Abstract 443P
Background
Tumours that display a non-T-cell inflamed phenotype such as mismatch repair proficient (MMRp) oesophagogastric and colorectal cancers are less responsive to checkpoint inhibitors. Epigenetic modulation of tumours to enhance immunogenicity may improve responsiveness to immunotherapy. EMERGE is a phase IIA/B study evaluating domatinostat (selective class I histone deacetylase inhibitor) in combination with avelumab (PD-L1 antibody) in patients with advanced oesophagogastric adenocarcinoma (OGA) and colorectal cancer (CRC).
Methods
Patients with advanced MMRp OGA and CRC who received at least one prior line of chemotherapy were treated at three escalating dose levels of domatinostat (orally); 100mg once daily (QD), 200mg QD and 200mg twice daily (BID; 400 mg total daily dose [TDD]) in combination with avelumab 10mg/kg q2w (from cycle 2 onwards) in a 3+3 design to evaluate the safety and tolerability of the combination and determine the recommended phase II dose (RP2D). Tumour assessment was initially performed at 8 weeks. Once RP2D was established, cohort expansion would include 29 CRC and 34 OGA patients treated at RP2D.
Results
At the time of data cut off, 27th April 2021, 13 patients (OGA 2; CRC 11) were enrolled in the study (domatinostat 100mg 4 patients, 200mg 3 patients, 400mg 6 patients). No dose limiting toxicities were reported. 12 patients (92.3%) experienced at least 1 treatment related adverse event (TRAE), 1 patient (7.7%) experienced a grade 3 TRAE (rise in alkaline phosphatase). No patients experienced a grade 4 or 5 TRAE. The most frequently occurring TRAEs (≥5%) were fatigue (23%), anorexia (14%), anaemia (8%), insomnia (8%), dry skin (6%) and nausea (6%). 3 patients (23.1%) experienced ≥ 1 serious adverse event (SAE); none were treatment related. 6 patients (46.2%) have so far achieved stable disease (SD) during treatment, 3 of whom have experienced SD for at least 5.5 months.
Conclusions
Domatinostat up to 200 mg BID (400mg TDD) in combination with avelumab 10mg/kg q2w was considered safe and 200 mg BID was determined as the RP2D. Cohort expansion in phase IIB is now recruiting for OGA and CRC.
Clinical trial identification
NCT03812796.
Editorial acknowledgement
Legal entity responsible for the study
Royal Marsden Hospital NHS Foundation Trust.
Funding
This research was financially supported and domatinostat provided by 4SC and avelumab was provided by Merck Serono Ltd., UK, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck KGaA and Pfizer.
Disclosure
E. Smyth: Financial Interests, Personal, Other: Aptitude Health; AstraZeneca; BMS; Celgene; Elsevier; Everest Clinical Research; First Word Group; Five Prime Therapeutics; Gritstone Oncology; Imedex; Merck; My Personal Therapeutics; Roche; Sai-Med; Servier; Zymeworks. S. Rao: Financial Interests, Personal, Advisory Role: Bayer; Roche; Financial Interests, Personal, Other: Incyte; Bayer. I. Chau: Financial Interests, Personal, Advisory Board: Astella; Astra-Zeneca; Bayer; Boehinger Ingelheim; Bristol Myers Squibb; Eli Lilly; Merck-Serono; MSD; OncXerna; Pierre Fabre; Roche; Incyte; Financial Interests, Personal, Invited Speaker: Eisai; Eli Lilly; Financial Interests, Personal, Other, DMC chairman: Five Prime Therapeutics; Financial Interests, Institutional, Other, Coordinating PI: Cilag-Janssen; Eli Lilly. N. Starling: Financial Interests, Personal and Institutional, Funding, + travel grant: AstraZeneca; Bristol Myers Squibb; Financial Interests, Institutional, Funding: Pfizer; NIHR EME; RMCC; RM/ICR BRC; Financial Interests, Personal, Other, Travel grant + honoraria: Eli Lilly; Merck; MSD Oncology; Financial Interests, Personal, Other, Travel grant: Roche; Financial Interests, Personal, Other, honoraria: Pierre Fabre; Servier; GSK; Amgen; Financial Interests, Personal, Advisory Board: Pfizer; AstraZeneca; MSD. D. Cunningham: Financial Interests, Institutional, Research Grant: MedImmune/AZ; Clovis; Eli Lilly; 4SC; Bayer; Celgene; NIHR EME; Roche; Financial Interests, Institutional, Other, IMP: Leap; Financial Interests, Personal, Ownership Interest, + advisory role: OVIBIO. All other authors have declared no conflicts of interest.