Neoadjuvant Ipilimumab + Nivolumab + Chemotherapy Enhances Pathologic Responses

Previous clinical trials have indicated that neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) produce greater rates of pathologic responses than CT alone in patients with operable non–small cell lung cancer (NSCLC). Cascone and colleagues report on the clinical findings and correlates of two arms of the phase II platform NEOSTAR clinical trial testing three cycles of neoadjuvant Nivo+CT and Ipi+Nivo+CT (Ipi administered with cycle 1 only) followed by surgical resection in a total of 44 patients with operable stage IB–IIIA NSCLC (22 patients in each arm). The primary endpoint of the study was major pathologic response (MPR) in the resected tumor specimens. Secondary endpoints included pathologic complete response (pCR), toxicity, overall survival (OS), and event-free survival (EFS), among others. The primary endpoint of this study was met in both arms with the MPR rates of 32.1% and 50% in the Nivo+CT arm and Ipi+Nivo+CT arm, respectively. MPR rates increased to 41.2% in the Nivo+CT arm and to 62.5% in the Ipi+Nivo+CT arm in patients without known EGFR/ALK alterations. pCR was observed in four patients (18.2%) in both arms, with rates of pCR also increasing to 23.5% and 25% in the Nivo+CT and Ipi+Nivo+CT arms, respectively, in patients without known EGFR/ALK aberrations. EFS and OS were not reached after median follow-up times. Among patients who experienced treatment-related adverse events (TRAE), 10 patients (45%) experienced grade 3–4 TRAEs in the Nivo+CT arm, while four patients (20%) had grade 3–4 TRAEs in the Ipi+Nivo+CT arm. Single-cell RNA sequencing of samples from both arms indicated that CD8⁺ effector/effector memory T cells, B cells, and myeloid cells as well as markers of tertiary lymphoid structures were preferentially increased in tumors from the Ipi+Nivo+CT arm, whereas the content of regulatory T cells in these tumors decreased. Analysis of gene expression scores showed that adding neoadjuvant Ipi to Nivo+CT resulted in favorable immunologic changes compared with Nivo+CT, with these changes being more pronounced in responders. Studies of the fecal microbiome revealed that therapeutic responses were associated with higher relative abundance of beneficial taxa as well as reduced relative abundance of proinvasive strains. In summary, the addition of one dose of Ipi to neoadjuvant Nivo+CT increased MPR rates, was well tolerated, and enhanced antitumor immune activity, suggesting that the addition of CTLA-4 blockade to PD-(L)1 axis inhibition plus CT deserves further investigation in patients with resectable NSCLC.

Cascone T, Leung CH, Weissferdt A, Pataer A, Carter BW, Godoy MCB, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med 2023;29:593–604.

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