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. 2024 Mar 21;9(4):102971. doi: 10.1016/j.esmoop.2024.102971

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☆

E Cartwright 1,†, S Slater 1,†, C Saffery 1, A Tran 1, F Turkes 1, G Smith 1, M Aresu 1, D Kohoutova 1, M Terlizzo 1, O Zhitkov 1, I Rana 1, EW Johnston 1, I Sanna 1, E Smyth 1, W Mansoor 2, C Fribbens 1, S Rao 1, I Chau 1, N Starling 1, D Cunningham 1,∗
PMCID: PMC10972804  PMID: 38518549

Abstract

Background

Most 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 methods

Eligible 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.

Results

Patients (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.

Conclusions

Responses 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 registration

NCT03812796 (registered 23rd January 2019)

Key words: Gastrointestinal cancer, colorectal cancer, mismatch repair, immune checkpoint inhibitor

Highlights

  • •

    Combining domatinostat with avelumab is safe and tolerable in patients with advanced MMRp OGA and CRC.

  • •

    The combination can achieve responses in some patients with OGA.

  • •

    This study demonstrates potential for an effective chemotherapy-free strategy to control pre-treated advanced OGA and CRC.

  • •

    Further clinical trials are required with alternative HDAC inhibitors to validate the results and move the field forward.

Introduction

Oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are among the most commonly diagnosed cancers, representing a significant global health burden.1 For patients with advanced disease, palliative chemotherapy, together with targeted molecular therapies in selected populations, is the mainstay of treatment2, 3, 4; however, prognosis remains poor. Together, OGA and CRC account for 20% of all cancer-related deaths and thus novel therapies are needed to improve survival.5

Targeting immune checkpoints with programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors has led to a paradigm shift in the management of several solid organ malignancies. The minority of patients with metastatic OGA and CRC have mismatch repair deficient (MMRd) disease, in whom immune checkpoint inhibitors (ICIs) have a well-established role and can result in durable responses.6 More than 95% of patients, however, have mismatch repair proficient (MMRp) tumours7,8 displaying a non-T-cell inflamed phenotype. For these patients, response rates to ICIs as monotherapy have been disappointing.9,10 Consequently, strategies for leveraging the benefits of ICIs in MMRp disease by combining them with drugs to enhance inflammation and T-cell infiltration, or with other immunotherapy agents, are under investigation.

Epigenetic modulation of tumours using histone deacetylase inhibitors (HDACi) can lead to increased tumour antigen presentation, increased immune cell infiltrate and increased chance of response to immunotherapy.11 Domatinostat is an oral selective class I HDACi. Preclinical data have shown that domatinostat induces beneficial effects on the tumour microenvironment through upregulation of expression of tumour-associated antigens and increased cytotoxic T-cell infiltrate. It has also been shown to act synergistically with anti-PD-L1 therapy to decrease tumour volume.11 Avelumab (anti-PD-L1 antibody) has demonstrated single-agent activity in multiple tumour types in PD-L1-positive and PD-L1-negative tumours.12 HDACi plus anti-PD-1 therapy has shown efficacy in melanoma,13 haematological malignancies14 and squamous cell anal cancer,15 demonstrating proof of concept for immunotherapy and HDACi combination strategies.

Herein we report the results of the dose escalation and expansion phases of the EMERGE trial, a multicentre, open-label, single-arm phase II trial designed to determine the recommended phase II dose (RP2D) of domatinostat and assess the efficacy and safety of domatinostat in combination with avelumab in patients with advanced MMRp OGA and CRC.

Methods

Participants

Adult patients with histologically confirmed advanced, unresectable or metastatic gastric, gastro-oesophageal junction (GOJ), oesophageal and colorectal adenocarcinomas were eligible. Patients were required to have measurable disease by RECIST version 1.1 and must have progressed on or after at least one prior line of chemotherapy. Tumours must have been assessed as MMRp by immunohistochemistry for MMR proteins. Other eligibility criteria were a European Cooperative Oncology Group performance status of 0 or 1 and adequate bone marrow, renal and liver function. Those with prior treatment with ICIs including anti-PD-1, anti-PD-L1 therapy or immunomodulatory drugs; active autoimmune disease requiring systemic immunosuppressive treatment in the past 2 years; and baseline prolongation of QT/QTc interval or long-QT syndrome on electrocardiogram were not allowed.

