Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Background: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp) and show limited response to immune checkpoint inhibitors. This study assessed the safety and efficacy of combining domatinostat, a histone deacetylase inhibitor, with avelumab, an anti-PD-L1 antibody, in patients with previously treated, inoperable, advanced or metastatic MMRp OGA and CRC.

Patients and Methods: This multicentre, open-label phase II trial consisted of a dose-escalation and dose-expansion phase. In the escalation phase, patients received increasing doses of domatinostat [100 mg once daily (OD), 200 mg OD, or 200 mg twice daily (BD)] for 14 days, followed by continuous dosing. Avelumab (10 mg/kg) was administered intravenously every two weeks (2qw) to determine the recommended phase II dose (RP2D). In the expansion phase, the objective response rate (ORR) over six months was evaluated per RECIST v1.1 criteria using a Simon two-stage optimal design, requiring 2/9 and 1/10 responses to advance to stage 2 in the OGA and CRC cohorts, respectively.

Results: A total of 40 patients were enrolled between February 2019 and October 2021. Twelve patients participated in the dose-escalation phase, confirming the RP2D as domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were reported. At the RP2D, 21 patients were treated, with 19 (9 OGA, 10 CRC) evaluable for the primary ORR analysis. Two CRC patients did not receive combination therapy and were excluded from the analysis. Six patients participated in both escalation and expansion phases. In the OGA cohort, the ORR was 22.2% (95% one-sided confidence interval lower bound: 4.1), with a median disease control duration of 11.3 months (range: 9.9–12.7 months). No responses were seen in the CRC cohort, and no treatment-related grade 3–4 adverse events were observed at the RP2D.

Conclusions: The OGA cohort met the criteria to advance to stage 2 with an acceptable safety profile, while the CRC cohort did not demonstrate sufficient efficacy to continue.