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 1 prior line of therapy were enrolled which was later amended to at least 2 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 PFS (mPFS) of 4.01 months, and median OS (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).