Trial design

The trial was a multicentre, open-label, single-arm phase II trial with two phases: a dose escalation phase to determine the RP2D of domatinostat and a dose expansion phase to assess the efficacy and safety of domatinostat in combination with avelumab. Patients were enrolled in two cohorts, OGA and CRC, across two UK institutions. The dose escalation phase of the trial utilised a 3 + 3 design with three dose levels for domatinostat; 100 mg once daily (OD), 200 mg OD and 200 mg twice daily (BD). Three patients were recruited to each dosing cohort and evaluated for dose-limiting toxicities (DLTs) as defined in the protocol (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.102971). Patients were treated sequentially at least a week apart, with the third patient in a cohort treated at least 48 h after the second. Doses were escalated until an RP2D was defined. The dose expansion phase was conducted using a Simon two-stage optimal design. The trial was registered with ClinicalTrials.gov (registration number NCT03812796).

Treatment

In the dose escalation phase, patients were allocated to receive domatinostat in the three dosing cohorts. The RP2D of domatinostat 200 mg BD was carried forward to the dose expansion phase. Treatment was delivered in 2-weekly cycles (2qw). For the first cycle, domatinostat was administered alone for 14 days. From cycle 2 onwards, domatinostat was continued at the same dose with treatment on days 1-14 in combination with avelumab 10 mg/kg 2qw. Avelumab was administered as an intravenous infusion over 1 h. Domatinostat was administered orally following fasting for 2 h before and 1 h after administration. Up to two dose modifications were permitted for domatinostat-related toxicity (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.102971). No avelumab dose modifications were permitted. Treatment was continued until progressive disease (PD), intolerable toxicity, death or patient withdrawal. Where pseudoprogression was suspected, treatment beyond PD was permitted.

Sample collection

Blood samples for pharmacokinetic testing were drawn from patients enrolled at the Royal Marsden Hospital at 0, 2, 4, 6, 8 and 24 h during cycle 1 day 1 in the dose escalation phase. Samples were taken at 0 and 3 h during cycles 1, 2, 3, 5, 7, 9, 13, 19 and 25 from patients in the dose expansion phase.

Provision of formalin-fixed paraffin-embedded tissue block from archival diagnostic and/or pretreatment biopsies was mandatory. Stool and blood samples were taken from patients at the Royal Marsden Hospital for translational research purposes (Supplementary Material S1, available at https://doi.org/10.1016/j.esmoop.2024.102971). The results of translational research work will be reported in a subsequent manuscript.

PD-L1 combined positive score testing

PD-L1 was assessed by combined positive score (CPS) retrospectively in the OGA cohort from archival and/or pretreatment tumour tissue samples. Testing was carried out using PD-L1 DAKO (22C3) companion diagnostic assay.

Response assessment

The best tumour response was assessed using contrast-enhanced computed tomography (CT) of the thorax, abdomen and pelvis by RECIST version 1.1 at 8 weeks and every 6 weeks (±7 days) thereafter. If pseudoprogression was suspected, a repeat CT scan was acquired 4-6 weeks later to confirm response assessment by modified RECIST for immunotherapy (iRECIST). Patients were followed up at 30 and 90 days after discontinuation of study treatment for safety and every 3 months thereafter for survival.

Toxicity

DLTs were evaluated in patients from the dose escalation phase. Safety and tolerability endpoints were analysed in the safety population; all registered patients received at least one dose of either study drug. Adverse events (AEs) and serious adverse events (SAEs) were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. For each patient, the highest grade experienced at each AE term at each timepoint was reported. Immune-related AEs (irAEs) were reported for AEs possibly, probably or definitely related to avelumab.

Endpoints

The primary endpoint of the dose escalation phase was the safe and tolerable RP2D for administration in the dose expansion phase. The primary endpoint of the dose expansion phase was the best objective response rate (ORR) 6 months from the initiation of combination treatment by RECIST version 1.1. The secondary endpoints were toxicity, duration of objective response (DoOR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The primary and secondary endpoints were analysed in the assessable efficacy population from the expansion phase; all eligible registered patients who received at least one cycle of domatinostat at the RP2D plus avelumab were assessable for response during the 6 months from combination treatment initiation.

