TY - JOUR
T1 - Phase I/Ib clinical trial of sabatolimab, an anti–TIM-3 antibody, alone and in combination with spartalizumab, an anti–PD-1 antibody, in advanced solid tumors
AU - Curigliano, Giuseppe
AU - Gelderblom, Hans
AU - Mach, Nicolas
AU - Doi, Toshihiko
AU - Tai, David
AU - Forde, Patrick M.
AU - Sarantopoulos, John
AU - Bedard, Philippe L.
AU - Lin, Chia Chi
AU - Stephen Hodi, F.
AU - Wilgenhof, Sofie
AU - Santoro, Armando
AU - Sabatos-Peyton, Catherine A.
AU - Longmire, Tyler A.
AU - Xyrafas, Alexandros
AU - Sun, Haiying
AU - Gutzwiller, Sabine
AU - Manenti, Luigi
AU - Naing, Aung
N1 - Funding Information:
Editorial assistance was provided by Laura Hilditch, PhD, and was funded by Novartis Pharmaceuticals Corporation.
Funding Information:
G. Curigliano reports personal fees from Roche, Daiichi Sankyo, AstraZeneca, Lilly, Pfizer, Novartis, Exact Science, and Ellipsis, as well as grants from Merck outside the submitted work. T. Doi reports grants and personal fees from Lilly, MSD, Daiichi Sankyo, Sumitomo Dainippon, Taiho, Novartis, Janssen Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, and Abbvie; personal fees from Amgen, Takeda, Chugai Pharma, Bayer, Rakuten Medical, Ono Pharma, Astellas Pharma, Oncolys Biopharma, and Otsuka Pharma; and grants from Merck Serono, Pfizer, IQVIA, and Eisai outside the submitted work. D. Tai reports grants from BMS and SIRTEX outside the submitted work. P.M. Forde reports grants from Novartis during the conduct of the study. P.M. Forde also reports personal fees from Amgen, Janssen, and Daiichi Sankyo; grants and personal fees from AstraZeneca; grants and other from BMS; and grants from Corvus and Kyowa outside the submitted work. P.M. Forde is a DSMB member of Polaris Pharma and Flame Therapeutics. P.L. Bedard reports grants from Novartis during the conduct of the study, as well as grants from BMS, Sanofi, Genentech/Roche, Novartis, GSK, Nektar Therapeutics, Merck, Lilly, Servier, PTC Therapeutics, SeaGen, Mersana, Amgen, and Zymeworks outside the submitted work. P.L. Bedard also reports uncompensated advisory board membership at Bristol-Myers Squibb, Sanofi, Pfizer, Genentech/Roche, Amgen, Lilly, SeaGen, Merck (past chair, Investigational New Drug Committee), Canadian Clinical Trials Group (Executive Board member), Breast International Group (Steering Committee member), American Association for Cancer Research (Project GENIE member), and NCI-BIO Breast Cancer Immunotherapy Task Force. C.-C. Lin reports personal fees from BeiGene, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, and Roche outside the submitted work. F.S. Hodi reports other from Novartis during the conduct of the study. F.S. Hodi also reports grants and personal fees from Bristol Myers Squibb and Novartis, as well as personal fees from Merck, EMD Serono, Sanofi, Bicara, Pionyr, Apricity, Compass Therapeutics, Surface, Torque, Iovance, Aduro, Eisai, Checkpoint Therapeutics, Takeda, Genentech, Bioentre, and Gossamer outside the submitted work. In addition, F.S. Hodi has a patent for MICA-Related Disorders pending and with royalties paid; a patent for Tumor Antigens and Uses Thereof issued; a patent for Angiopoiten-2 Biomarkers Predictive of Anti-immune Checkpoint Response pending; a patent for Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms pending; a patent for Therapeutic Peptides pending; a patent for Methods of Using Pembrolizumab and Trebananib pending; a patent for Vaccine Compositions and Methods for Restoring NKG2D Pathway Function Against Cancers pending and with royalties paid; a patent for Antibodies that Bind to MHC Class I Polypeptide-Related Sequence A pending and with royalties paid; and a patent for Anti-galectin Antibody Biomarkers Predictive of Anti-immune Checkpoint and Anti-angiogenesis Responses pending. A. Santoro reports other from BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD, Arqule, Sanofi, Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, Lilly, Sandoz, and Novartis during the conduct of the study. C. Sabatos-Peyton reports that Novartis holds patent rights related to sabatolimab and spartalizumab, including their uses; she also reports that she is an inventor on patents relevant to TIM-3, that she is currently an employee of Novartis, and that she was an employee of Costim Pharmaceuticals, which was acquired by Novartis (including sabatolimab and spartalizumab) and she has certain financial benefits due to the acquisition. A. Xyrafas reports other from Novartis during the conduct of the study and outside the submitted work. S. Gutzwiller reports personal fees and other from Novartis Pharmaceuticals Corporation outside the submitted work. L. Manenti reports other from Novartis during the conduct of the study; in addition, L. Manenti has a patent 20200223924 issued. A. Naing reports personal fees from Novartis during the conduct of the study. A. Naing also reports grants from NCI, EMD Serono, MedImmune, Karyopharm Therapeutics, Incyte, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Tizona Therapeutics, Immune Deficiency Foundation, Jeffery Modell Foundation, Chao Physician-Scientist Award, and Baxalta; grants and nonfinancial support from ARMO Biosciences; grants and personal fees from Novartis, CytomX Therapeutics, and Kymab; and personal fees from Genome & Company, OncoSec KEYNOTE-695, STCube Pharmaceuticals, Takeda, CSL, Behring, Horizon, and Pharming outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This study was sponsored by Novartis Pharmaceuticals Corporation. Funding support was received for the Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, San Antonio, TX (Cancer Center Support Grant P30CA054174).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Purpose: Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors. Patients and Methods: Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W. Results: Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy. Conclusions: Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
AB - Purpose: Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors. Patients and Methods: Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W. Results: Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy. Conclusions: Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
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U2 - 10.1158/1078-0432.CCR-20-4746
DO - 10.1158/1078-0432.CCR-20-4746
M3 - Article
C2 - 33883177
AN - SCOPUS:85109174113
VL - 27
SP - 3620
EP - 3629
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 13
ER -