rates were 67% and 53%, respectively. In the open surgery population, the median EFS was NR (95% CI, 40.4-NR) in the nivolumab arm (n = 105) vs 42.1 months (95% CI, 18.2-NR) in the chemotherapy-alone arm (n = 106; HR, 0.74; 95% CI, 0.48-1.13). The 3-year EFS rates were 61% and 51%, respectively.

Regarding the extent of resection, the median EFS was NR (95% CI, 44.4-NR) with nivolumab/chemotherapy (n = 115) in patients who received lobectomy vs 34.3 months (95% CI, 16.6-NR) in those who received chemotherapy alone (n = 82; HR, 0.62; 95% CI, 0.40-0.96). The 3-year EFS rates were 64% and 49%, respectively. Similarly, EFS was NR (95% CI, 19.4-NR) in patients who received nivolumab plus chemotherapy (n = 25) prior to pneumonectomy vs 21.1 months (95% CI, 13.9-NR) for those given chemotherapy alone (n = 34; HR, not calculable). The 3-year EFS rates were 67% and 48%, respectively.

Notably, in patients who achieved complete resection, the 3-year EFS rates were 64% in the nivolumab arm vs 51% in the chemotherapy-alone arm (HR, 0.65; 95% CI, 0.43-0.98).

TTDM was also improved with the addition of nivolumab to chemotherapy vs chemotherapy alone (HR, 0.55; 95% CI, 0.39-0.78). Median TTDM was NR (95% CI, 48.6-NR) in the nivolumab arm vs 34.3 months (95% CI, 23.6-NR) in the chemotherapy-alone arm. At 3 years, 71% of patients who received nivolumab were without distant metastasis vs 50% of those who received chemotherapy alone.

Regarding recurrence patterns after surgery, 28% (n = 42/149) of patients in the nivolumab arm experienced disease recurrence vs 42% (n = 56/135) of those in the chemotherapy alone arm. More patients experienced locoregional recurrence than distant recurrence with nivolumab plus chemotherapy, at 19% and 10%, respectively. With chemotherapy alone, locoregional recurrence and distant recurrence occurred in equal frequency, at 22%.

The median OS was not yet reached with either nivolumab plus chemotherapy (95% CI, NR-NR) or chemotherapy alone (95% CI, 46.8-NR; HR, 0.62; 99.34%, 0.36-1.05; P = .0124). The 3-year OS rate was 78% with nivolumab vs 64% with chemotherapy alone. However, the significance boundary for OS was not crossed, preventing investigators from drawing definitive conclusions. “OS [data] remained immature at this update but continued to show a promising trend favoring neoadjuvant nivolumab plus chemotherapy,” Girard reported.

Investigators also probed for potential biomarkers of response by evaluating patients’ baseline 4-gene inflammatory signature score by pCR and major pathologic response (MPR). The 4-gene signature, comprised of CD8A, STAT1, LAG3, and CD274 encoding PD-L1, was enriched in patients who achieved pCR (n = 21) and MPR (n = 30) with nivolumab plus chemotherapy.

Additionally, a high 4-gene inflammatory signature was associated with improved EFS with nivolumab/chemotherapy vs a low signature (HR, 0.65; 95% CI, 0.30-1.39). Although the median EFS was NR in both the high (95% CI, 40.4-NR) and low (95% CI, 10.5-NR) signature groups, the 3-year EFS rate in the investigative arm was 70% in the high signature group vs 55% in the low signature group. The 4-gene inflammatory score did not appear to affect response with chemotherapy alone (HR, 1.00; 95% CI, 0.52-1.92).

Regarding safety, the most common treatment-related adverse effects (TRAEs) were comparable between arms. “The safety profile of neoadjuvant nivolumab plus chemotherapy was consistent with previous reports,” Girard added. Frequent TRAEs with the combination included nausea (grade 1/2, 32%; grade 3/4, 1%), anemia (grade 1/2, 20%; grade 3/4, 3%), constipation (grade 1/2, 21%), decreased appetite (grade 1/2, 16%; grade 3/4, 1%), neutropenia (grade 1/2, 6%; grade 3/4, 11%), and decreased neutrophil count (grade 1/2, 7%; grade 3/4, 7%).

Immune-mediated AEs that occurred in at least 2% of patients in the nivolumab arm were rash (8%), hyperthyroidism (4%), and hypothyroidism/thyroiditis (3%).

TRAEs leading to discontinuation were similar between the nivolumab (any grade, 10%; grade 3/4, 6%) and chemotherapy-alone (any grade, 10%; grade 3/4, 3%) arms. Treatment-related serious AEs were also comparable between arms (nivolumab: any grade, 12%; grade 3/4, 8%; chemotherapy alone: any grade, 10%; grade 3/4, 8%).

Surgery-related AEs were less common with nivolumab plus chemotherapy (any grade, 45%; grade 3/4, 11%) compared with chemotherapy alone (any grade, 49%; grade 3/4, 15%). Notably, grade 5 surgery-related pulmonary embolism and aortic rupture occurred in 2 patients in the nivolumab arm but were deemed unrelated to treatment.

Disclosures: Dr Girard reported research support/funding from Amgen, AstraZeneca, AbbVie, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Gilead, Hoffman-La Roche, Janssen, Leo Pharma, Lilly, Merck, Merck Sharp and Dohme, Novartis, and Sivan; symposia from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Medtronic, Mirati, Merck Sharp and Dohme, and Pfizer; consultancy fees/honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Hoffman-La Roche, Leo Pharma, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and Takeda; other from the president of ITMIG; and study support by Bristol Myers Squibb.

References

1. Forde PM, Spicer J, Girard N. Neoadjuvant nivolumab (N) + platinum-doublet chemotherapy (C) for resectable NSCLC: 3-y update from CheckMate 816. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 840.
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
3. US Food and Drug Administration approves Opdivo (nivolumab) with chemotherapy as neoadjuvant treatment for certain adult patients with resectable non-small cell lung cancer. News release. Bristol Myers Squibb; March 4, 2022. Accessed March 30, 2023. https://news.bms.com/news/