The best ORR was defined as the proportion of patients who experienced complete response (CR) or partial response (PR) by RECIST version 1.1 criteria during the 6 months from combination treatment initiation. A sensitivity analysis was carried out using iRECIST criteria. The best DCR was defined as the proportion of patients who experienced CR, PR or stable disease (SD) by RECIST version 1.1 criteria at any point during 6 and 12 months from combination treatment initiation. DoOR was defined as the first documented radiological tumour response (CR or PR by RECIST version 1.1) to tumour progression, unequivocal clinical progression or death from any cause and censored at the last radiological assessment if no event occurred. PFS was defined as the time from combination treatment initiation to radiological tumour progression, unequivocal clinical progression or death from any cause; patients were censored at the last radiological assessment if no event occurred. OS was defined as the time from combination treatment initiation to death from any cause; patients still alive at data cut-off were censored. Follow-up was defined as observation time from the initiation of combination treatment to death or last follow-up.

Sample size and statistical analyses

Using a Simon two-stage optimal design, in the OGA cohort, to rule out the best ORR of 15% while aiming for a rate of 35% with a one-sided significance level of 5% and 80% power, 2/9 responses (PR or CR) were required at interim analysis for the first stage and 9/34 for the planned second stage. In the CRC cohort, to rule out the best ORR of 5% while aiming for a rate of 20% with a one-sided significance level of 5% and 80% power, 1/10 responses (PR or CR) were required at interim analysis for the first stage and 4/29 for the planned second stage. The accrual target was inflated by 30% to account for dropouts. In February 2022, 4SC AG discontinued the domatinostat development programme due to a lack of efficacy signals in other tumour types, and consequently, recruitment to the trial closed. Thus the interim analysis is presented as the final analysis.

Results

Patient characteristics

Between February 2019 and October 2021, 40 patients were registered, of whom 28 were eligible following screening (Figure 1). Two patients withdrew consent before commencing treatment, one patient died, and the remaining nine patients were ineligible. Twelve patients (10 CRC and 2 OGA) were treated with domatinostat 100 mg OD (n = 3), 200 mg OD (n = 3) and 200 mg BD (n = 6) in combination with avelumab and evaluated for DLTs in the dose escalation phase. One CRC patient was allocated to receive 200 mg OD but incorrectly dosed at 100 mg OD and not evaluated for DLTs. In April 2021, the RP2D was determined as domatinostat 200 mg BD plus avelumab 10 mg/kg 2qw following a review of safety data. The characteristics of the eligible patients are summarised for each cohort in Table 1 and Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.102971.

Figure 1.

Figure 1

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Flow diagram and analysis populations. BD, twice daily; CRC, colorectal cancer; DLT, dose-limiting toxicity; OD, once daily; OGA, oesophagogastric adenocarcinoma; RP2D, recommended phase II dose.

Table 1.

Baseline characteristics for eligible patients (escalation and expansion phases) by tumour cohort (n = 28)

