Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial)

Abstract

Purpose: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported.

Methods: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m² once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial.

Results: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72).

Conclusion: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.

FIG 1.

Kaplan-Meier curves for (A) PFS and (B) OS in the ITT population (N = 46). ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival.

FIG 2.

Kaplan-Meier curves for (A) PFS and (B) OS by ctDNA levels at baseline, using a cutoff of < 1% MAF. ctDNA, circulating tumor DNA; HR, hazard ratio; MAF, mutant allele fraction; OS, overall survival; PFS, progression-free survival; ref, reference category.

FIG 3.

Kaplan-Meier curves for (A) PFS and (B) OS according to ctDNA detection after neoadjuvant treatment and Kaplan-Meier curves for (C) PFS and (D) OS by clinical response assessed on CT scans (landmark approach). Among patients who had undetectable ctDNA after neoadjuvant treatment, five were diagnosed as having progression disease. All of these patients (n = 5) underwent surgery. Regarding pathology assessments, two of them were diagnosed as having pCR, one as having major pathologic response and two were diagnosed as incomplete pathologic response. One of the patients showing undetectable ctDNA after treatment but incomplete pathologic response died, representing the unique death event among patients with undetectable ctDNA after treatment. Among patients with ctDNA detection after treatment (n = 13), two patients did not undergo surgery, three patients showed an incomplete pathologic response, one patient showed a major pathologic response, and seven patients had pCR. Of these, two patients showed progressive disease despite having pCR. CR, complete response; CT, computed tomography; ctDNA, circulating tumor DNA; HR, hazard ratio; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival; PR, partial response; ref, reference category; SD, stable disease.