Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Abstract

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.

• Authors: Tina Cascone, William N William Jr, Annikka Weissferdt, Cheuk H Leung, Heather Y Lin, Apar Pataer, Myrna C B Godoy, Brett W Carter, Lorenzo Federico, Alexandre Reuben, Md Abdul Wadud Khan, Hitoshi Dejima, Alejandro Francisco-Cruz, Edwin R Parra, Luisa M Solis, Junya Fujimoto, Hai T Tran, Neda Kalhor, Frank V Fossella, Frank E Mott, Anne S Tsao, George Blumenschein Jr, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren Averett Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Mara B Antonoff, Humam Kadara, Cara Haymaker, Chantale Bernatchez, Nadim J Ajami, Robert R Jenq, Padmanee Sharma, James P Allison, Andrew Futreal, Jennifer A Wargo, Ignacio I Wistuba, Stephen G Swisher, J Jack Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Boris Sepesi
• Journal: Nature medicine (Nat Med) Vol. 27 Issue 3 Pg. 504-514 (03 2021) ISSN: 1546-170X [Electronic] United States
• PMID: 33603241 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Ipilimumab
• Nivolumab

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Female
• Humans
• Ipilimumab (administration & dosage)
• Lung Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Neoadjuvant Therapy
• Nivolumab (administration & dosage)