In a phase II NADIM II study conducted among patients with previously untreated, stage IIIA or IIIB resectable non-small cell lung cancer (NSCLC), neoadjuvant chemotherapy plus nivolumab, followed by adjuvant treatment with nivolumab resulted in a significantly higher percentage of patients with a pathological complete response (pCR) than neoadjuvant chemotherapy alone. Perioperative treatment with chemotherapy and nivolumab resulted also in a higher percentage of patients undergoing resection than chemotherapy alone.
None of the patients who had had a pCR had a relapse at 2 years of follow-up with 95.2% data maturity. Survival outcomes were also better with chemotherapy and nivolumab than with chemotherapy alone. The findings are published by Dr. Mariano Provencio of the Medical Oncology Department, Hospital Universitario Puerta de Hierro–Majadahonda in Madrid, Spain, and colleagues on 28 June 2023 in The New England Journal of Medicine. Drs. Bartomeu Massuti and Atocha Romero contributed equally to this article.
The authors wrote in the background that preoperative chemotherapy has been shown to significantly improve overall survival (OS) among patients with resectable NSCLC. However, the absolute difference in 5-year recurrence-free survival and OS between preoperative chemotherapy and surgery alone is only 5%, and outcomes remain poor with a 5-year OS of approximately 36%. A strong association between a pCR and survival after neoadjuvant treatment has been shown across studies, but number of patients with a pCR after neoadjuvant chemotherapy is low.
Evidence of a synergistic effect of chemotherapy in combination with immune checkpoint inhibitor (ICI) was first shown in the single-group, phase II NADIM study and subsequently in the randomised, phase III CheckMate 816 study. Although the NADIM study included patients with stage IIIA, and the CheckMate 816 included patients with stage IB to IIIA, both studies showed a benefit with respect to pCR and event-free survival with chemotherapy and ICI. The NADIM study also showed encouraging results for OS rate, 81.9% at 36 months.
Given the poor survival outcomes with preoperative platinum-based chemotherapy, and the fact that surgery has been shown to be safe and effective after neoadjuvant chemoimmunotherapy, the NADIM II study was conducted to assess neoadjuvant treatment with nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab, as compared with standard-of-care neoadjuvant chemotherapy in patients with resectable stage IIIA or IIIB NSCLC. In this open-label, phase II study, patients who had R0 resections received adjuvant treatment with nivolumab for 6 months.
The primary endpoint was a pCR (0% viable tumour in resected lung and lymph nodes). Secondary endpoints included progression-free survival (PFS) and OS at 24 months and safety. In total, 86 patients underwent randomisation; 57 were assigned to neoadjuvant nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab and 29 were assigned to neoadjuvant chemotherapy.
A pCR occurred in 37% of the patients in the group who received neoadjuvant nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab and in 7% of those who received neoadjuvant chemotherapy (relative risk 5.34, 95% confidence interval [CI] 1.34 to 21.23; p = 0.02). Surgery was performed in 93% of the patients in the group treated with neoadjuvant nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab and in 69% in the group who received neoadjuvant chemotherapy (relative risk 1.35, 95% CI 1.05 to 1.74).
Kaplan–Meier estimates of PFS at 24 months were 67.2% in the group treated with neoadjuvant nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab and 40.9% in the group who received neoadjuvant chemotherapy (hazard ratio [HR] for disease progression, disease recurrence, or death 0.47, 95% CI 0.25 to 0.88). Kaplan–Meier estimates of OS at 24 months were 85.0% in the group treated with neoadjuvant nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab and 63.6% in the group who received neoadjuvant chemotherapy (HR for death 0.43, 95% CI 0.19 to 0.98).
Grade 3 or 4 adverse events occurred in 11 patients in the group treated with neoadjuvant nivolumab plus platinum-based chemotherapy, followed by adjuvant treatment with nivolumab (19%) and in 3 patients in the group who received neoadjuvant chemotherapy (10%).
The NADIM II authors commented that they found a higher percentage of patients with a pCR (37%) than was observed in the CheckMate 816 study (24%). The percentage of patients who underwent pneumonectomy was similar in the two NADIM II study groups, but lower than in the CheckMate 816 study. Regional differences in surgical procedures may explain this discrepancy when both studies are compared overall. Unlike in the CheckMate 816 study, patients with an R0 resection in NADIM II received adjuvant treatment with nivolumab after surgery. In a post-hoc analysis, the improved survival among patients who received complete adjuvant treatment as compared with those who did not suggests a positive effect of this treatment. This finding is consistent with the results of the IMpower010 study.
In NADIM II study, pre-treatment ctDNA added some prognostic information to that of the clinical stage. A major limitation for clinical decision making based on ctDNA levels is that ctDNA quantification is not standardised, and the concordance between different platforms that are used to assess the amount of ctDNA has been scarcely evaluated.
The authors concluded that perioperative treatment with chemotherapy and nivolumab resulted in a higher percentage of patients with a pCR and a higher percentage of patients undergoing resection than chemotherapy alone. Survival outcomes were also better with chemotherapy and nivolumab than with chemotherapy alone.
The study was supported by Bristol Myers Squibb; the European Union Horizon 2020 Research and Innovation programme (European Commission) grant, Instituto de Salud Carlos III grant co-funded by the European Regional Development Fund and European Social Fund from the European Commission, and the Ministry of Science and Innovation grant. Medical writing assistance was funded by the Spanish Lung Cancer Group.
Reference
Provencio M, Nadal E, González-Larriba JL, et al. Perioperative Nivolumab and Chemotherapy in Stage III Non–Small-Cell Lung Cancer. NEJM; Published online 28 June 2023. DOI: 10.1056/NEJMoa2215530