Baseline characteristics CRC (n = 18) OGA (n = 10) Overall (n = 28)
Sex, n (%)
 Female 7 (39) 1 (10) 8 (29)
 Male 11 (61) 9 (90) 20 (71)
Age (years)
 Median (range) 49 (36-82) 60 (48-80) 55 (36-82)
Ethnicity, n (%)
 White 14 (78) 6 (60) 20 (71)
 Asian 0 (0) 2 (20) 2 (7)
 Caribbean 0 (0) 1 (10) 1 (4)
 White other 2 (11) 0 (0) 2 (7)
 Not disclosed 2 (11) 1 (10) 3 (11)
Histological differentiation, n (%)
 Poor 1 (6) 3 (30) 4 (14)
 Poor/moderate 0 (0) 3 (30) 3 (11)
 Moderate 17 (94) 4 (40) 21 (75)
ECOG, n (%)
 0 4 (22) 0 (0) 4 (14)
 1 14 (78) 10 (100) 24 (86)
Smoking status, n (%)
 N/A 1 (6) 1 (10) 2 (7)
 Never smoked 14 (78) 4 (40) 18 (64)
 Ex-smoker 3 (17) 4 (40) 7 (25)
 Current smoker 0 (0) 1 (10) 1 (4)
Total number of prior lines of chemotherapy
 Median (IQR) 3 (2-3) 3 (1-3) 3 (2-3)
 Range 1-5 1-5 1-5
Previous surgery, n (%)
 Primary tumour resection 12 (67) 3 (30) 15 (54)
 Other 0 (0) 1 (10) 1 (4)
 No surgery 6 (33) 6 (60) 12 (43)
Prior radiotherapy treatment, n (%)
 Yes 7 (39) 3 (30) 10 (36)
 No 11 (61) 7 (70) 18 (64)
Sites of metastases, n (%)
 Liver metastases present 11 (61) 5 (50) 16 (57)
 No liver metastases present 7 (39) 5 (50) 12 (43)
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CRC, colorectal cancer; ECOG, European Cooperative Oncology Group; IQR, interquartile range; OGA, oesophagogastric adenocarcinoma.

A total of 21 patients (12 CRC and 9 OGA) were treated in the dose expansion phase, of whom two patients with CRC did not receive combination treatment and were not assessable for the primary endpoint. In these 21 patients, the median number of cycles received was 4 (range 2-29) in the OGA cohort and 4 (range 1-18) in the CRC cohort. The median time on treatment was 1.4 months (range 0.9-13.1) and 1.7 months (range 0.1-9) in the OGA and CRC cohorts, respectively. In the OGA cohort, 8/9 (88.9%) patients discontinued treatment due to PD and 1/9 (11.1%) due to patient choice. In the CRC cohort, 2/12 (16.7%) discontinued treatment due to disease-related symptoms (grade 3 bilirubin rise and grade 3 colonic obstruction) before initiation of combination treatment and 10/12 (83.3%) discontinued treatment due to PD. Six out of nine patients in the OGA cohort treated in the dose expansion phase had a PD-L1 CPS ≥5 on pretreatment archival tissue.

Efficacy

Nineteen (9 OGA and 10 CRC) out of 21 (90.5%) patients treated at the RP2D were assessable for antitumour activity (Figures 2 and 3 and Supplementary Figures S1 and S2, available at https://doi.org/10.1016/j.esmoop.2024.102971). In the OGA cohort, the best ORR during 6 months was 22.2% [95% one-sided confidence interval (CI) lower bound 4.1] by RECIST version 1.1. Two responses were observed: one CR and one PR. The PD-L1 CPS status was available for the patient with PR (≥5). There were no further responses after the 6-month period. The median DoOR was 9.5 months (range 6.2-12.7). The best DCR during the 6 months from the initiation of combination treatment was 22.2% (95% CI 2.8% to 60.0%). The median duration of disease control was 11.3 months (range 9.9-12.7 months). According to the sensitivity analysis by iRECIST, one patient with OGA with the best response of CR experienced immune PR following progression by RECIST version 1.1; therefore the median DoOR and duration of disease control by iRECIST were 10.0 months (range 6.2-13.7 months) and 11.8 months (range 9.9-13.7 months), respectively. In the CRC cohort, no responses were observed. Three out of 10 patients had SD, resulting in a DCR of 30.0% (95% CI 6.7% to 65.2%). The median duration of disease control was 1.6 months (range 0.9-7.0 months) by RECIST version 1.1 and 3.5 months (range 1.6-7.0 months) by iRECIST.

Figure 2.

Figure 2

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Swimmer plot showing status for assessable patients treated at the recommendedphase II dose by tumour cohort (n = 19). CPS, combined positive score; CR, complete response; CRC, colorectal cancer; iCPD, immune confirmed progressive disease; iPR, immune partial response; OGA, oesophagogastric adenocarcinoma; PD-L1, programmed death-ligand 1; PR, partial response; SD, stable disease.

Figure 3.

