Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: The PACT phase Ia/Ib trial

Amita Patnaik; Timothy A. Yap; Hyun Cheol Chung; Maria J. de Miguel; Yung Jue Bang; Chia Chi Lin; Wu Chou Su; Antoine Italiano; Kay Hoong Chow; Anna M. Szpurka; Danni Yu; Yumin Zhao; Michelle Carlsen; Shelly Schmidt; Burkhard Vangerow; Leena Gandhi; Xiaojian Xu; Johanna Bendell

doi:10.1158/1078-0432.CCR-20-2821

Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: The PACT phase Ia/Ib trial

Amita Patnaik, Timothy A. Yap, Hyun Cheol Chung, Maria J. de Miguel, Yung Jue Bang, Chia Chi Lin, Wu Chou Su, Antoine Italiano, Kay Hoong Chow, Anna M. Szpurka, Danni Yu, Yumin Zhao, Michelle Carlsen, Shelly Schmidt, Burkhard Vangerow, Leena Gandhi, Xiaojian Xu, Johanna Bendell

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1267-1277
Number of pages	11
Journal	Clinical Cancer Research
Volume	27
Issue number	5
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-2821
Publication status	Published - 2021 Mar 1

Bibliographical note

Funding 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,

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2020 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1078-0432.CCR-20-2821

Cite this

Patnaik, A., Yap, T. A., Chung, H. C., de Miguel, M. J., Bang, Y. J., Lin, C. C., Su, W. C., Italiano, A., Chow, K. H., Szpurka, A. M., Yu, D., Zhao, Y., Carlsen, M., Schmidt, S., Vangerow, B., Gandhi, L., Xu, X., & Bendell, J. (2021). Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: The PACT phase Ia/Ib trial. Clinical Cancer Research, 27(5), 1267-1277. https://doi.org/10.1158/1078-0432.CCR-20-2821

@article{2b29e39d4ca2419ca3c83fa32059fcb4,

title = "Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: The PACT phase Ia/Ib trial",

abstract = "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.",

author = "Amita Patnaik and Yap, {Timothy A.} and Chung, {Hyun Cheol} and {de Miguel}, {Maria J.} and Bang, {Yung Jue} and Lin, {Chia Chi} and Su, {Wu Chou} and Antoine Italiano and Chow, {Kay Hoong} and Szpurka, {Anna M.} and Danni Yu and Yumin Zhao and Michelle Carlsen and Shelly Schmidt and Burkhard Vangerow and Leena Gandhi and Xiaojian Xu and Johanna Bendell",

note = "Funding 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, Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2021",

month = mar,

day = "1",

doi = "10.1158/1078-0432.CCR-20-2821",

language = "English",

volume = "27",

pages = "1267--1277",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "5",

}

Patnaik, A, Yap, TA, Chung, HC, de Miguel, MJ, Bang, YJ, Lin, CC, Su, WC, Italiano, A, Chow, KH, Szpurka, AM, Yu, D, Zhao, Y, Carlsen, M, Schmidt, S, Vangerow, B, Gandhi, L, Xu, X & Bendell, J 2021, 'Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: The PACT phase Ia/Ib trial', Clinical Cancer Research, vol. 27, no. 5, pp. 1267-1277. https://doi.org/10.1158/1078-0432.CCR-20-2821

TY - JOUR

T1 - Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors

T2 - The PACT phase Ia/Ib trial

AU - Patnaik, Amita

AU - Yap, Timothy A.

AU - Chung, Hyun Cheol

AU - de Miguel, Maria J.

AU - Bang, Yung Jue

AU - Lin, Chia Chi

AU - Su, Wu Chou

AU - Italiano, Antoine

AU - Chow, Kay Hoong

AU - Szpurka, Anna M.

AU - Yu, Danni

AU - Zhao, Yumin

AU - Carlsen, Michelle

AU - Schmidt, Shelly

AU - Vangerow, Burkhard

AU - Gandhi, Leena

AU - Xu, Xiaojian

AU - Bendell, Johanna

N1 - Funding 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, Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85102516128&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85102516128&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-2821

DO - 10.1158/1078-0432.CCR-20-2821

M3 - Article

C2 - 33229456

AN - SCOPUS:85102516128

SN - 1078-0432

VL - 27

SP - 1267

EP - 1277

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 5

ER -

Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: The PACT phase Ia/Ib trial

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