posted on 2024-07-23, 12:00authored byEdward Maldonado, W. Kimryn Rathmell, Geoffrey I. Shapiro, Naoko Takebe, Jordi Rodon, Devalingam Mahalingam, Nikolaos A. Trikalinos, Arash R. Kalebasty, Mamta Parikh, Scott A. Boerner, Celene Balido, Gregor Krings, Timothy F. Burns, Emily K. Bergsland, Pamela N. Munster, Alan Ashworth, Patricia LoRusso, Rahul R. Aggarwal
Supplementary Figure S2 shows an example of no loss of H3K36me3 by IHC (A) and loss of H3K36me3 by IHC (B). Images are at 40x power. Of note, the portal did not allow for uploading of a TIFF file alone as a "supplemental data" file, so the image included in this document is a TIFF file. We can easily provide the TIFF file if needed as well.
History
ARTICLE ABSTRACT
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 SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 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 SETD2-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.
WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-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 SETD2-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.