Figure 3

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Waterfall plot showing the best change in the sum of target lesions for assessable patients treated at the recommended phase II dose by tumour cohort (n = 19). CPS, combined positive score; CRC, colorectal cancer; OGA, oesophagogastric adenocarcinoma; PD-L1, programmed death-ligand 1.

Survival

At the time of data cut-off (5 January 2023), all 19 assessable patients treated at the RP2D had experienced PD and 17/19 (89.5%) had died. PFS and OS data in assessable patients treated at the RP2D domatinostat in combination with avelumab are presented in Table 2 and Supplementary Figures S3–S6, available at https://doi.org/10.1016/j.esmoop.2024.102971. In the OGA cohort, the 6-month PFS rate was 22.2% (95% CI 3.4% to 51.3%) by RECIST version 1.1 and iRECIST. The median PFS was 1.1 months (95% CI 0.9-11.0 months) and 1.2 months (95% CI 0.9-11.0 months) by RECIST version 1.1 and iRECIST, respectively. The median OS for the OGA cohort was 6.3 months (95% CI 2.2-undefined months). In the CRC cohort, the 6-month PFS rate was 10.0% (95% CI 0.6% to 35.8%) by RECIST version 1.1 and iRECIST. The median PFS was 1.1 months (95% CI 1.1-2.1 months) and 1.1 months (95% CI 1.1-2.3 months) by RECIST version 1.1 and iRECIST, respectively. The median OS for the CRC cohort was 6.3 months (95% CI 2.8-17.9 months).

Table 2.

Efficacy endpoints for assessable patients treated at the recommended phase II dose by tumour cohort (n = 19)

Endpoints OGA cohort (n = 9) CRC cohort (n = 10)
The best ORR during 6 months, % (95% one-sided CI) 22.2 (4.1a) 0.0 (0a)
DoOR (months), median (range) 9.5 (6.2-12.7) —
The best DCR during 6 months, % (95% CI) 22.2 (2.8% to 60.0%) 30.0 (6.7% to 65.2%)
Duration of disease control (months), median (range) 11.3 (9.9-12.7) 1.6 (0.9-7.0)
PFS (months), median (95% CI) 1.1 (0.9-11.0) 1.1 (1.1-2.1)
OS, median (95% CI) 6.3 (2.2-undefined) 6.3 (2.8-17.9)
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CI, confidence interval; CRC, colorectal cancer; DCR, disease control rate; DoOR, duration of objective response; ORR, objective response rate; OGA, oesophagogastric adenocarcinoma; OS, overall survival; PFS, progression-free survival.

a

Lower confidence interval bound.

At 12 months, the OS rate in the OGA cohort was 22.2% (95% CI 3.4% to 51.3%) with a median follow-up of 6.3 months (range 2.2-21.7 months). The 12-month OS rate in the CRC cohort was 30.0% (95% CI 7.1% to 57.8%) with a median follow-up of 7.2 months (range 2.8-19.1 months). One patient with OGA and one patient with CRC were still alive at the data cut-off, both with a follow-up period of 17.5 months from the combination treatment initiation.

Safety

There were no DLTs during the dose escalation phase of the trial. Treatment-related adverse events (TRAEs) according to the dosing cohort are listed in Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.102971. In the dose expansion phase, the most common TRAEs across both cohorts were fatigue (57%), anaemia (29%), anorexia (29%), nausea (29%), diarrhoea (24%) and fever (24%; Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2024.102971). The most common irAEs were fatigue (38%), fever (24%), maculopapular rash (19%), anaemia (14%), anorexia (14%), diarrhoea (14%), infusion-related reaction (14%) and vomiting (14%). Overall, treatment was well tolerated and no grade ≥3 TRAEs or irAEs were reported. No treatment-related SAEs or deaths occurred. In the assessable efficacy population, 2 (20%) patients with CRC experienced a treatment interruption or dose reduction due to a TRAE; no patients with OGA had cycles affected by a TRAE.

