Abstract
Original language | English |
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Pages (from-to) | 3077-3089 |
Number of pages | 13 |
Journal | Nature medicine |
Volume | 29 |
Issue number | 12 |
Early online date | 2023 |
DOIs | |
Publication status | Published - Dec 2023 |
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In: Nature medicine, Vol. 29, No. 12, 12.2023, p. 3077-3089.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Nivolumab plus ipilimumab in advanced salivary gland cancer
T2 - a phase 2 trial
AU - Vos, Joris L.
AU - Burman, Bharat
AU - Jain, Swati
AU - Fitzgerald, Conall W. R.
AU - Sherman, Eric J.
AU - Dunn, Lara A.
AU - Fetten, James V.
AU - Michel, Loren S.
AU - Kriplani, Anuja
AU - Ng, Kenneth K.
AU - Eng, Juliana
AU - Tchekmedyian, Vatche
AU - Haque, Sofia
AU - Katabi, Nora
AU - Kuo, Fengshen
AU - Han, Catherine Y.
AU - Nadeem, Zaineb
AU - Yang, Wei
AU - Makarov, Vladimir
AU - Srivastava, Raghvendra M.
AU - Ostrovnaya, Irina
AU - Prasad, Manu
AU - Zuur, Charlotte L.
AU - Riaz, Nadeem
AU - Pfister, David G.
AU - Klebanoff, Christopher A.
AU - Chan, Timothy A.
AU - Ho, Alan L.
AU - Morris, Luc G. T.
N1 - Funding Information: A.L.H. reports research funding for clinical trials from Allos Therapeutics, Astellas Pharma, AstraZeneca, Bayer, Ayala Pharmaceuticals, Bristol Myers Squibb, Genentech, Celldex Therapeutics, Daiichi Sankyo, Eisai., Elevar Therapeutics, Eli Lilly & Company, Genentech/Roche, Hoikpia, Kolltan Pharmaceuticals, Kura Oncology, Merck, Novartis, Pfizer, Poseida and Verastem; service in consulting/advisory roles for AffyImmune Therapeutics, AstraZeneca, Ayala Pharmaceuticals, Bristol Myers Squibb, Cellestia Biotech, Coherus, CureVac, Eisai, Elevar Therapeutics, Exelixis, Expert Conncet, Genzyme, InxMed, Kura Oncology, McGivney Global Advisors, Merck, Novartis, CureVac, Prelude Therapeutics, Regeneron, Rgenta, Remix Therapeutics, Sanofi, Sun Pharma, the Chemotherapy Foundation and TRM Oncology; service on speakers’ bureaus for Medscape, Omniprex America, Novartis and Physician Education Resource; and receipt of travel/accommodations expenses from Janssen Oncology, Merck, Kura Oncology, Ignyta, Ayala Pharmaceuticals and KLUS Pharma, outside the submitted work. A.L.H. is also inventor on a patent for the use of lesional dosimetry methods for tailoring targeted radiotherapy in cancer. L.G.T.M. is listed as an inventor on intellectual property held by MSK on using tumor mutation burden to predict immunotherapy response, with pending patent, which has been licensed to Personal Genome Diagnostics. T.A.C. reports, all outside the submitted work, being a co-founder of Gritstone Oncology and holding equity; holding equity in An2H and acknowledging grant funding from Bristol Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H and Eisai; having served as an advisor for Bristol Myers, MedImmune, Squibb, Illumina, Eisai, AstraZeneca and An2H; andd being an inventor on intellectual property held by MSK on using tumor mutation burden to predict immunotherapy response, with pending patent, which has been licensed to Personal Genome Diagnostics. C.A.K. is a scientific co-founder and equity holder of Affini-T Therapeutics; is a compensated member of the scientific and/or clinical advisory boards for Achilles Therapeutics, Affini-T Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics and T-knife; has consulted for Bristol Myers Squibb, Decheng Capital, PACT Pharma and Roche/Genentech; and has patents broadly related to cell and gene therapy outside the scope of this work. N.R. reports research funding from ArcherDx and Repare Therapeutics and personal fees from Illumina, PaigeAI and Pfizer Canada, outside the submitted work. E.J.S. reports institutional research funding from Merck, outside the submitted work, and personal fees from Eli Lilly & Company, Blueprint Medicines Corporation, Regeneron Pharmaceuticals, Loxo Oncology and Eisai, outside the submitted work. L.A.D. reports research funding and personal fees from CUE-101, Eisai, CUE-101, Replimune Group and Regeneron Pharmaceuticals and service on an advisory board at Merck, outside the submitted work. V.T. reports holding stock in Infinity Pharmaceuticals, Bluebird Bio and Mersana Therapeutics. C.L.Z. is linked to investigator-initiated clinical trials in collaboration with Bristol Myers Squibb, outside the submitted work. D.G.P. reports grants from the National Institutes of Health (NIH) and the Philanthropy–Serra Fund; research support from Hookipa Pharma; and personal fees from Nykode and Hookipa Pharma, outside the submitted work. B.B. is an employee of AstraZeneca. Z.N. is an employee of PPD, part of Thermo Fisher Scientific. W.Y. is an employee of Eli Lilly & Company. V.M. is listed as an inventor on a patent assigned to MSK broadly related to determinants of cancer response to immunotherapy. J.L.V., S.J., C.W.R.F., F.K., C.Y.H., M.P., N.K., R.M.S., I.O., A.K., L.S.M., J.V.F., K.K.N., J.E. and S.H. declare no competing interests. Funding Information: We are grateful to our patients and their families for their bravery and support of cancer research. This study was supported, in part, by National Institutes of Health (NIH) grant R01 DE027738 (to L.G.T.M., A.L.H. and T.A.C.); the Geoffrey Beene Cancer Research Center (to L.G.T.M. and A.L.H.); the Jayme and Peter Flowers Fund; the Sebastian Nativo Fund; Congressionally Directed Medical Research Programs Award CA210784 and the MSK Population Science Research Program (to L.G.T.M.); the Overman Fund (to A.L.H.); NIH grants R37 CA259177, R01 CA269733 and P50 CA217694 (to C.A.K.); and NIH/NCI Cancer Center Support Grant P30 CA008748 (institutional, to MSKCC). Bristol Myers Squibb provided the study drugs and funding (institutional, to MSKCC) to support conduct of the clinical trial, including research biopsies, but was not involved in data analysis,manuscript writing or the decision to submit this manuscript. In addition, we acknowledge using the MSKCC Integrated Genomics Operation Core, funded by NCI Cancer Center Support Grant P30 CA08748, Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: We are grateful to our patients and their families for their bravery and support of cancer research. This study was supported, in part, by National Institutes of Health (NIH) grant R01 DE027738 (to L.G.T.M., A.L.H. and T.A.C.); the Geoffrey Beene Cancer Research Center (to L.G.T.M. and A.L.H.); the Jayme and Peter Flowers Fund; the Sebastian Nativo Fund; Congressionally Directed Medical Research Programs Award CA210784 and the MSK Population Science Research Program (to L.G.T.M.); the Overman Fund (to A.L.H.); NIH grants R37 CA259177, R01 CA269733 and P50 CA217694 (to C.A.K.); and NIH/NCI Cancer Center Support Grant P30 CA008748 (institutional, to MSKCC). Bristol Myers Squibb provided the study drugs and funding (institutional, to MSKCC) to support conduct of the clinical trial, including research biopsies, but was not involved in data analysis,manuscript writing or the decision to submit this manuscript. In addition, we acknowledge using the MSKCC Integrated Genomics Operation Core, funded by NCI Cancer Center Support Grant P30 CA08748, Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/12
Y1 - 2023/12
N2 - Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .
AB - Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .
UR - http://www.scopus.com/inward/record.url?scp=85168571899&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41591-023-02518-x
DO - https://doi.org/10.1038/s41591-023-02518-x
M3 - Article
C2 - 37620627
SN - 1078-8956
VL - 29
SP - 3077
EP - 3089
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -