Dr Timothy A. Yap - UT MD Anderson Cancer Center, Houston, USA

I presented data from our first in human phase I trial of the oral first in class covalent Werner helicase, or WRN, inhibitor RO7589831in patients with microsatellite instable, or MSI, and/or mismatch repair deficient, or dMMR, advanced solid tumours.

What is WRN? Well, WRN stands for Werner helicase, which is an enzyme that belongs to the RecQ family and it plays a crucial role in the maintenance of genome integrity. WRN actually serves as a DNA caretaker enzyme, playing a critical role in the unwinding of non-canonical secondary DNA structures such as Holliday junctions, bubbles and Fox duplexes, which are formed in response to DNA damage and/or DNA repair processes.

RO7 is a first in class covalent WRN inhibitor and this is important because WRN inhibition actually represents an synthetic lethal vulnerability and also a therapeutic opportunity in cancers with microsatellite instability or MSI. By inhibiting WRN, this actually leads to an accumulation of DNA double strand breaks, mitotic cleavage and eventually to apoptosis and cell death. So RO7 actually engages covalently with a cysteine 727 that’s located in an allosteric pocket of the WRN helicase. This covalent binding actually locks the helicase in a single conformation, preventing it from transitioning to the subsequent conformational state that’s critical for its helicase activity.

So in this clinical trial we provided the first early clinical proof of concept for effectively drugging WRN. The most common adverse events that were drug related were mainly manageable grade 1-2 nausea, vomiting and diarrhoea that were seen in a minority of patients. We showed that RO7 was rapidly absorbed and eliminated with a half-life of 4.4 hours and PK was predicted to reach steady state after 14 days.

Importantly, we observed that WRN resulted in RECIST tumour shrinkage that was observed across different dose levels and indications, including five RECIST partial responses in three patients with endometrial cancer and a patient with colorectal cancer and a patient with ovarian cancer. Importantly, all of these patients were MSI patients who were PD-1 or PD-L1 inhibitor resistant. We also observed very durable disease stabilisation in a majority of MSI checkpoint inhibitor resistant tumours. These data are supported by the metabolic responses that we observed in a majority of patients and, interestingly, metabolic responses measured by FDG-PET were associated with RECIST PRs and durable stable disease.

We also observed early ctDNA reductions in the majority of patients with molecular responses and we also saw that early ctDNA reductions were associated significantly with partial responses and patients with durable stable disease.

Currently, dose optimisation is ongoing with three randomised cohorts to establish the recommended phase II dose.