In a phase I trial reported in the Journal of Clinical Oncology, Timothy A. Yap, MBBS, PhD, FRCP, and colleagues identified recommended phase II doses of the first-in-class ATR (ataxia telangiectasia and Rad3–related) kinase inhibitor berzosertib alone and in combination with carboplatin and found evidence of activity in patients with advanced solid tumors.
“To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. [Berzosertib] was well tolerated, with target engagement and preliminary antitumor responses observed.”— Timothy A. Yap, MBBS, PhD, FRCP, and colleagues
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As stated by the investigators, “Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin.”
Study Details
In the study, 40 patients with solid tumors refractory to standard therapy received intravenous berzosertib alone (n = 17) once or twice weekly at a starting dose of 60 mg/m2 or in combination with carboplatin (n = 23; carboplatin on day 1 and berzosertib on days 2 and 9 in 21-day cycles).
Key Findings
Among patients receiving monotherapy, no dose-limiting toxicities were observed and the recommended phase II dose for once- or twice-weekly administration was 240 mg/m2. The most common treatment-related adverse events of any grade were flushing (24%), followed by nausea, pruritus, headache, and infusion-related reactions (12% each).
Among 17 patients receiving monotherapy evaluable for efficacy, objective response was observed in 1 patient (6%), who had a complete response, and stable disease was observed in an additional 5 (29%). The patient with a complete response had progression-free survival of 29 months at last assessment.
The recommended phase II dose for combination therapy was berzosertib at 90 mg/m2 with carboplatin at AUC 5. The most common adverse events of any grade were neutropenia (48% of patients; grade 3 or 4 in 26%), thrombocytopenia (39%; grade 3 or 4 in 4%), and anemia (57%; grade 3 or 4 in 4%). A grade 3 or 4 nonhematologic adverse event was observed in one patient (grade 3 hypersensitivity reaction).
Among 21 patients receiving combination therapy evaluable for efficacy, 1 patient (5%) had a partial response and 15 (71%) had stable disease, with 10 having stable disease for ≥ 4 months and 6 for ≥ 6 months.
Pharmacodynamic studies showed marked inhibition of phosphorylation of CHK1, the downstream ATR substrate.
The investigators concluded: “To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. [Berzosertib] was well tolerated, with target engagement and preliminary antitumor responses observed.”
Dr. Yap, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Vertex Pharmaceuticals, Experimental Cancer Medicine Centre (of The Institute of Cancer Research), and the National Institute for Health Research Biomedical Research Centre (jointly of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). For full disclosures of the study authors, visit ascopubs.org.
