A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.

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Déclaration de conflit d'intérêts

Conflicts of interest Roisin O'Cearbhaill - reports personal fees from once off advisory boards from Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Immunogen, R-Pharm, Miltenyi, 2seventybio and Bayer, outside the submitted work; received honoraria for lectures from Gynecologic Oncology Foundation, Curio, PER/MJH, SITC, Gynecologic Oncology Canada and support to attend meetings from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech, Acrivon, Link Therapeutics and Transgene. NRG representative for the ComboMATCH and iMATCH studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation, Acrivon and Lyell Immunopharma. Robert Soslow is a co-editor for the journal Modern Pathology. Dmitriy Zamarin has grants/contracts from AstraZeneca, Merck, Plexxikon, Synthekine and Genentech. He has patient licensng fees through Merck. He has received consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa, Kalivir, Xencor and GSK. Patents planned, issued or pending include Merck for use of oncoltic NDV for cancer therapy. He also has stock options for Accurius, Immunos and Calidi Biotherapeutics. Kathleen Moore's institution receives research funding from PTC Therapeutics, Lilly, Clovis, Genentech, GSK and Verastem. Her Royalties/licenses are up to date. She received consulting fees from AstraZeneca, Aravive, Alkemeres, Aadi, Blueprint pharma, Clovis, Caris Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Inxmed, Imab, Iovance, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, OncXerna, Onconova, Tarveda, VBL Therapeutics and Verastem. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from PRIME, RTP, Medscape, Great Debates and Updates. She has received support for attending meetings and/or travel from AstraZeneca. She has a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid through GOG P Associate Director. Mark Shahin received grants or contracts from GSK, AstraZeneca and Merck. He also received consulting fees from GSK, AstraZeneca and Immunogen. He received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, AstraZeneca, Merck, Eisai, Immunogen and SeaGen. He has a leadership or fiduciary role with UniteForHer. Premal Thaker's institution received grants/contracts from Merck and GSK. He has received consulting fees from Novartis for endometrial cancer, Merck, AstraZeneca, Clovis Oncology, GSK, Novocure, R-Pharm, Immunon, Zentalis and Aadi Bioscience. Andrea E. Wahner-Hendrickson has an NCI grant (P50 CA 136393) for Mayo Ovarian Cancer SORE (Co-project leader), TORL – Site PI Clinical Trial and Prolynx – IIT. She ha received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from George Washington University for Medical Oncology Board Review (CME) – ovary and uterine. She participates on a Data Safety Monitoring Board or Advisory Board at Mayo Clinic DSMB NCI CIRB (early emphasis). She has unpaid Leadership or fiduciary roles in other board, society, committee or advocacy group with Oxcia Advisory Board and MN ovarian cancer advisory board. Carol Aghajanian received clinical trial funding to institution (MSK): Abbvie – MSK PI, GOG 3005, AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator & MSK PI, DO81RC00001; ENGOT – ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 & 3; Genentech/Roche – MSI PI, GOG 3015 (Imagyn050). She has received consulting fees from Abbvie – Advisory Board 5/8/20; Roche/Genentech – Advisory Board 8/21/20; Eisai/Merck – Advisory Board 9/12/20; AstraZeneca/Merck – Advisory Boards 9/30/20 & 10/14/20; and Repare Therapeutics – Advisory Board 10/15/20. She has participated on an Advisory Board – 6/30/21 (no consulting fee) for Blueprint Medicine. She also served as Leadership or fiduciary role in other board, society, committee or advocacy group for GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology Board of Directors (unpaid). Austin Miller, Heather Lankes, Deborah Delair, Sheila Segura, Shweta S. Chavan, Robert DeBernardo, and John Moroney have no conflicts of interest to declare.