NCI 10211: A Phase II, Single-Arm Study of Berzosertib in Combination with Irinotecan in Patients with Advanced TP53 Mutant Gastroesophageal Cancer

Background Mutations in TP53 are common in gastroesophageal cancer and portend a poor prognosis. Tumor cells with TP53 mutations increasingly rely on ataxia-telangiectasia and Rad3-related (ATR) protein to respond to and repair DNA damage induced by cytotoxic chemotherapy. We aimed to assess the efficacy of ATR inhibitor, berzosertib, with irinotecan in patients harboring TP53-mutated, metastatic gastroesophageal cancer. Methods NCI 10211 is a phase II trial that enrolled patients with TP53-mutated, unresectable or metastatic gastroesophageal adenocarcinoma to receive berzosertib with irinotecan on day 1, 15 in 28-day cycles. Initially, patients who had progressed on at least one prior line of therapy were enrolled which was later amended to at least two prior lines of therapy. The primary outcome was objective response rate (ORR), and secondary outcomes included progression free survival (PFS) and overall survival (OS). Nine patients underwent biopsy for correlative studies, which included assay evaluation of ℽH2AX, NBS1, and KAP1 p-Ser 824 expression. Results Of the 17 patients enrolled, 16 were evaluable for the primary endpoint of ORR. The ORR was 0%, disease control rate (DCR) of 56.2%, median progression free survival (mPFS) of 4.01 months, and median overall survival (mOS) of 6.21 months. The study did not meet its primary endpoint. The most common treatment-related adverse events were nausea (52.9%), anemia (41.2%), diarrhea (41.2%), and lymphopenia (41.2%) without any unexpected adverse events. Conclusion This novel combination of ATR inhibitor berzosertib with irinotecan did not lead to objective responses in patients with TP53-mutated, advanced gastroesophageal adenocarcinoma. The combination regimen was well tolerated without unexpected adverse events. This trial was registered with ClinicalTrials.gov (NCT03641313).