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.

Neoadjuvant Chemotherapy Plus Immunotherapy in Early-Stage Resectable Non–Small-Cell Lung Cancer

“…Additionally, the ctDNA levels were able to predict OS with superior performance compared with the radiologic assessment of response (C-index 0.82 v 0.72). 23 Consistently, among 89 patients with ctDNA evaluated in the CheckMate 816 trial, ctDNA clearance was associated with numerically longer EFS and higher pCR rates 17 for both groups of patients—those treated with chemotherapy alone or chemoimmunotherapy. Incorporating ctDNA evaluation in further studies and clinical practice may help identify those patients who may already be cured by surgery and a short course of perioperative (neoadjuvant) therapy, avoiding expensive and potentially toxic adjuvant treatments.Role of genomic molecular profileMost ICI neoadjuvant studies excluded patients with nonsquamous NSCLC harboring EGFR or ALK alterations.…”

“…Indeed, although PD-L1 staining levels were found to potentially predict radiologic and pathologic response in different trials, 16,22 no correlation was found between PD-L1 or TMB and survival in the NADIM trial. 23 In the CheckMate 816 trial, despite the benefit observed across PD-L1 subgroups, a signal of greater magnitude of benefit with nivolumab plus chemotherapy was observed between the PD-L1–positive group (PD-L1 ≥ 1%, HR 0.41; PD-L1 ≥ 50%, HR 0.24) compared with negative tumors (HR 0.85). 17 Circulating tumor DNADynamic evaluation of circulating tumor (ctDNA) through liquid biopsy may further individualize lung cancer treatment.…”

Comprehensive analysis of T cell receptor repertoire in patients with KRAS mutant non-small cell lung cancer

“…Immunotherapy might be a promising approach to potentially reduce recurrence rates and improve survival based on the hypothesis that immune checkpoint inhibitors acts indirectly through modulating the immune system to promote immune recognition and eradicate micrometastases. Results from Checkmate 816, NADIM and IMpower 010 have indicated ICIs have clear utility in resectable NSCLC (65)(66)(67). However, more reliable and applicable biomarkers are required to determine the clinical benefit versus their potential risk.…”

Circulating Tumor DNA as a Cancer Biomarker: An Overview of Biological Features and Factors That may Impact on ctDNA Analysis

“…In the neoadjuvant setting, ctDNA has been shown to correlate well with tumor response to treatment. Recently, NADIM investigators have shown that ctDNA clearance after neoadjuvant chemo-immunotherapy outperformed tumor response to treatment measured by CT-scans and according to RECIST criteria in the prediction of survival ( 94 ). Similarly, a significant association between pathological complete response and ctDNA clearance was reported in the CheckMate 816 trial ( 95 ).…”