Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial

Abstract

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)

Neoadjuvant Chemoimmunotherapy for NSCLC

“…Overall, there was a low risk of bias among RCTs, with bias arising due to unbalanced treatment arms in 1 study and potentially multiple analyses of the same data in another study (eFigure 2 in Supplement 1). For nonrandomized studies, bias concerns were mostly associated with inadequate length of follow-up (eTable 4 in Supplement 1).…”

“…After title and abstract screening, 519 studies were excluded, and an additional 41 studies were removed after full-text screening. A total of 42 publications and 6 abstracts met inclusion criteria, including 43 trials and 5 follow-up studies, from which we extracted 54 study arms; 5431 patients were included overall in the 43 trials (4020 males [74.0%]; median age range, 55-70 years) (Table; eTable 3 and eFigure 1 in Supplement 1). There were 8 RCTs comparing neoadjuvant chemoimmunotherapy with chemotherapy, namely CheckMate 816, KEYNOTE-671, NADIM II, AEGEAN, Neotorch, Checkmate 77T, TD-FOREKNOW, and RATIONALE 315 (Table).…”

“…Across 3387 patients (2582 males [76.2%]; median age range, 61-66 years) included in 8 RCTs, there were 1688 patients (49.8%) treated with chemotherapy, 1699 patients (50.2%) treated with chemoimmunotherapy, 1882 patients (55.6%) who had squamous histology, and 2443 patients (72.1%) who had stage III disease. Across all studies, there were 27 neoadjuvant chemotherapy and 27 neoadjuvant chemoimmunotherapy arms; 21 arms included only patients with stage III disease. Studies ranged from 10 patients to 400 patients per arm, and there were 2347 patients assigned to neoadjuvant chemoimmunotherapy and 3084 patients assigned to neoadjuvant chemotherapy.…”

“…For neoadjuvant chemoimmunotherapy studies, there were 533 patients treated with nivolumab, 434 patients treated with pembrolizumab, 433 patients treated with durvalumab, 381 patients treated with toripalimab, 226 patients treated with tislelizumab, 169 patients treated with sintilimab, 46 patients treated with ipilimumab, 43 patients treated with camrelizumab, 37 patients treated with adebrelimab, 30 patients treated with atezolizumab, and 15 patients treated with avelumab. For 11 studies, more than a single arm was extracted per study. For 4 studies, a follow-up study was found (2 were found for CheckMate 816), and the updated data were used instead of the original data.…”

“…We also compared these clinical variables across all trials, including RCTs and nonrandomized single-arm trials . For single-arm studies, there was also a significantly higher MPR and pCR for chemoimmunotherapy than chemotherapy (eFigures 27-28 in Supplement 1).…”