Greywolf reports early responses with oral ERAP1 inhibitor in solid tumours
Oxford-based Greywolf Therapeutics has reported early clinical activity for its first-in-class oral ERAP1 inhibitor GRWD5769 in combination with the anti-PD-1 antibody cemiplimab across six solid tumour types, presenting Phase 1b data from the EMITT-1 trial at the 2026 ASCO Annual Meeting.
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The results remain early and come from small, non-randomised expansion cohorts. However, the signal is notable because most patients had cancers that had already developed secondary resistance to prior anti-PD-1 therapy, a setting in which renewed treatment with PD-1 blockade alone would generally be expected to have limited activity.
GRWD5769 is designed to inhibit endoplasmic reticulum aminopeptidase 1, or ERAP1, an enzyme involved in shaping the peptides presented on MHC-I molecules. By altering this antigen presentation process, Greywolf aims to make tumour cells more visible to the immune system and broaden the T-cell response. The drug is given orally on a cyclical three-week on/off schedule and was tested in combination with cemiplimab, Regeneron and Sanofi’s approved anti-PD-1 therapy.
Across six completed Phase 1b expansion cohorts, Greywolf reported objective response rates ranging from 13% to 36%. The highest response rate was seen in urothelial carcinoma, where 5 of 14 evaluable patients had partial responses, corresponding to an ORR of 36%. In non-small cell lung cancer, 3 of 14 patients responded, giving an ORR of 21%, while durable clinical benefit reached 55% and progression-free survival was reported at 33 weeks.
Other signals were seen in hepatocellular carcinoma, microsatellite-stable colorectal cancer without liver metastases, cervical cancer and head and neck squamous cell carcinoma. In MSS colorectal cancer without liver metastases, 2 of 12 evaluable patients had partial responses, with durable clinical benefit reported in 51% of patients and progression-free survival of 33 weeks.
The colorectal cancer cohort is particularly interesting because MSS colorectal tumours are typically poorly responsive to checkpoint inhibitors. However, the absence of liver metastases is an important qualifier, as this subgroup may be more favourable for immunotherapy than the broader MSS colorectal cancer population.
Still early results
The study did not include a cemiplimab-only control arm, making it impossible to determine how much of the observed activity was attributable to GRWD5769 rather than PD-1 rechallenge, patient selection or tumour-specific factors. This limitation is particularly relevant because the trial combines a novel agent with an established checkpoint inhibitor across several biologically distinct tumour types.
Still, the company argues that the pattern of responses supports the hypothesis that ERAP1 inhibition can modify antigen presentation and help overcome resistance to PD-1 blockade. “Seeing the combination of strong durable clinical benefit rates and sustained PFS in a population that had already failed anti-PD-1 therapy, and in MSS-CRC where it isn’t licensed, is a clinically meaningful signal,” said Tom Lillie, Chief Medical Officer of Greywolf Therapeutics.
The treatment was reported to be well tolerated in combination with cemiplimab, with no safety signals and most adverse events described as Grade 1. If confirmed in larger studies, this safety profile could be important for a drug intended to be combined with immunotherapies.
Greywolf is now advancing the EMITT-1 programme into Stage 2 cohort expansions to inform a randomised Phase 2 study. The trial is ongoing across 28 centres in Australia, France, Spain and the United Kingdom.
