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Authors | M.L. Telli, S. Lord, E. Dean, V. Abramson, H-T. Arkenau, C. Becerra, S.M. Tolaney, R. Tang, M.S. Penney, J. Pollard, G. Conboy, S.Z. Fields, G. Shapiro | ||||||||||||
Title | Initial results of a phase 1 dose expansion cohort of M6620 (formerly VX-970), an ATR inhibitor, in combination with cisplatin in patients with advanced triple-negative breast cancer (NCT02157792) | ||||||||||||
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URL | https://www.annalsofoncology.org/article/S0923-7534(20)37666-3/fulltext | ||||||||||||
Abstract Text | Background: ATR is a regulator of the cellular response to replication stress and signals DNA damage repair through homologous recombination. Many cancers depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with preclinical anticancer activity in combination with DNA-damaging chemotherapy in TNBC models. Given the prevalence of DNA damage repair defects in TNBC, this study evaluated the safety and efficacy of VX-970 in combination with Cis in an expansion cohort of pts with BRCA1/2 wild-type mTNBC. Methods: Eligible pts had advanced ER-, PR-, and HER2- BC with 0-2 prior non–platinum-based therapies. First line pts were eligible if relapse occurred ≥ 3 months after prior (neo)adjuvant chemotherapy. Measurable disease per RECIST 1.1 was required. Of a maximum 50 pts planned for enrollment, ≥30 were required to be BRCA1/2 germline wild-type and to have basaloid molecular subtype tumors on central testing. Pts received intravenous Cis 75 mg/m2 on day 1 with VX-970 140 mg/m2 on days 2 and 9 of each 21-day cycle. In pts intolerant to Cis or at investigator’s discretion, treatment could be switched to carboplatin AUC 5 with VX-970 90 mg/m2. Results: At the time of this analysis, 35 female pts with mTNBC who received ≥1 cycle of study drug were included in the safety set (median age, 48 y [range 35-74 y]). Grade ≥3 related TEAEs occurred in 16/35 pts: neutropenia (n = 8), anemia (n = 5), vomiting (n = 4), nausea (n = 3), and 1 pt each with thrombocytopenia, neutrophil count decreased, platelet count decreased, hypokalemia, generalized weakness, rigors, and acute kidney injury. Of these 35 pts, 18 were BRCA1/2 wild-type and had basaloid TNBC with at least 1 baseline scan and 1 on-treatment scan at the time of the data cut. Preliminary objective response rate was 38.9% (n = 7 [all partial response]), and disease control rate (CR+PR+SD) was 72.2% (n = 13). Conclusions: Combination VX-970 and Cis shows encouraging antitumor activity and tolerability in mTNBC. The study is ongoing; updated safety and efficacy results will be presented. Clinical trial identification: NCT02157792 |
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