The combination of neoadjuvant nivolumab and platinum doublet chemotherapy was recently approved by the US Food and Drug Administration for patients with stage IB (≥4 cm)-IIIA NSCLC. The approval was based on results from the phase III CHECKMATE-816 trial, which showed significant improvement vs. chemotherapy alone in median event-free survival (31.6 vs. 20.8 months) and pathologic complete response (pCR) rate (24% vs. 2.2%). Survival data from the small, Spanish, single-arm, multicenter, phase II NADIM I trial further support a neoadjuvant nivolumab-chemotherapy combination in resectable NSCLC. In this trial, 46 patients with stage IIIA NSCLC received neoadjuvant paclitaxel and carboplatin plus nivolumab on day 1 of each 21-day cycle, for three cycles. This was followed by adjuvant nivolumab monotherapy for 1 year). The primary analysis from the study reported a 24-month progression-free survival (PFS) rate of 77.1% in the intention-to-treat (ITT) population and a pCR rate of 63.4%.

Updated results were recently published, which showed a PFS rate at 36 months of 69.6% in the ITT population and 81.1% in the per-protocol (PP) population, which included 37 patients who underwent tumor resection and received at least one cycle of adjuvant therapy. Furthermore, the mature overall survival (OS) results from this study were reported. These results are impressive: the OS rate at 36-month was 81.9% for the ITT population and 91.0% in the PP population, which is nearly three times higher than historical series have reported.

An important part of the NADIM I study was the analysis of tissue and plasma biomarkers that were collected prospectively. Neither expression of PD-L1 in tumor cells nor TMB ≥ 10 mut/Mb were associated with improved PFS or OS; however, the sample size was small. In contrast, patients with low levels of circulating tumor DNA (ctDNA; mutant allele fraction [MAF] <1%) before neoadjuvant therapy had significantly improved PFS and OS compared with patients with high pretreatment ctDNA levels (hazard ratio [HR], 0.20 and 0.07, respectively). The investigators then evaluated whether tumor response to treatment may serve as a surrogate for the prediction of long-term survival. They found that radiologic responses assessed by CT scans and according to RECIST v1.1 criteria did not predict survival outcomes. Similarly, pCR was not considered to be predictive of improved PFS and OS; however, after accounting for two patients with pCR who died due to COVID-19 as competing risk events, pCR was indeed shown to be a predictor of improved PFS. Predictive value for OS was not estimable due to lack of events. When ctDNA levels following neoadjuvant treatment were evaluated, it was found that patients with undetectable ctDNA levels (< 0.1% MAF) had significantly improved PFS (HR, 0.26; P =0.038) and OS (HR, 0.04; P =0.015).

In their conclusion, the authors highlighted that the 3-year survival rates seen in the NADIM I study are unprecedented (with data maturity of 94%) for patients with stage IIIA NSCLC and have not been reported previously in neoadjuvant NSCLC trials. These data further support the efficacy of neoadjuvant nivolumab plus chemotherapy. Additionally, the study indicates that ctDNA may be a useful predictor of outcomes to neoadjuvant treatment.

Reference:
Provencio M, et al. J Clin Oncol. 2022 May 16. [Online ahead of print].