Boston, MA – October 14, 2026 – Verastem Oncology (NASDAQ: VSTM) announced today a significant stride forward in its development of VS-7375, a novel oral KRAS G12D (ON/OFF) inhibitor. Buoyed by encouraging clinical activity and a favorable safety profile observed in the ongoing TARGET-D 101 Phase I/II trial, the company is preparing to advance VS-7375 into late-stage, pivotal Phase III studies. This strategic decision marks a critical juncture for the drug’s development, particularly in its potential to address unmet needs in metastatic pancreatic ductal adenocarcinoma (mPDAC), metastatic colorectal cancer (mCRC), and advanced non-small cell lung cancer (NSCLC).
The promising data, revealed on October 14th, centers on VS-7375’s unique dual mechanism of action. The investigational therapy is engineered to bind to both the active and inactive states of the KRAS G12D mutation, a notoriously challenging target in oncology. This differentiated approach aims to achieve more robust and sustained inhibition of the oncogenic pathway, offering hope for patients with limited treatment options. Verastem’s commitment to this program is underscored by their alignment with the U.S. Food and Drug Administration (FDA) on the design of a Phase III study for VS-7375 in the first-line mPDAC setting, signaling a clear pathway towards potential regulatory review.
The Promise of VS-7375: Targeting a Stubborn Oncogene
KRAS mutations, particularly the G12D variant, are among the most prevalent and difficult-to-treat oncogenic drivers in several aggressive cancers. Historically, KRAS-mutated tumors have been considered "undruggable." However, recent scientific advancements, including the development of targeted inhibitors like VS-7375, are beginning to shift this paradigm.
VS-7375 is an oral, small molecule inhibitor designed to specifically target the KRAS G12D mutation. Its innovative "ON/OFF" binding capability is intended to provide a more comprehensive blockade of the aberrant signaling that fuels cancer cell growth and survival. This dual inhibition strategy differentiates VS-7375 from other KRAS inhibitors and holds the potential for enhanced efficacy.
The TARGET-D 101 trial has been instrumental in evaluating VS-7375 across various patient populations and treatment settings. The trial has enrolled patients with advanced solid tumors harboring the KRAS G12D mutation, with specific cohorts focusing on mPDAC, mCRC, and advanced NSCLC. The early data from these cohorts has consistently demonstrated "robust clinical activity with a favourable safety and tolerability profile," according to Verastem’s statement.
A Turning Point for mPDAC: High-Dose Data Fuels Phase III Ambitions
The most impactful data supporting the advancement of VS-7375 into Phase III studies originates from the metastatic pancreatic ductal adenocarcinoma (mPDAC) cohort of the TARGET-D 101 trial. In patients receiving the 900mg daily monotherapy dose, compelling response rates were observed. Specifically, in the second-line (2L) PDAC setting, a confirmed objective response rate (ORR) of 50% was achieved. When considering the second-line plus (2L+) setting, the ORR remained strong at 41%, including two complete responses (CRs) – one confirmed and one unconfirmed. Furthermore, in the third-line/fourth-line (3L/4L) setting, a confirmed ORR of 36% was reported.
Beyond response rates, the disease control rate (DCR) in the 2L+ setting reached an impressive 86%. Crucially, the six-month progression-free survival (PFS) and overall survival (OS) rates were 67% and 80%, respectively, underscoring the potential for VS-7375 to significantly impact patient outcomes in this notoriously difficult-to-treat cancer.
The data from the 900mg cohort clearly outperformed the 600mg dose, providing a strong scientific rationale for advancing this higher dose in future studies. Verastem’s proactive engagement with the FDA has resulted in alignment on the Phase III study design, which will investigate VS-7375 in the first-line mPDAC setting. This represents a significant opportunity to intervene earlier in the treatment paradigm for mPDAC patients.
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, commented on the findings: "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." This molecular evidence of drug activity provides further validation of VS-7375’s mechanism of action and its potential to effectively target the underlying driver of these cancers.
