In short
VS-7375 (also known as GFH375) is an investigational oral substance that blocks the cancer-driving KRAS G12D protein. It is being studied in a Phase 1/2 trial (NCT07020221) in up to 804 participants with advanced solid tumours carrying the KRAS G12D mutation, including pancreatic, lung and colorectal cancers. The trial is authorised and tests VS-7375 both alone and in combination with other cancer medicines.
Key points
- VS-7375 is an oral KRAS G12D inhibitor being tested in advanced solid tumours with the KRAS G12D mutation.
- The trial is Phase 1/2 and authorised, with a planned enrolment of 804 participants.
- It includes participants with pancreatic cancer (PDAC), non-small cell lung cancer (NSCLC) and colorectal cancer.
- VS-7375 is given by mouth and is tested both alone and in combinations with other cancer drugs.
- The main goals are safety, the recommended dose and the tumour response rate (ORR).
- The study also examines how VS-7375 affects the breakdown of midazolam and repaglinide in the body.
What is VS-7375?
VS-7375, also referred to as GFH375, is an investigational substance being developed as a KRAS G12D inhibitor. It is designed to block both the active (ON) and inactive (OFF) forms of the KRAS G12D protein, which is why it is described as a KRAS G12D (ON/OFF) inhibitor in the trial title. The substance is not yet authorised as a medicine and is currently being evaluated in clinical research. The registry record lists VS-7375/GFH375 as an oral drug, and the trial is the first registered study of this substance in the EU Clinical Trials Information System.
How does VS-7375 work?
The KRAS gene provides instructions for making a protein that helps control cell growth. When the gene carries a mutation called G12D, the resulting KRAS protein stays switched on and drives uncontrolled cell division, which can lead to cancer. VS-7375 is designed to attach to the mutated KRAS G12D protein and block its activity, both when the protein is in its active (ON) state and when it is in its inactive (OFF) state. By inhibiting this driver protein, the substance aims to slow or stop the growth of tumours that depend on the KRAS G12D mutation.
Which conditions is VS-7375 studied for?
The trial includes participants with advanced or metastatic solid tumours that carry the KRAS G12D mutation. The conditions studied are:
- Pancreatic ductal adenocarcinoma (PDAC) — a common form of pancreatic cancer, studied in participants who have received one to three prior lines of therapy.
- Non-small cell lung cancer (NSCLC) — a type of lung cancer, studied in participants who have received one to four prior lines of therapy, as well as in previously untreated metastatic NSCLC.
- Colorectal adenocarcinoma — a type of bowel cancer, studied in participants who have received one to four prior lines of therapy.
- Other KRAS G12D-mutated solid tumours — additional tumour types with the same mutation, studied in participants who have received one or more prior lines of therapy.
How is VS-7375 given?
VS-7375 is given by mouth as an oral formulation, on a daily schedule. In the drug interaction part of the study, the dose used is 600 mg once daily. The trial also includes comparison medicines given by intravenous infusion: cetuximab, carboplatin, pembrolizumab, pemetrexed, gemcitabine and nab-paclitaxel. These are used as combination partners in different parts of the study.
What do the clinical trials show?
The registered study is a Phase 1/2, open-label trial with a planned enrolment of 804 participants. Its status is authorised, meaning the trial has received approval and can begin or is already recruiting. The study is divided into five parts:
- Part A — dose escalation of VS-7375 alone, to find the maximum tolerated dose or the maximum feasible dose.
- Part B — dose expansion of VS-7375 alone in participants with PDAC, NSCLC and other solid tumours who have received prior therapy.
- Part C — dose escalation of VS-7375 in combination with cetuximab, with carboplatin plus pembrolizumab plus pemetrexed, or with gemcitabine plus nab-paclitaxel.
- Part D — dose expansion of the combination regimens in metastatic colorectal cancer, previously untreated metastatic NSCLC and previously untreated metastatic PDAC.
- Part E — a drug-drug interaction study of VS-7375 with midazolam and repaglinide.
The main things the trial measures are safety (adverse events, serious adverse events, dose-limiting toxicities, laboratory results), the recommended dose, and the confirmed objective response rate (ORR), which is the proportion of participants whose tumours shrink by a predefined amount according to RECIST v1.1 criteria. In Part E, the trial also measures the pharmacokinetics of midazolam and repaglinide — how much of these drugs is in the blood over time (AUC0-t, AUC0-inf) and the highest blood concentration reached (Cmax) — to understand whether VS-7375 affects how the body breaks them down.
Who can take part depends on the part of the study. Part A includes participants with any KRAS G12D-mutated solid tumour. Part B includes participants with advanced or metastatic PDAC who have received one prior line of therapy, NSCLC who have received one or two prior lines, and other solid tumours who have received one or two prior lines. Parts C and D include participants with specific cancers and defined numbers of prior therapies, and Part E includes participants with metastatic KRAS G12D-mutated PDAC, NSCLC, colorectal adenocarcinoma or other solid tumours who have received several prior lines of therapy.
What side effects are known?
The registry record for this trial does not list specific side effects for VS-7375. Because the substance is still in early clinical testing, its safety profile is being evaluated in the study itself. The trial measures adverse events, treatment-related adverse events, serious adverse events and dose-limiting toxicities as primary outcomes, which means the side effect profile of VS-7375 will be established from the results of this research.