The ATR inhibitor berzosertib produced responses with or without the DNA-damaging agent carboplatin.
Major Finding: The ATR inhibitor berzosertib produced responses with or without the DNA-damaging agent carboplatin.
Concept: In this 40-patient phase I trial, one patient in the monotherapy group showed a complete response.
Impact: Berzosertib appears safe, and ATR inhibitors warrant further study with or without DNA-damaging drugs.
Inhibitors of the serine/threonine protein kinase ATR, a mediator of the DNA-replication stress response, are under investigation for a variety of malignancies. Preclinical evidence has suggested that ATR inhibitors may synergize with chemotherapeutic drugs that inhibit DNA repair, prompting Yap and colleagues to initiate a phase I trial of the ATR inhibitor berzosertib (M6620) with or without carboplatin in patients with advanced solid tumors. One patient in the monotherapy group experienced a complete response with no progression by the time of last assessment (29 months) and one patient in the combination-therapy group experienced a partial response lasting 6 months. Notably, heavily pretreated disease was the norm among these patients, including the one who experienced a complete response and the one who experienced a partial response. The patient who experienced a complete response had immunohistochemistry-confirmed loss of ARID1A (along with ARID1A mutation) and ATM, and had mismatch-repair deficiency. Additionally, the patient experiencing a partial response had a germline BRCA1 mutation, and her ovarian cancer was platinum-refractory and had progressed twice on two different PARP inhibitor regimens. Stable disease was the best response among 29.4% of those who received berzosertib alone and 71.4% of those who received the combination treatment. The most common treatment-emergent adverse events deemed to be related to treatment were flushing, nausea, pruritus, headache, and infusion reactions in the berzosertib monotherapy group and hematologic abnormalities (including neutropenia, thrombocytopenia, and anemia) in the group receiving combination therapy. In summary, the ATR inhibitor berzosertib appears safe alone or in combination with carboplatin and shows signs of efficacy in patients with heavily pretreated advanced solid tumors, suggesting that further study of this or other ATR inhibitor–DNA-damaging drug combinations is warranted.
Yap TA, O'Carrigan B, Penney MS, Lim JS, Brown JS, de Miguel Luken MJ, et al. Phase I trial of first-in-class ATR inhibitor M6620 (VX-970) as monotherapy or in combination with carboplatin in patients with advanced solid tumors. J Clin Oncol 2020 Jun 22 [Epub ahead of print].
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