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.
Original language | English (US) |
---|---|
Pages (from-to) | 504-514 |
Number of pages | 11 |
Journal | Nature medicine |
Volume | 27 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2021 |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
MD Anderson CCSG core facilities
- Biostatistics Resource Group
- Microbiome Facility
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In: Nature medicine, Vol. 27, No. 3, 03.2021, p. 504-514.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer
T2 - the phase 2 randomized NEOSTAR trial
AU - Cascone, Tina
AU - William, William N.
AU - Weissferdt, Annikka
AU - Leung, Cheuk H.
AU - Lin, Heather Y.
AU - Pataer, Apar
AU - Godoy, Myrna C.B.
AU - Carter, Brett W.
AU - Federico, Lorenzo
AU - Reuben, Alexandre
AU - Khan, Md Abdul Wadud
AU - Dejima, Hitoshi
AU - Francisco-Cruz, Alejandro
AU - Parra, Edwin R.
AU - Solis, Luisa M.
AU - Fujimoto, Junya
AU - Tran, Hai T.
AU - Kalhor, Neda
AU - Fossella, Frank V.
AU - Mott, Frank E.
AU - Tsao, Anne S.
AU - Blumenschein, George
AU - Le, Xiuning
AU - Zhang, Jianjun
AU - Skoulidis, Ferdinandos
AU - Kurie, Jonathan M.
AU - Altan, Mehmet
AU - Lu, Charles
AU - Glisson, Bonnie S.
AU - Byers, Lauren Averett
AU - Elamin, Yasir Y.
AU - Mehran, Reza J.
AU - Rice, David C.
AU - Walsh, Garrett L.
AU - Hofstetter, Wayne L.
AU - Roth, Jack A.
AU - Antonoff, Mara B.
AU - Kadara, Humam
AU - Haymaker, Cara
AU - Bernatchez, Chantale
AU - Ajami, Nadim J.
AU - Jenq, Robert R.
AU - Sharma, Padmanee
AU - Allison, James P.
AU - Futreal, Andrew
AU - Wargo, Jennifer A.
AU - Wistuba, Ignacio I.
AU - Swisher, Stephen G.
AU - Lee, J. Jack
AU - Gibbons, Don L.
AU - Vaporciyan, Ara A.
AU - Heymach, John V.
AU - Sepesi, Boris
N1 - Funding Information: We thank the patients and their families for participating in this study. We thank all the members of our regulatory, clinical, data coordination and translational research teams in the Departments of Thoracic/Head and Neck Medical Oncology and Thoracic Surgery at the MD Anderson Cancer Center for their support on this trial. We thank the members of the strategic alliance teams at Bristol Myers Squibb and the MD Anderson Cancer Center (E. B. Roarty and A. Spelman) for their support. We thank the members of the Translational Molecular Pathology Immune-Profiling Laboratory (TMP-IL) B. Sanchez Espiridon, S. Wijeratne, for their assistance with sample procurement and inventory, C.-W. B. Chow, W. Lu, L. Kakarala, M. Jiang, A. Tamegnon, and J. Zhou for their technical assistance, and D. Lorenzini for pathology assistance in imaging analysis. We thank L. Little and C. Gumbs from the Department of Genomic Medicine for assistance with TCR sequencing. We thank the MD Anderson’s Program for Innovative Microbiome and Translational Research (PRIME-TR) for supporting the analysis and interpretation of the microbiome results presented herein (Drs. J. A. Wargo and N. J. Ajami are the program director and executive scientific director for PRIME-TR, respectively). We thank Mr. D. Aten, Sr. Medical Illustrator in Creative Communications at MD Anderson Cancer Center, for his assistance with figure formatting. Funding support for the clinical trial was provided by Bristol Myers Squibb. Support for the study was also partially provided by the National Institutes of Health (NIH)/National Cancer Institute (NCI) through the University of Texas Lung Specialized Program of Research Excellence (SPORE; grant no. 5P50CA070907 to T.C., L.A.B., F.S., J.M.K., J.A.R., I.I.W., D.L.G. and J.V.H.), the NIH/NCI P30 CA016672 Cancer Center Support Grant, the Conquer Cancer Foundation of the American Society of Clinical Oncology Career Development Award 2018 Project ID 12895 (to T.C.), the Connie Rasor Endowment for Cancer Research (to D.L.G.), the Bruton Endowed Chair in Tumor Biology (to J.V.H.), and the TMP-IL at the Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center. The study was also partially supported by the generous philanthropic contributions to the University of Texas MD Anderson Cancer Center Lung Cancer Moon Shot Program, the University of Texas MD Anderson Cancer Center Physician Scientist Program (from the T. J. Martell Foundation, to T.C). the Khalifa Bin Zayed Al Nahyan Foundation (to T.C.), the Ford Petrin Donation (to J.V.H.), the Rexanna’s Foundation for Fighting Lung Cancer (to T.C., D.L.G., J.V.H. and B.S.) and the Bob Mayberry Foundation (to T.C.). Funding Information: T.C. reports speaker’s fees from the Society for Immunotherapy of Cancer and Bristol Myers Squibb, consulting fees from MedImmune/AstraZeneca and Bristol Myers Squibb, advisory role fees from EMD Serono and Bristol Myers Squibb, and research funding to the MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/ AstraZeneca, EMD Serono and Bristol Myers Squibb. W.N.W.Jr reports consulting or advisory role fees from Clovis Oncology and AstraZeneca, speaker’s fees from Boehringer Ingelheim, honoraria from Roche/Genentech, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Bayer, Pfizer and Eli Lilly, and research funding from OSI Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Merck. M.C.B.G. has received research funding from Siemens Healthcare. H.T.T. reports research