Cascone et al. report achieving the primary endpoint (Major Pathologic Response, MPR) in a randomized phase 2 trial of neoadjuvant chemotherapy (CT) + Nivolumab (Nivo) or + Nivo and Ipilimumab (Ipi), followed by surgical resection in patients with stage IB-IIIA NSCLC (with or without known tumor EGFR/ALK alterations). There were no new safety signals, and MPR rates were greater than historical rates for just CT, and greatest in the dual CPI cohort. The latter also had the greatest increases in post-therapy tumor density of CD8+ TEM and B cells, CXCL9+ TAMs, and tertiary lymphoid structure markers. Patients achieving MPR had a more beneficial baseline fecal microbiota.
Contributed by Paula Hochman
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 .).
Author Info: (1) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tcascone@mdanderson.org. (2) Department of Biostatis
Author Info: (1) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tcascone@mdanderson.org. (2) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Hospital BP, a Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil. (9) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Platform for Innovative Microbiome and Translational Research (PRIME-TR), Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (34) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (35) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (36) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (37) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (38) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (39) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (40) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (41) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (42) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (43) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (44) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (45) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (46) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (47) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (48) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (50) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (51) Platform for Innovative Microbiome and Translational Research (PRIME-TR), Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (52) Platform for Innovative Microbiome and Translational Research (PRIME-TR), Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (53) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (54) The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (55) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (56) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (57) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
