n-(3-fluoro-4-((1-methyl-6-(1h-pyrazol-4-yl)-1h-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1-2-dihydropyridine-3-carboxamide and abemaciclib

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 were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Benzimidazoles; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Niacinamide; Prognosis; Ramucirumab