A phase 2 study of the WEE1 inhibitor AZD1775 in SETD2-deficient advanced solid tumor malignancies.

Edward Maldonado University of California San Francisco, San Francisco, CA info_outline Edward Maldonado, Wendy Kimryn Rathmell, Geoffrey Shapiro, Jordi Rodon Ahnert, Devalingam Mahalingam, Nikolaos Trikalinos, Arash Rezazadeh, Victor Ricardo Adorno Febles, Mamta Parikh, Scott Anthony Boerner, Gregor Krings, Naoko Takebe, Patricia LoRusso, Rahul Raj Aggarwal

Authors Edward Maldonado University of California San Francisco, San Francisco, CA info_outline Edward Maldonado, Wendy Kimryn Rathmell, Geoffrey Shapiro, Jordi Rodon Ahnert, Devalingam Mahalingam, Nikolaos Trikalinos, Arash Rezazadeh, Victor Ricardo Adorno Febles, Mamta Parikh, Scott Anthony Boerner, Gregor Krings, Naoko Takebe, Patricia LoRusso, Rahul Raj Aggarwal Organizations University of California San Francisco, San Francisco, CA, Vanderbilt University Medical Center, Nashville, TN, Dana-Farber Cancer Institute, Boston, MA, The University of Texas MD Anderson Cancer Center, Houston, TX, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, University of California Irvine Medical Center, Orange, CA, Perlmutter Cancer Center at NYU Langone Health, New York, NY, University of California Davis, Sacramento, CA, Yale University, Canton, MI, University of California, San Francisco, San Francisco, CA, Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, Yale School of Medicine, New Haven, CT Abstract Disclosures Research Funding U.S. National Institutes of Health U.S. National Institutes of Health Background: AZD1775 is an inhibitor of the WEE1 kinase, leading to loss of genome integrity. Pathogenic SETD2 mutations lead to genome-wide loss of histone H3K36 trimethylation (H3K36me3) and hypersensitivity to WEE1 inhibition with a synthetic lethal effect. AZD1775 was studied in 2 cohorts of patients: A) Patients (pts) with locally advanced/metastatic solid tumor malignancy other than clear cell renal cell carcinoma (ccRCC) and B) pts with locally advanced/metastatic ccRCC. Methods: Eligible pts had a locally advanced/metastatic cancer with progression on ≥ 1 prior systemic therapy (including prior tyrosine kinase inhibitor or checkpoint inhibitor for cohort B), and a pathogenic SETD2 mutation by CLIA-certified next generation sequencing panel. Pts received AZD1775 at a starting dose of 300 mg PO daily on days 1-5, 8-12 of each 21-day cycle. The primary objective was to determine the objective response rate (ORR) by RECIST 1.1 criteria in each cohort. Planned sample size was 9 pts in each cohort in stage 1 of a Simon two-stage design. Secondary objectives were to determine the clinical benefit rate (CBR) (defined as partial response or stable disease [SD] > 4 months), duration of response (DOR), and safety. Correlative assays include the evaluation of H3K36me3 mark by immunohistochemistry (IHC) in archival tumor tissue. Results: Between 05/2019 and 10/2021, 18 pts whose tumor harbored a pathogenic mutation in SETD2 were enrolled (9/cohort). The median age was 60 years (range 45 – 74), ECOG PS 0 in 8 (44.4%). One patient remains on treatment; 17 have discontinued (disease progression, n = 9; adverse event, n = 4; patient withdrawal, n = 2; patient death, n = 1). The median duration of treatment was 1.89 months (range 0.75 – 13.5). There were no confirmed objective responses and therefore enrollment was halted following accrual to stage 1. Tumor regression of any magnitude was observed in 5/17 (29%) evaluable pts. Stable disease was the best overall response in 10/17 (59%) evaluable pts, including 3 pts with SD for > 4 months. One patient with RCC remains on treatment with SD for 14+ months duration. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Twelve pts (67%) experienced a Grade ≥ 3 adverse event. Evaluation of H3K36me3 using IHC as an exploratory biomarker is underway. Conclusions: AZD1775 given as monotherapy failed to achieve an objective response in SETD2- altered RCC and other solid tumor malignancies. However, a subset of pts derived clinical benefit as manifested by tumor regressions and/or durable stable disease. Evaluation of AZD1775 in combination with other DNA damage-inducing agents that cause replication stress may be warranted, potentially with the integration of the H3K36me3 mark as a biomarker for patient selection. Clinical trial information: NCT03284385.

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