funding from Bayer-AS, Bristol Myers Squibb, Ziopharm and Guardant Health. N.K. reports consulting or advisory role fees from Merck, Bristol Myers Squibb, Abbvie and Roche. A.S.T. reports advisory board/consultant fees from Bristol Myers Squibb, Eli Lilly, Genentech, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, Sellas Life Science, Takeda, Epizyme and Huron, and receives research grants from Eli Lilly, Millennium, Polaris, Genentech, Merck, Boehringer Ingelheim, Bristol Myers Squibb, Ariad, Epizyme, Seattle Genetics, Takeda and EMD Serono. G.B.Jr receives personal fees and research funding from Amgen, Bayer, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Genentech, MedImmune, Merck, Roche and Xcovery, research funding from Adaptimmune, Exelixis, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite pharma, Macrogenics, Torque, AstraZeneca, Tmunity, Regeneron, Beigene, Novartis and Repertoire Immune Medicines, and personal fees from Abbvie, Adicet, Amgen, Araid, Clovis Oncology, AstraZeneca, Bristol Myer Squibb, Celgene, Genentech, Gilead, Merck, Novartis, Roche, Virogin Biotech, John & Johnson/Janssen and Maverick Therapeutics. X.L. receives consultant and advisory fees from Eli Lilly, AstraZeneca and EMD Serono, and research funding from Eli Lilly, Boehringer Ingelheim and Spectrum Pharmaceuticals. J.Z. reports grants from Merck, Johnson and Johnson, and consultant fees, advisory fees or honoraria from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, OrigMed and Roche outside the submitted work. M.A. reports research funding to the MD Anderson Cancer Center from Genentech, Nektar therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce therapeutics, Bristol Myers Squibb, Eli Lilly and Adaptimmune, and receives advisory fees from GlaxoSmithKline and Shattuck labs. B.G. reports research funding to MD Anderson Cancer Center from Pfizer Inc., ISA Pharmaceuticals, MedImmune/AstraZeneca and Cue Bio. L.A.B. receives advisory/consultant fees and research funding from AstraZeneca, AbbVie, GenMab, PharmaMar and Sierra Oncology, advisor/consultant fees from Genentech, Bristol Myers Squibb, Alethia, Merck and Pfizer, as well as research funding from ToleroPharmaceuticals. W.L.H. receives research funding from Johnson & Johnson. J.A.R. reports fees as consultant, scientific advisor, ownership interest, inventor on intellectual property licensed by Genprex and PI on Genprex-sponsored research. H.K. receives funding to the MD Anderson Cancer Center from Johnson and Johnson. C.H. serves as an advisory board member for Briacell. R.R.J. receives consultant role fees from Merck, Karius and Microbiome DX, advisory member role fees from Seres and Kaleido, and patent licensing fees from Seres. P.S. reports consulting, advisory roles and/or stocks/ownership for Achelois, Apricity Health, BioAlta, Codiak BioSciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lava Therapeutics, Lytix Biopharma, Marker Therapeutics, Oncolytics, Infinity Pharma, BioNTech, Adaptive Biotechnologies and Polaris, and owns a patent licensed to Jounce Therapeutics. J.P.A. reports consulting, advisory roles and/or stocks/ownership for Achelois, Apricity Health, BioAtla, Codiak BioSciences, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lava Therapeutics, Lytix Biopharma, Marker Therapeutics, Polaris, BioNTech and Adaptive Biotechnologies, and owns a patent licensed to Jounce Therapeutics. J.A.W. is an inventor on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center which covers methods to enhance immune checkpoint blockade responses by modulating the microbiome, reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Exelixis and Bristol Myers Squibb, serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol Myers Squibb, Merck, Biothera Pharmaceuticals and Microbiome DX, and receives research support from GlaxoSmithKline, Roche/ Genentech, Bristol Myers Squibb and Novartis. I.I.W. reports honoraria from Genentech/ Roche, Bayer, Bristol Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Platform Health, Daiichi, Merck, Flame, Oncocyte and MSD, and research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis and Akoya. S.G.S. reports speaker, travel and lodging expenses— Egyptian Society of Surgical Oncology/Best of SSO Cairo; West Hawaii Cancer Symposium; review panel participant, travel and lodging expenses—Peter MacCallum Cancer Centre; unpaid advisory board participant—Ethicon. D.L.G. reports honoraria for scientific advisory boards from AstraZeneca, Sanofi, Alethia Biotherapeutics and Janssen, and research support from Janssen, Takeda, Ribon Therapeutics and AstraZeneca. J.V.H. reports fees for advisory committees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GSK, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum and Takeda, research support from AstraZeneca, GlaxoSmithKline, Spectrum, and royalties and licensing fees from Spectrum. B.S. reports consulting fees from Bristol Myers Squibb. The remaining authors report no competing interests. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-020-01224-2
DO - 10.1038/s41591-020-01224-2
M3 - Article
C2 - 33603241
AN - SCOPUS:85101064680
SN - 1078-8956
VL - 27
SP - 504
EP - 514
JO - Nature medicine
JF - Nature medicine
IS - 3
ER -