Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial
Background: Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1, while olaparib inhibits poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effects of PARP inhibitors.
Objective: This study aimed to evaluate the safety, tolerability, and efficacy of adavosertib combined with olaparib in patients with refractory solid tumors, focusing on determining the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D).
Patients and Methods: In part A (dose finding), eligible patients had refractory solid tumors with no established treatment and had received at least one prior systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Adavosertib was administered either once daily (qd) or twice daily (bid) for 3 consecutive days with 4 days off treatment (3/4 schedule), or 5 consecutive days with 2 days off (5/2 schedule), alongside olaparib (bid) for 14 or 21 days in a 21-day cycle.
Results: A total of 130 patients were enrolled: 120 in part A and 10 in part B. The MTD for bid dosing of adavosertib was 175 mg (on days 1-3 and 8-10 of a 21-day cycle) plus continuous olaparib at 200 mg bid; the once-daily MTD (and RP2D) was 200 mg adavosertib (on days 1-3 and 8-10) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) included fatigue (64.3% for bid dosing and 15.4% for qd dosing), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in 88.9% of patients, including thrombocytopenia (66.7%) and anemia (55.6%). In part A, the overall objective response rate (ORR) was 14.8% (95% CI: 8.7-22.9); for the MTD/RP2D cohorts, ORR was 30.8% (95% CI: 9.1-61.4) for bid dosing and 9.1% (95% CI: 0.2-41.3) for qd dosing. In the SCLC dose-expansion cohort, ORR was 11.1% (95% CI: 0.3-48.2), disease control rate was 22.2%, and median progression-free survival was 1.5 months (95% CI: 1.3-4.2).
Conclusions: The adverse events and DLTs observed with both bid and once-daily MTD/RP2D dosing schedules were manageable and aligned with the known safety profiles of adavosertib and olaparib. Limited antitumor activity was observed with the combination of adavosertib and olaparib in this patient population.