On July 28, 2026 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with RAS/MAPK pathway-driven cancers, reported that the first patient has been dosed in the TARGET-D 203 Phase 2 registration-directed trial evaluating VS-7375, an investigational oral KRAS G12D (ON/OFF) inhibitor with best-in-class potential, to treat patients with KRAS G12D-mutated metastatic colorectal cancer (mCRC). The Company has now initiated treatment across all three of its TARGET-D registration-directed Phase 2 clinical trials evaluating VS-7375 in patients with KRAS G12D-mutated pancreatic, colorectal, and lung cancers.
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"KRAS G12D is the most common KRAS mutation found in colorectal cancer and is associated with a worse prognosis for patients compared with KRAS wildtype – underscoring the need for an FDA-approved treatment option specifically for KRAS G12D-mutated cancers. We believe VS-7375 with EGFR blockade has the potential to significantly improve outcomes for patients with KRAS G12D-mutated metastatic colorectal cancer due to its differentiated profile and encouraging preliminary data from our ongoing Phase 1/2 trial," said Michael Kauffman, M.D., Ph.D., president of development at Verastem Oncology. "VS-7375 has demonstrated preliminary anti-tumor activity in combination with full dose cetuximab with no unexpected toxicities. Dosing the first patient in TARGET-D 203 marks an important milestone in our clinical development program as we continue to advance VS-7375 and build on the encouraging data generated to date."
TARGET-D 203 (NCT07659795) is a Phase 2, open-label, multi-center study to evaluate VS-7375 at 900 mg once daily (QD) both as monotherapy and in combination with anti-EGFR therapies, including cetuximab or panitumumab, in previously treated KRAS G12D-mutated mCRC. The study is also evaluating VS-7375 in combination with cetuximab and chemotherapy in the first line setting in patients with KRAS G12D-mutated mCRC.
In June 2025, Verastem initiated TARGET-D 101, its Phase 1/2 dose escalation, dose expansion, and combination clinical trial evaluating the safety and efficacy of VS-7375 in patients with KRAS G12D-mutated metastatic pancreatic ductal carcinoma (mPDAC), mCRC, advanced non-small cell lung cancer (NSCLC), and other solid tumor cancers. In a recent update, the Company shared that VS-7375 demonstrated encouraging anti-tumor activity across multiple KRAS G12D-driven tumor types, including mPDAC, mCRC, and advanced NSCLC, with evidence of dose-dependent activity, favorable pharmacokinetics supporting target exposure, and a favorable and manageable safety and tolerability profile. Patient follow-up continues to mature across monotherapy and combination cohorts, and the Company expects to share an update in the second half of 2026.
About Colorectal Cancer
Colorectal cancer (CRC) is the third most common cancer and the second-leading cause of cancer-related death in the U.S. In 2026, an estimated 158,850 people will be diagnosed with colon and rectal cancer. CRC is increasingly affecting younger adults, with one in five new diagnoses now occurring in people younger than age 55, and patients diagnosed before the age of 50 are more likely to present with advanced or metastatic disease at diagnosis. Metastatic colorectal cancer (mCRC), or stage IV disease, occurs when the cancer spreads beyond the colon or rectum to distant organs. Approximately 50% of colorectal cancer cases harbor KRAS mutations, with KRAS G12D accounting for approximately 15% of all CRC cases. Despite advances in the treatment of mCRC, there has been minimal progress in the treatment of patients with KRAS G12D-mutated disease, and no therapies targeting KRAS G12D have been approved for this patient population. Survival outcomes remain poor, underscoring the need for new and improved treatment options.
About KRAS G12D
KRAS G12D represents 26% of all KRAS mutations, making it the most prevalent KRAS mutation in human cancers. When the KRAS gene is mutated, it can promote cancer development and growth. Patients with KRAS G12D-mutant tumors often have poorer outcomes, underscoring the need for therapies designed specifically to inhibit this mutation potently and for a long duration. The KRAS G12D mutation occurs most commonly in pancreatic (40%), colorectal (15%), endometrial (8%), biliary tract (7-15%), and non-small cell lung (5%) cancers. Currently, no therapies are approved by the U.S. Food and Drug Administration (FDA) specifically targeting KRAS G12D mutations in cancer.
About VS-7375, an Oral KRAS G12D (ON/OFF) Inhibitor & TARGET-D Clinical Program
VS-7375 is a potential best-in-class, potent, and selective investigational oral KRAS G12D dual ON/OFF inhibitor. It is designed to uniquely bind to both the active (ON) and inactive (OFF) states of KRAS G12D, with the potential to inhibit KRAS G12D signaling and tumor growth more completely than compounds that block KRAS G12D only in the OFF state or only in the ON state.
In June 2025, Verastem initiated TARGET-D 101, a Phase 1/2 dose escalation, dose expansion, and combination clinical trial evaluating the safety and efficacy of VS-7375 in patients with KRAS G12D-mutated metastatic pancreatic ductal carcinoma (mPDAC), metastatic colorectal cancer (mCRC), advanced non-small cell lung cancer (NSCLC), and other solid tumors. Verastem has further expanded the VS-7375 clinical program with the initiation of three Phase 2 registration-directed, open-label clinical trials: TARGET-D 201 (NCT07644559) in second-line advanced or metastatic PDAC, TARGET-D 202 (NCT07659782) in second/third-line advanced or metastatic NSCLC, and TARGET-D 203 (NCT07659795) in metastatic CRC. In June 2026, the company announced the first patient was dosed in the TARGET-D 201 trial, and in July 2026, the first patient was dosed in the TARGET-D 202 trial.
In July 2025, U.S. Food and Drug Administration (FDA) granted Fast Track Designation (FTD) to VS-7375 for the first-line treatment of patients with KRAS G12D-mutated locally advanced or metastatic adenocarcinoma of the pancreas and for the treatment of patients with KRAS G12D-mutated locally advanced or metastatic pancreatic ductal carcinoma who have received at least one prior line of standard systemic therapy. In June 2026, the FDA also granted FTD to VS-7375 for the treatment of adult patients with KRAS G12D-mutated unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received platinum-based chemotherapy and an anti-PD-(L)1 antibody either concurrently or sequentially.
In December 2023, Verastem selected VS-7375 as its lead program from its collaboration with GenFleet Therapeutics, which aims to advance three oncology discovery programs related to RAS/MAPK pathway-driven cancers. The collaboration provides Verastem with an exclusive option to obtain a license for each of the three compounds in the collaboration after the successful completion of pre-determined milestones in a Phase 1 trial. In January 2025, Verastem exercised its license for VS-7375. The licenses would give Verastem development and commercialization rights outside the GenFleet markets of mainland China, Hong Kong, Macau, and Taiwan. GenFleet is developing VS-7375 as GFH375 in China.
(Press release, Verastem, JUL 28, 2026, View Source [SID1234669465])