Expanding Horizons: Benefit Demonstrated in mCRC and NSCLC
The promising results with VS-7375 are not confined to mPDAC. The drug has also shown encouraging activity in metastatic colorectal cancer (mCRC) and advanced non-small cell lung cancer (NSCLC), further solidifying its potential as a broad-spectrum KRAS G12D inhibitor.
In mCRC patients treated with the 900mg dose in the third-line (3L) treatment setting, VS-7375 demonstrated a 33% ORR when used in combination with an anti-EGFR therapy. While the lower 600mg combination cohort showed slightly less pronounced results, with four out of 24 patients achieving objective responses (including three confirmed and one unconfirmed), a significant 14 patients remained on treatment, indicating durable disease control. Verastem’s decision to advance the 900mg dosing for mCRC patients reflects the superior efficacy observed at this level.
For advanced NSCLC, patients receiving 600mg QD monotherapy exhibited a confirmed ORR of 43% in the 2L+ setting. Responses were observed relatively early, with some as soon as six weeks into treatment. The six-month landmark PFS rate stood at 72%, with a majority of patients remaining on therapy, highlighting the drug’s potential for sustained benefit. The 900mg QD dose level is currently being evaluated in the TARGET-D 202 Phase II registration-directed advanced NSCLC trial, suggesting Verastem is actively exploring optimal dosing strategies for this indication.
Furthermore, when VS-7375 was investigated as a triplet therapy – in combination with standard-of-care (SoC) chemotherapy and immunotherapy – in the first-line setting for KRAS G12D-mutated lung adenocarcinoma, it achieved an impressive 75% ORR. This data point is particularly significant, showcasing VS-7375’s potential in combination regimens and its applicability in earlier lines of therapy for NSCLC.
Across all monotherapy and combination cohorts within TARGET-D 101, regardless of tumor type, VS-7375 consistently maintained a favorable and manageable safety profile at both the 600mg and 900mg dose levels. This safety profile is a critical factor for long-term treatment and for combination therapies, where the risk of additive toxicity is a key consideration.
Looking Ahead: A Strategic Roadmap for Global Impact
Verastem Oncology has outlined a clear and ambitious development plan for VS-7375, building on the momentum generated by the recent data readout. The company anticipates releasing more mature data in the coming months, including further results from the TARGET-D 101 mCRC 900mg combination cohort and initial data from the 600mg combination arm by the end of 2026.
Crucially, Verastem plans to engage with the FDA again before the end of the current year to discuss and refine the Phase III pivotal trial designs for both first-line mCRC and first-line advanced NSCLC. The company’s objective is to initiate enrollment in both of these critical trials by the end of the first half of 2027, signaling a robust commitment to accelerating VS-7375’s path to market.
The landscape of KRAS-targeting therapies is rapidly evolving, with several other promising candidates in late-stage development. Merck & Co.’s (MSD) calderasib, an oral covalent inhibitor, is undergoing studies in NSCLC and mCRC. Eli Lilly is also investing heavily in KRAS inhibition with olomorasib, which is currently in Phase III NSCLC trials. Additionally, Genentech, a subsidiary of Roche, is advancing divarasib in late-stage studies, also for NSCLC.
The focus on NSCLC as a primary indication for these therapies is well-justified. KRAS is the most common oncogenic driver mutation in NSCLC, present in approximately 25% to 30% of all NSCLC patients, particularly those with lung adenocarcinoma. Metastatic pancreatic ductal adenocarcinoma (mPDAC) and metastatic colorectal cancer (mCRC) are also recognized as key battlegrounds for pan-RAS inhibitors and KRAS G12D-specific drugs, underscoring the significant unmet medical need that VS-7375 aims to address.
Verastem Oncology’s strategic progression of VS-7375 into Phase III trials, backed by compelling clinical and molecular data, positions the company as a key player in the emerging field of KRAS-targeted therapies. The company’s proactive approach with regulatory bodies and its clear development roadmap suggest a strong determination to bring this potentially transformative treatment to patients suffering from some of the most aggressive forms of cancer. The coming months and years will be critical in determining whether VS-7375 can live up to its promise and redefine the treatment landscape for KRAS G12D-mutated cancers.
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