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 - 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.
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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 -