Pharmacokinetic studies

Pharmacokinetic blood samples were analysed in seven patients from the dose escalation phase (four patients dosed at 100 mg OD and three at 200 mg OD). Data indicate that domatinostat concentrations peaked at 2 h after dosing. The geometric mean (% coefficient of variation) Cmax and area under the concentration–time curve of domatinostat ranged from ∼67 to 156 ng/ml and 123 to 220 ng/ml and 598 to 1740 ng/ml × h and 1860 to 2460 ng/ml × h, respectively, across the 100-200-mg domatinostat OD dosing at cycle 1 day 1 (single dose) and cycle 1 day 8 (steady state). Accumulation of domatinostat exposure was thus greater with the 200 mg OD dosing after 7 days, compared with the 100 mg OD dosing. These pharmacokinetic profiles were consistent with those previously reported for domatinostat monotherapy.

PD-L1 CPS and treatment outcome

Archival tissue was available for testing in all nine patients treated in the OGA cohort of the dose expansion phase. One patient had insufficient tumour tissue for testing. Six out of eight (75.0%) patients who underwent testing had PD-L1 CPS ≥5. Of the six patients, one had PR and five had PD as the best objective response. As there were no responses in the CRC cohort, PD-L1 CPS testing was not carried out in these patients’ samples.

Discussion

The dose escalation phase of the trial met its primary endpoint by establishing a safe and tolerable RP2D of 200 mg BD domatinostat in combination with avelumab 10 mg/kg 2qw. The expansion phase demonstrated antitumour activity in the OGA cohort, meeting the statistical requirement of two out of nine responses to progress to the second-stage recruitment. No responses were seen in the CRC cohort, suggesting a lack of efficacy. Criteria were not met to continue recruitment in this patient group.

In the OGA cohort of our study, we report the best ORR during 6 months of 22.2% and a median OS of 6.3 months with domatinostat plus avelumab. This is comparable to other currently approved second-line treatment options, and our combination appears to have a favourable side-effect profile when compared with previously published AEs from systemic chemotherapy.16, 17, 18 For patients with metastatic OGA without targetable molecular variants (e.g. HER2), approved options after fluoropyrimidine-based chemotherapy are irinotecan and paclitaxel with or without ramucirumab (anti-VEGFR-2 antibody)17 where funding is available. A head-to-head phase III trial of weekly paclitaxel versus fortnightly irinotecan in patients with metastatic gastric cancer refractory to fluoropyrimidine plus platinum chemotherapy demonstrated response rates of 20.9% and 13.6%, and a median OS of 9.5 months and 8.4 months, respectively. Grade 3-4 AEs were seen in 28.7% of patients treated with paclitaxel and 39.1% treated with irinotecan,16 compared with no grade 3-4 AEs in our trial in patients treated at the RP2D. In the chemorefractory setting, the phase III TAGS trial demonstrated an improved median OS of 5.7 months (95% CI 4.8-6.2 months) with trifluridine–tipiracil.19 Moreover, the median OS of 6.3 months demonstrated by the chemotherapy-free combination in our trial appears to be encouraging when compared with immunotherapy monotherapy in the chemorefractory setting. In the Asian population of the phase III ATTRACTION-02 trial, nivolumab compared with placebo in patients with gastric and GOJ adenocarcinoma following two or more prior lines of therapy demonstrated a median OS of 5.3 versus 4.1 months (HR 0.62, 95% CI 0.51-0.76; P < 0.0001) after 2 years of follow-up irrespective of PD-L1 positivity.20

In the first-line setting, upfront chemotherapy and immunotherapy combinations are now standard of care for patients with metastatic OGA, irrespective of MMR status.21, 22, 23 Updated survival data from the randomised phase III CheckMate 649 trial have shown a durable improvement in median OS, confirming the benefit of first-line nivolumab in combination with chemotherapy for patients with metastatic OGA.24 While the PD-L1-enriched subgroup derived the maximum benefit, the improvement in survival was seen across all subgroups. Similarly, the randomised phase III KEYNOTE-859 trial confirmed survival benefit for patients with locally advanced or metastatic gastric and GOJ adenocarcinoma treated with pembrolizumab in combination with 5-fluorouracil and platinum-based chemotherapy compared with chemotherapy alone with responses seen irrespective of PD-L1 CPS.25 In our trial, PD-L1 CPS [assessed by the DAKO (22C3) companion diagnostic assay] did not appear to influence outcomes, although the sample size was small. Six patients were found to have PD-L1 CPS ≥5, one of whom had a response while the other five patients experienced PD as the best response. For one patient in the OGA cohort who experienced sustained CR and remained alive at the time of data cut-off, PD-L1 CPS was unknown; therefore it is unclear whether it influenced the response. Mechanisms of primary resistance to the combination of HDACi and PD-L1 are unknown and clearly, the role of PD-L1 CPS testing is yet to be fully established. Further translational analysis for this study population is ongoing.

