EMERGE: A multi-centre, non-randomised, single-arm phase II study investigating domatinostat plus avelumab in patients with previously treated advanced mismatch repair-proficient oesophagogastric and colorectal adenocarcinoma

Abstract

Background: Mismatch repair proficient (MMRp) oesophagogastric (OG) and colo- rectal cancers (CRC) respond less frequently to checkpoint inhibition. Epigenetic modulation of tumours using HDAC inhibitors can increase the chance of response to immunotherapy. We previously reported dose escalation (EMERGE phase IIA) and the established recommended phase II dose (RP2D) of domatinostat (selective class I HDAC inhibitor) 200mg BID continuously plus avelumab 10mg/kg q2w. Methods: Patients with MMRp advanced OG and CRC who received at least one prior line of chemotherapy were enrolled in two cohorts. Patients were treated with a two- week domatinostat prime (orally) followed by combination domatinostat and avelu- mab from cycle 2 onwards. The trial was conducted using a Simon two-stage optimal design. The primary endpoint was best objective response rate (ORR) 6 months from initiation of combination treatment by RECIST 1.1. A secondary end point was disease control rate (DCR) during the same period. The total accrual target was 29 in the CRC cohort and 34 patients in the OG cohort, with interim analysis due to take place once 10 CRC patients and 9 OG patients had been evaluated for best ORR; 1 response and 2 responses were required in the respective cohorts to proceed to stage two. Results: 21 patients were recruited between January 2020 and October 2021. In the OG cohort 9 patients were treated. 56% patients had received 2 prior lines of systemic anti-cancer therapy (SACT). The median duration of treatment was 1.8 months (range: 0.9-12.8). The best ORR was 22.2% [95% CI: 2.8, 60.0] (one PR and one CR). The patient with PR had a combined positive score (CPS) of 9, whilst the CPS was unavailable for the patient with CR. At time of data cut off on 25th February 2022, both patients remained on treatment at cycles 28 and 16 respectively. The median CPS for the patients whose disease did not respond to treatment was 12 (range: 0- 26). In the CRC cohort, 12 patients were treated; of these, 2 did not receive avelumab and were non-evaluable. In the evaluable CRC population, 90% received 2 prior lines of SACT. No responses were observed. DCR was 30.0% [95% CI: 6.7, 65.2]. The median duration of treatment was 2 months (range: 1.3-9.0). The most common treatment related adverse events (TRAE) of any grade were fatigue (58%), anaemia (37%) and nausea (32%). There were no grade 3 TRAEs reported. Conclusions: For OG adenocarcinoma the ORR of 22.2% met the criteria to expand the stage two recruitment with a favourable safety profile. In CRC there was insuf- ficient signal to progress to stage two.