BackgroundMost oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC.Patients and methodsEligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively.ResultsPatients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D.ConclusionsResponses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2.Trial registrationNCT03812796 (registered 23rd January 2019)

Immune-checkpoint inhibitors (ICIs) showed limited efficacy in mismatch repair proficient (MMRp) metastatic colorectal cancer (mCRC) to date. Many RAS/BRAF wildtype mCRCs respond to EGFR antibodies (cetuximab/panitumumab) and we previously showed that acquired resistance to these is characterised by an inflamed phenotype and PD-L1 and LAG3 upregulation. The single arm phase 2 iSCORE trial investigated whether RAS/BRAF wildtype MMRp mCRCs that had acquired resistance to prior chemotherapy and an EGFR antibody benefit from nivolumab (anti-PD1) and relatlimab (anti-LAG3) ICIs. Patients (pts) with RAS/BRAF wildtype MMRp mCRC that had responded to chemotherapy + EGFR antibody and subsequently progressed were recruited for treatment with nivolumab (480mg iv) and relatlimab (160mg iv) every 4 weeks. The primary endpoint was disease control rate at 6 months (DCR6) from treatment initiation. To detect an increase in DCR6 from 10% to 30%, with a two-sided 5% significance and power of 80%, 25 pts were needed. Secondary endpoints included duration of disease control, best objective response (ORR) during 6 months, progression free survival (PFS), overall survival (OS) and safety. Pre-treatment and on-treatment biopsies were obtained for biomarker analyses. 32 pts were registered. 25pts who received at least one dose of nivolumab/relatlimab were included in the primary endpoint analysis. 24% of pts had received ≥2 prior lines of systemic therapy. The median number of cycles administered was 2 (range: 1-12). 1pt remained on treatment (cycle 11) at the time of data cut-off (30/01/2023). Among 25 evaluable pts, best objective responses during 6 months by RECIST 1.1 were one CR, one PR, two SD and 20 PD; 1pt died without a follow-up scan. One PR and one SD were reported during treatment in two additional pts by iRECIST after pseudoprogression. Median duration of disease control for pts with clinical benefit (CR, PR, SD) by iRECIST was 9.0mo [range:1.8-11.1]. 4/7pts [57.1%] without liver metastases and 2/18pts [11.1%] with liver metastases achieved clinical benefit by iRECIST. The best ORR during 6 months was 8% [95% CI:1.0-26.0] by both RECIST 1.1 and iRECIST. DCR6 was 12% [95% CI:2.5-31.2] by RECIST 1.1 and 16% [95% CI:4.5-36.1] by iRECIST in all 25pts. At data cut-off, median PFS and OS were 1.6mo [95% CI:1.6-1.8] and 15.2mo [95% CI:6.4-18.5], respectively. Five grade 3 treatment related adverse events (TRAE) were reported across 5pts; no grade 4/5 TRAEs occurred. The most common TRAEs (any grade) were fatigue (24%) and acneiform rash (12%). In pre-treatment biopsies, the median PD-L1 combined positive score (CPS) was 0 [range:0-3] for pts without liver metastases and PD-L1 CPS was 0 for all four of these with clinical benefit. The median PD-L1 CPS was 1.5 [range:0-65] for pts with liver metastases, with PD-L1 CPS 6 and 12 in the 2pts with clinical benefit. The prespecified endpoint of 25% DCR6 was not met with nivolumab/relatlimab. However, the clinical benefit rate in pts without liver metastases and prolonged disease control in two pts with liver metastases are encouraging. Nivolumab/relatlimab was well tolerated. Biomarker analyses, including TMB and T-cell quantification, are ongoing and will be presented.

Mismatch repair proficient (MMRp) oesophagogastric (OG) and colorectal 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. 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 avelumab 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. 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. 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 insufficient signal to progress to stage two.

Immune checkpoint inhibitor (ICI) monotherapy has limited efficacy in patients (pts) with mismatch repair proficient (MMRp) oesophagogastric adenocarcinoma (OGA). Dickkopf-1 (DKK1) modulates Wnt/β-Catenin signaling and promotes a T-cell excluded or ‘immune desert’ tumour microenvironment (TME). DKN-01, a DKK1 neutralising antibody, can favourably reprogram the TME by reducing levels of myeloid-derived suppressor cells (MDSCs) and increasing entry of effector T-cells and may improve responses when added to ICI monotherapy. This phase IIa study (3+3 design) evaluated the safety and efficacy of DKN-01 (300mg/600mg) and atezolizumab (840mg) given intravenously q2W in pts with pre-treated, anti PD1/PDL1 naïve, MMRp advanced OGA. The primary endpoint was to establish the safety, tolerability, and recommended phase II dose (RP2D) for the efficacy phase. Safety, efficacy, and translational analyses (including intratumoural DKK1/PD-L1, peripheral MDSC and NK cell populations, TCR diversity analysis, tumour genomics and stool microbiome) are ongoing. Eleven pts were treated on study (5 pts at DKN-01 300mg, 6 at 600mg). Eight pts completed the DLT period (3 at 300mg, 5 at 600mg) and were therefore evaluated for the safety endpoint. No dose limiting toxicities were observed. Of the 11 treated pts, 10 (90.9%) experienced at least one treatment-related AE (TRAE). The most common TRAEs (experienced by ≥ 2 pts) were fatigue (36%), anaemia (18%), hypothyroidism (18%), diarrhoea (18%) and pain (18%). One pt experienced G3 urticaria and 1 experienced an SAE of G2 pneumonitis, both were treatment related. Of the 8 pts evaluated for the safety endpoint, 1 pt (12.5%) had PR and 4 pts (50%) had SD as their best response. No clear trend between peripheral MDSC levels at baseline and during treatment have yet been observed. Additional biomarker work is ongoing. DKN-01 plus atezolizumab has a manageable safety profile with no new safety signals in pts with advanced OGA. DKN-01 600mg plus atezolizumab 840mg q2W was the RP2D taken through to the ongoing expansion phase to confirm efficacy.

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).