Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). Patients and Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N ¼ 15) or combined with ramucirumab (N ¼ 10), abemaciclib (N ¼ 24), or merestinib (N ¼ 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
|Number of pages||11|
|Journal||Clinical Cancer Research|
|Publication status||Published - 2021 Mar 1|
Bibliographical noteFunding Information:
A. Patnaik reports grants from Eli Lilly and Company during the conduct of the study as well as grants from Merck, Pfizer, Eli Lilly and Company, Plexxikon, Corvus Pharmaceuticals, Tesaro, Abbvie, Forty Seven, Five Prime Therapeutics, Infinity Pharmaceuticals, Pieris Pharmaceuticals, Surface Oncology, Livzon, Vigeo Therapeutics, Astellas Pharma, Klus Pharma, Symphogen, Syndax, Arcus, Fochon, Upsher-Smith, Exelixis, Innovent Biologics (Suzhou), and Seattle Genetics outside the submitted work. T.A. Yap reports grants from Artios, Constellation, Cyteir, Eli Lilly, Forbius, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Novartis, Ribon Therapeutics, Regeneron, Sanofi, Scholar Rock, Tesaro, and Vertez Pharmaceuticals; grants and personal fees from AstraZeneca, Bayer, Clovis, EMD Serono, F-Star, Merck, Pfizer, Repare, and Seattle Genetics; and personal fees from Almac, Aduro, Atrin, Axiom, Bristol Myers Squibb, Calithera, Cybrexa, Guidepoint, Ignyta, I-Mab, Janssen, Roche, Rubius, Schrodinger, Varian, and Zai Labs outside the submitted work. H.C. Chung reports grants and other from Lilly during the conduct of the study. Dr. Chung also reports grants from Lilly, GSK, MSD, Merck-Serono, BMS/ONO, Taiho, Amgen, Beigene, and Incyte, as well as personal fees from Merck-Serono, Lilly, Taiho, Celltrion, MSD, Lilly, Quintiles, BMS, Gloria, Beigene, Amgen, and Zymework outside the submitted work. M.J. de Miguel reports other from MSD, Roche, Pharmamar, Novartis, Abbvie, Array, Eisai, Sanofi, and Janssen outside the submitted work. Y.-J. Bang reports personal fees from AstraZeneca, Novartis, Genentech/Roche, MSD, Merck-Serono, Bayer, BMS, Eli Lilly, Taiho, Daiichi-Sankyo, Astellas, BeiGene, GreenCross, Samyang Biopharm, Hanmi, and Genexine, as well as grants from AstraZeneca, Novartis, Genentech/ Roche, MSD, Merck-Serono, Bayer, BMS, GSK, Pfizer, Eli Lilly, Boehringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, Daiichi Sankyo, Astellas, BeiGene, Green Cross, CKD Pharma, and Genexine outside the submitted work. C.-C. Lin reports personal fees from BeiGene, Blueprint Medicines, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, and Roche outside the submitted work. A. Italiano reports grants and personal fees from Bayer; grants from AstraZeneca, Novartis, Chugai, MSD, Merck, and Ipsen; nonfinancial support from Epizyme; and personal fees from Springworks outside the submitted work. A.M. Szpurka reports other from Eli Lilly and Company during the conduct of the study. M. Carlsen reports personal fees from Eli Lilly and Company during the conduct of the study, as well as personal fees from Eli Lilly and Company outside the submitted work. B. Vangerow reports other from Eli Lilly and Company outside the submitted work. L. Gandhi reports other from Eli Lilly during the conduct of the study. J. Bendell reports grants and other from Gilead, Genentech/Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Nektar, ARMO, Ispen, Merrimack, Oncogenex, Evelo,
FORMA, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Pfizer, Seattle Genetics, Bicycle Therapeutics, and Relay Therapeutics; grants from Koltan, SynDevRex, Forty Seven, AbbVie, Onyx, Sanofi, Agios, Takeda, Eisai, Celldex, Cytomx, Boston Biomedical, Tarveda, Tyrogenex, Marshall Edwards, Pieirs, Mersana, Calithera, Blueprint, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Unum Therapeutics, Vyriad, Harpoon, ADC, Millennium, Imclone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Tempest Tx, Shattuck Labs, Synthorx Inc, Revolution Medicines, Zymeworks, AtlasMedx, Scholar Rock, NGM Biopharma, Mabspace, REPARE Therapeutics, and NeoImmune Tech; and other from Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2 (Translational Drug Development), Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Amgen, Evelo, Piper Biotech, Samsung Bioepios, Treadwell Therapeutics, IGM Biosciences, and Fusion Therapeutics outside the submitted work. No disclosures were reported by the other authors.
The authors thank the patients, their families, and the investigational staff who participated in this study. Medical writing was provided by Dr. Jonathan Pitt (Evidera; Paris, France) and funded by Eli Lilly and Company. This study was funded by Eli Lilly and Company.
© 2020 American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Cancer Research