In our study, no responses were observed in the CRC cohort; however, DCR was 30.0% (95% CI 6.7% to 65.2%), and median OS was 6.3 months (95% CI 2.8-17.9 months). Approved treatments for patients with nonmutated metastatic chemorefractory MMRp disease are limited to regorafenib and trifluridine–tipiracil with or without bevacizumab (anti-VEGF antibody) where funding is available. The ORRs to these treatments are only up to 6.1% but DCRs of ∼40% and a median OS of 10.8 months have been achieved,26, 27, 28 raising the question of whether ORR is the most appropriate measure of benefit in this context. DCR, survival and toxicity might be considered more important in assessing the benefit of later lines of treatment given the limited number of options in this space. In the single-arm CAROSELL phase II trial evaluating the HDACi CXD101 and nivolumab in patients with metastatic CRC who previously received a median of 3 anticancer therapies, the primary endpoint was immune DCR. In this study, four (9%) patients achieved a PR, while 18 (39%) achieved SD with an immune DCR of 48%, meeting the primary endpoint. The median OS was 7.0 months (95% CI 5.13-10.22 months).29 Interestingly, encouraging results have recently demonstrated enhanced benefits with the addition of bevacizumab to the HDACi plus ICI combination. The phase II study of sintilimab (anti-PD-1 antibody) and chidamide (HDACi) with or without bevacizumab in patients with MMRp/microsatellite stable (MSS) metastatic CRC following at least two prior lines of systemic therapy reported an ORR of 13% and 44% (P = 0.008), with a median OS of 18.9 months and a median OS that was not reached (P = 0.41) in the doublet and triplet arms, respectively.30

Currently, in metastatic CRC, ICIs are reserved for patients with MMRd disease only in the first-line setting,31 and second line following fluoropyrimidine-based chemotherapy.32 Impressively, the novel anti-CTLA-4/anti-PD-1 combination of botensilimab plus balstilimab demonstrated a median OS of 20.9 months (95% CI 10.6-not reported months) in 87 heavily pretreated patients (chemotherapy and/or immunotherapy) with MSS CRC with a median follow-up of 9.3 months.33 Of note, enhanced responses were seen in an earlier subgroup analysis of 24 patients without active liver metastases, demonstrating ORR of 42% and DCR of 96%, compared with 24% and 73%, respectively, in all assessable patients.34 A similar pattern was seen in the nonrandomised phase I trial of regorafenib, ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-L1 antibody) in patients with metastatic MSS CRC with ORR of 0% versus 36.4%, and a median OS of 7 months versus >22 months in those with liver metastases compared with those without,35 suggesting the presence of liver metastases negatively impact immune system activation. The results from such early-phase trials show the potential for enhancing the effects of ICIs in metastatic MMRp/MSS CRC.

Our trial investigates a new combination of anticancer therapy which demonstrates the potential for a well-tolerated chemotherapy-free treatment to control disease in patients with OGA. It is, however, limited by the single-arm design with no comparator arm, and thus it does not allow clear establishment of the role of HDACi and ICI combination in this setting. Early closure of the trial also limits the degree of interpretation of data and the weight of the conclusions drawn. The sample size was small, limiting the significance of interpretation of the impact of PD-L1 CPS status on disease response. Further translational work is ongoing using blood and tumour tissue samples to assess response and resistance mechanisms to HDACi and immunotherapy combination including dynamic immune surveillance mechanisms and evolutionary changes leading to relapse.

