Utilising novel therapies in the treatment of gastrointestinal cancers

Abstract

Background: Gastrointestinal (GI) malignancies are common and frequently lethal diseases. For most, treatment options revolve around chemotherapy where efficacy beyond second line is negligible, and toxicity is high. Novel and better tolerated treatments which improve survival are thus urgently required. Hypothesis: Recently elucidated oncogenic pathways in oesophagogastric and colorectal cancer can be therapeutically exploited for patient benefit. Results: 1. Based on pre-clinical models of c-MYC/HER2 amplified OG cancer which demonstrated a profound synthetic lethal interaction with BTK inhibition, 8 patients with c-MYC/HER2 amplified oesophagogastric cancer were treated with the BTK-inhibitor ibrutinib in the iMYC trial. No responses were observed; however, one patient with a dual c-MYC and HER2 co-amplified tumour achieved disease control for 32 weeks with a marked metabolic response in the primary tumour. Grade >3 GI haemorrhage occurred in 3 patients and was fatal in 2 cases which was considered a new safety finding for ibrutinib in this population. 2. Dermatinostat (HDAC inhibitor) can favourably reprogramme the TME for collaboration with ICIs. The combination of domatinostat and avelumab was found to be safe and tolerable in patients with OGA and CRC in the phase IIa EMERGE study. 5 patients with CRC experienced disease control at 6 months and 1 patient with OGA had a PR. Domatinostat 200mg BD combined with avelumab 10mg/kg was determined as the R2PD. 3. DKK1 modulates Wnt/beta-catenin signalling and promotes a T cell excluded or 'immune desert' TME. The DKK1 neutralising antibody, DKN-01, in combination with atezolizumab was found to be safe and tolerable in 11 patients treated in the phase IIa WAKING study. One patient with DKK1-high tumour achieved a PR. DKN-01 600mg with atezolizumab 840mg was the R2PD for ongoing expansion phase. Conclusion: Some signals of efficacy have been seen in these early trials of novel therapies in GI cancer patients. Consideration into how to deal with intratumoural heterogeneity and incorporate novel trial design into future efforts to evaluate new therapies will be required.