Verastem reported encouraging Phase 1/2 data for VS-7375, a KRAS G12D inhibitor, showing anti-tumor activity in pancreatic, colorectal, and lung cancers with a favorable safety profile.
Written By: Kirti Kumbhar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
Verastem Oncology has reported positive preliminary results from the ongoing TARGET-D 101 Phase 1/2 trial (NCT07020221) evaluating VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, in patients with advanced KRAS G12D-mutated solid tumors. The data showed early anti-tumor activity across multiple dose levels and tumor types, including metastatic pancreatic ductal adenocarcinoma (mPDAC), metastatic colorectal cancer (mCRC), and advanced non-small cell lung cancer (NSCLC), while maintaining a manageable safety profile.
Targeting a Major Cancer Driver
KRAS G12D is the most prevalent KRAS mutation, accounting for approximately 26% of all KRAS-driven cancers. The mutation is frequently found in pancreatic, colorectal, biliary tract, endometrial, and lung cancers and is associated with poor clinical outcomes. Despite its prevalence, no FDA-approved therapies specifically target KRAS G12D.
VS-7375 is an investigational oral inhibitor that binds both the active (ON) and inactive (OFF) forms of KRAS G12D. This dual-state approach may provide broader pathway inhibition compared with agents that target only one conformational state of the protein.
Early Clinical Activity Across Tumor Types
In previously treated metastatic pancreatic cancer, the strongest activity emerged at the 900 mg once-daily dose. Among 14 evaluable patients with elevated baseline CA19-9 levels, 93% achieved more than a 50% reduction in the tumor marker. Investigators also observed evidence of dose-dependent activity between the 600 mg and 900 mg dose levels. All evaluable patients remained on treatment at the data cutoff.
Combination studies produced additional encouraging signals. In pancreatic cancer, combining VS-7375 with the EGFR inhibitor cetuximab generated deeper and faster tumor reductions, even at the lower 400 mg dose. The drug also showed compatibility with standard chemotherapy consisting of gemcitabine plus nab-paclitaxel.
In metastatic colorectal cancer, preliminary efficacy was observed when VS-7375 was combined with full-dose cetuximab at both 600 mg and 900 mg daily doses. In advanced NSCLC, investigators reported promising activity with 600 mg once-daily monotherapy, although follow-up remains limited.
Favorable Safety Profile
Across monotherapy and combination cohorts, treatment-related adverse events were primarily low-grade gastrointestinal events, including nausea, vomiting, and diarrhea. Most events occurred during the first treatment cycle and declined substantially with continued treatment. Grade 3 toxicities remained uncommon, and investigators reported no clinically meaningful cytopenias, liver function abnormalities, or cumulative toxicities.
The safety profile also appeared favorable in combination regimens, with no significant overlapping toxicities observed alongside cetuximab or chemotherapy.
Development Program Expands
Verastem executives highlighted the broad activity observed across tumor types and emphasized the potential role of combination strategies in KRAS G12D-driven cancers. The company has already launched three registration-directed Phase 2 studies: TARGET-D 201 (NCT07644559) in pancreatic cancer, TARGET-D 202 (NCT07659782) in NSCLC, and TARGET-D 203 (NCT07659795) in colorectal cancer. The first patient was dosed in TARGET-D 201 on June 16, 2026.
Separately, Verastem and Erasca announced plans to evaluate VS-7375 in combination with ERAS-0015, Erasca’s investigational pan-RAS molecular glue, initially in preclinical models of KRAS G12D-mutated tumors. The companies may advance the combination into clinical testing pending further evaluation.
Regulatory Path Forward
Verastem expects to provide additional TARGET-D 101 updates in the second half of 2026 and complete enrollment across its three Phase 2 studies by year-end. The company also plans FDA discussions on Phase 3 pivotal trial designs in first-line pancreatic, colorectal, and non-small cell lung cancers before the end of 2026, with patient enrollment in Phase 3 studies anticipated in the first half of 2027.
What This Means for Patients
KRAS G12D mutations are common in pancreatic, colorectal, and lung cancers, but no approved targeted therapies currently address this genetic driver. Early results from VS-7375 suggest the drug may shrink tumors while maintaining a manageable safety profile. If future studies confirm these findings, patients with KRAS G12D-mutated cancers could gain a new precision medicine option that may be used alone or in combination with existing treatments.
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About the Writer
Kirti Kumbhar (LinkedIn) is an M.Pharm graduate with experience in Quality Assurance at Lupin Limited and a strong interest in clinical research, regulatory affairs, and Trial Master File (TMF) management. She has developed knowledge of regulatory documentation, quality systems, compliance, and healthcare research through her professional experience. Passionate about clinical development and continuous learning, Kirti is committed to supporting high-quality healthcare documentation, regulatory excellence, and research-driven healthcare advancements.