Data from A Phase II Trial of the WEE1 Inhibitor Adavosertib in <i>SETD2</i><i>-</i>Altered Advanced Solid Tumor Malignancies (NCI 10170)

Abstract

<div>Abstract<p>We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1–5 and 8–12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic <i>SETD2</i> mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of <i>SETD2</i> loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45–74). The median duration of treatment was 1.28 months (range 0–24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in <i>SETD2</i>-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.</p>Significance:<p>WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with <i>SETD2</i>-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by <i>SETD2</i>-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.</p></div>