Conclusions

Our ICI and HDACi combination appears to have antitumour activity in OGA sufficient for further investigation. Despite a lack of response in CRC, DCR and survival rates are comparable to other licensed treatments with an acceptable toxicity profile. As the treatment options following progression after chemotherapy are limited in most patients with MMRp disease whose tumours do not harbour targetable molecular variants, our approach may go some way to address this unmet need. Leveraging the benefits of ICI by combining it with immunomodulating drugs remains an attractive strategy for less immunogenic tumours.

Overall, this combination met the efficacy signal required to warrant further investigation in OGA with a tolerable safety profile and value may be gained from investigating ICIs in combination with other HDACis in larger sample sizes. Moreover, combining such approaches with anti-VEGF may be beneficial in both OGA and CRC, given that ramucirumab and bevacizumab, respectively, have demonstrated efficacy in the advanced setting. Further translational work is underway which may provide further insights into mechanisms of response and resistance to immunotherapy combinations in this setting.

Acknowledgements

The authors acknowledge and thank the patients, families and carers for their participation in the EMERGE study.

Funding

The trial was supported by the National Institute for Health and Care Research Centre (NIHR) at The Royal Marsden NHS Foundation Trust and Institute of Cancer Research (ICR) (no grant number). 4SC AG, Martinsried, Germany supported the trial financially and provided Domatinostat. Avelumab was provided by Merck (CrossRef Funder ID: 10.13039/100009945), as part of a previous alliance between Merck and Pfizer.

Disclosure

DC received research funding from Clovis, Eli-Lilly, 4SC, Bayer, Celgene, Leap and Roche and sits on the scientific advisory board for OVIBIO. IC is on the advisory board of Eli-Lilly, Bristol Myers Squibb (BMS), MSD, Roche, Merck, AstraZeneca, OncXerna, Boehringer Ingelheim, Incyte, Astella, GSK, SOTIO, Eisai, Daiichi-Sankyo, Taiho, Servier, Seagen, Turning Point Therapeutics, Novartis, BioNTech, Takeda and Elevation Oncology; received research funding from Eli-Lilly and Janssen-Cilag; and honoraria from Eli-Lilly, Eisai, Servier and Roche. NS has served on advisory boards for Pfizer, Servier, AstraZeneca, MSD Oncology, Novartis, Guardant, GSK, Gilead, Seagen and Janssen; received research funding from Merck, AstraZeneca, BMS, Pfizer and Guardant Health; and honoraria from Merck, Novartis, MSD Oncology, Eli-Lilly, Pierre Fabre, Amgen, Eli-Lilly Bangladesh, GSK, Seagen, BMS, AstraZeneca and Servier. SR receives financial support from Boehringer, Merck, Servier and Bayer; has served on advisory boards for HOOKIPA, Bayer, BeiGene, AstraZeneca, Merck, Seagen and Servier. CF has received financial support from AAA and Servier. ES receives financial support from the NIHR Biomedical Research Centre in Oxford; receives grants and personal fees from Bristol Myers Squibb and AstraZeneca; receives personal fees from Amgen, Daiichi Sankyo, Mirati, Merck, Viracta, Astellas, Novartis, Pfizer, Zymeworks and BeiGene, outside the submitted work; receives nonfinancial support from Mirati; and is the European Organisation for Research and Treatment of Cancer Gastric Cancer Taskforce Chair and an Ireland Oesophagogastric Cancer Group Trustee. WM has consulting and advisory roles with Ipsen, Novartis, Pfizer, MSD, BMS and Servier; has been involved in the speakers’ bureau with Ipsen, Novartis, MSD and Servier; has travel grants from MSD, Ipsen, BMS and Servier; and institutional grants from Nordic and MSD. The other authors have declared no conflicts of interest.

Data Sharing

Data are available upon reasonable request.

Ethics Approval

The study protocol was approved by the institutional review board (London, UK; Research Ethics Committee (REC) Ref Number 18/LO/0320, IRAS Project ID: 228232). The study was conducted in accordance with the Good Clinical Practice Guidelines and Declaration of Helsinki. Written informed consent was obtained from all patients before the study procedures taking place.

Supplementary data

Supplementary Tables and Figures
mmc1.docx (375.8KB, docx)

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Associated Data

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Supplementary Materials

Supplementary Tables and Figures
mmc1.docx (375.8KB, docx)

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