Phase II Study of Adavosertib in Patients With Tumors Containing BRCA1 and BRCA2 Mutations: Results From the NCI-MATCH ECOG-ACRIN Cancer Research Group (EAY131) Subprotocol Z1I.

Inhibition of WEE1, a tyrosine kinase responsible for G2 arrest, results in premature mitotic entry and double-strand DNA breaks. Adavosertib is a selective, ATP-competitive, and small-molecule WEE1 kinase inhibitor. In an adavosertib single-agent, Phase I trial, partial responses (PRs) were observed in patients with solid tumors carrying pathogenic variants (PVs) in BRCA1/2. In this trial, we further evaluated adavosertib in patients with PV in BRCA1/2 solid tumors. Eligible patients met criteria for the National Cancer Institute-Molecular Analysis for Therapy Choice master protocol and had a diagnosis of advanced BRCA-mutated solid tumor (germline or somatic mutations were accepted); 33 patients were enrolled, and 30 received study treatment. Adavosertib was administered orally, 300 mg once daily, with 5 days on and 2 days off over a 3 week cycle of 2 weeks on and 1 week off, until disease progression or unacceptable toxicity. Radiologic assessment was performed every three cycles. The primary end point was overall response rate (ORR); secondary end points included 6-month overall survival (OS6) and 6-month progression-free survival rate (PFS6). The ORR was 3.3% (90% CI, 0.2 to 14.9); the OS6 was 57.3% (90% CI, 41.9 to 72.7); the PFS6 was 23.4% (90% CI, 10.7 to 36.2). One PR (fallopian tube serous carcinoma) and six cases of stable disease (SD, >6 months) were observed. In patients with SD <6 months or progressive disease (nonresponders), significantly increased PI3K/AKT/mTOR signaling pathway gene transcripts suggested activation of this resistance mechanism. The primary reason for treatment discontinuation was disease progression. Common side effects included myelosuppression, fatigue, nausea, anemia, vomiting, and diarrhea. In heavily pretreated, advanced solid tumor patients with PV in BRCA1/2, adavosertib treatment resulted in low ORR, and this trial did not meet the primary end point.