Verastem Oncology’s KRAS inhibitor has shown promise in several tumour types, including metastatic pancreatic ductal adenocarcinoma (mPDAC), metastatic colorectal cancer (mCRC), and advanced non-small cell lung cancer (NSCLC).
In the ongoing TARGET-D 101 Phase I/II trial, VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, was investigated in patients with advanced KRAS G12D-mutated solid tumours. VS-7375 is a dual ON/OFF inhibitor designed to bind to both active and inactive states of the KRAS G12D mutation.
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Data from the cohorts have demonstrated “robust clinical activity with a favourable safety and tolerability profile”, Verastem said on 14 October.
mPDAC high-dose data supports Phase III trial
Patients in the mPDAC cohort treated with 900mg QD monotherapy demonstrated a confirmed objective response rate (ORR) of 50% when the drug was used in second-line (2L) PDAC, and 41% when in the 2L+ setting. This includes two complete responses (CR), one confirmed and one unconfirmed, as well as a 36% confirmed ORR in the 3L/4L setting.
Disease control rate (DCR) was 86% in 2L+, and the six-month progression-free survival (PFS) and OS rates were 67% and 80%, respectively.
The 900mg cohort showed stronger data than the 600mg, supporting the advancement of this dosing in further studies. This comes as Verastem has aligned with the US Food and Drug Administration (FDA) on the Phase III study design to evaluate VS-7375 in the first-line mPDAC setting.
“The clinical activity observed with VS-7375 is complemented by striking molecular responses in patients with pancreatic cancer, including deep reductions in KRAS G12D variant allele frequency and ctDNA clearance in more than half of the evaluable patients,” said Dr Manuel Hidalgo, director of the Gastrointestinal Cancer Center at New York University (NYU) Langone Health and an investigator in the ongoing Phase I/II trial.
Benefit also seen in mCRC and NSCLC
In mCRC patients treated with the 900mg dose in the 3L treatment setting, there was a 33% ORR, when used in combination with anti-EGFR. In the lower 600mg combination cohort, four of 24 patients achieved objective responses, including three confirmed responses and one unconfirmed response, with 14 patients remaining on treatment.
Again, Verastem is advancing with the 900mg dosing for these patients.
In NSCLC, patients who received 600mg QD monotherapy had a confirmed ORR of 43% in 2L+ NSCLC, with responses observed as early as six weeks. The six-month landmark PFS rate was 72%, with the majority of patients remaining on treatment.
The 900 mg QD dose level is currently being evaluated in the TARGET-D 202 Phase II registration-directed advanced NSCLC trial.
When used in the first line as a triplet therapy with standard of care (SoC) chemotherapy and immunotherapy, it achieved a 75% ORR in KRAS G12D adenocarcinoma of the lung.
Across monotherapy and combination cohorts in TARGET-D 101 in all tumour types, VS-7375 continued to demonstrate a favourable and manageable safety profile at both the 600mg and 900mg dose levels.
More data is expected from Verastem in the coming months for VS-7375, including more mature data from the TARGET-D 101 mCRC 900mg combination cohort, as well as initial data from the 600mg combination arm by year-end 2026.
The company also plan to meet with the FDA before the end of the year to review Phase III pivotal trial designs in 1L mCRC and 1L advanced NSCLC, and open both trials to enrolment by the end of H1 2027.
Other KRAS-targeting drugs in late-stage studies include MSD’s calderasib, which is an oral covalent inhibitor, in NSCLC and mCRC studies. Lilly is also hoping to gain access to the potential of KRAS inhibition with olomorasib which is also in Phase III NSCLC trials. Finally, Roche’s subsidiary Genentech is running late-stage studies of divarasib, also in NSCLC.
NSCLC is a frequent indication for these therapies as KRAS is the most common oncogenic driver mutation in NSCLC, with about 25% to 30% of all NSCLC patients, specifically those with lung adenocarcinoma, harbouring a KRAS mutation. mPDAC and mCRC are also primary battlegrounds for pan-RAS inhibitors and KRAS G12D-specific drugs.
