GenFleet Therapeutics announced the data of GFH375 (known as VS-7375 outside of China) from our partner Verastem Oncology’s preclinical research were featured in three poster presentations - including two late-breaking research posters - at the 2026 American Association for Cancer Research (AACR) Annual Meeting in April 2026. The studies highlighted the potent and differentiated profile of GFH375, an oral KRAS G12D (ON/OFF) inhibitor, demonstrating superior anti-tumor activity, enhanced potency and selectivity, and more durable pathway suppression compared with other KRAS/RAS inhibitors across animal models and cellular assays. The studies also showed several resistance mechanisms in response to ON-only RAS inhibitors for which efficacy of GFH375/VS-7375 is retained. Additionally, strong scientific rationale for a range of rational combination strategies was also shown.
GFH375 entered the world’s first phase III registrational trial as an oral KRAS G12D inhibitor in China in 2025 and was granted with China’s first Breakthrough Therapy Designations for a KRAS G12D inhibitor monotherapy treating G12D-mutant pancreatic cancer and non-small cell lung cancer (NSCLC) respectively in 2026; VS-7375 also received U.S. FDA’s Fast Track Designation for treatment across all lines of G12D-mutant metastatic pancreatic ductal adenocarcinoma (PDAC). Multiple monotherapy and combination trials of GFH375/VS-7375 are ongoing in China (by GenFleet) and outside of China (by Verastem).
LBA 197 | VS-7375, a non-covalent dual ON/OFF KRAS G12Dinhibitor, displays superior activity to ON-only KRAS G12Dinhibitors in preclinical models of pancreatic cancer
LBA 183 | Strong durable tumor regressions with the KRAS G12D (ON/OFF) inhibitor VS-7375 in combination with PRMT5 inhibition in MTAP-deleted/KRAS G12D-mutant pancreatic cancer
Poster 7100 | VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents
Enhanced anti-tumor activity versus other KRAS/RAS inhibitors (RMC-9805 and RMC-6236)
In the preclinical research conducted in models harboring KRAS G12D mutant tumors, GFH375 alongside with comparators RMC-9805 and RMC-6236 were administered at animal dose levels that correlate with their respective human RP2D; GFH375 exhibited significantly greater tumor growth inhibition, across KRAS G12D-mutant PDAC, NSCLC and colorectal cancer (CRC) models.
In G12D-mutant PDAC cellular assays, GFH375 was 5-48 fold more potent and selective than RMC-9805; following drug washout, GFH375 suppressed pERK signaling more durably than RMC-9805, and maintained superior, longer lasting ERK inhibition at a 10 fold lower concentration.
Strong rationale for combination regimens in advanced KRAS-mutant cancers
In PDAC, NSCLC and CRC models, combination regimens demonstrated enhanced anti-tumor activity versus single-agent therapy. The combo regimens include GFH375 with cetuximab, or with FAK inhibitor ± the RAF/MEK clamp avutometinib, or with PRMT5 inhibitors (particular benefit observed in KRAS G12D–mutant, MTAP-deleted PDAC). Prior published research demonstrated that MTA-cooperative PRMT5 inhibitors selectively address MTAP-deleted, KRAS-mutant pancreatic cancers. Data from Verastem’s preclinical research further validated the absence of cross-resistance between RAS and PRMT5 inhibitors, supporting sequential or combination approaches for the 25% of KRAS-mutant PDAC patients with concurrent MTAP deletion; PRMT5 and KRAS govern independent signaling pathways and distinct transcriptional programs yet converge on core PDAC survival pathways, including cell-cycle progression and MYC-driven oncogenesis. Mechanistic analyses linked dysregulated MYC signaling to PRMT5 inhibitor resistance; while RAS inhibition reduced viability of PRMT5i-resistant cells, it no longer suppressed MYC expression. In PDAC models, GFH375 exerted more durable inhibition of MYC-driven gene transcription than RMC-9805 and RMC-6236, further strengthening the rationale for combining GFH375 with PRMT5 inhibitors to overcome potential resistance.
Mechanistic insights into the development and reversibility of therapeutic resistance
Resistance profiling was performed in escalating concentration and in a 30-day drug washout culture paradigm parallelly to evaluate the reversibility of resistance in PDAC cell lines; high concentration of GFH375 still achieved IC₅₀ activity in some resistant cell line, and the acquired resistance was partially reversible as 30 days of drug withdrawal restored partial sensitivity to GFH375 in all cell lines. GFH375 also induced rapid and sustained suppression of KRAS effector signaling and ERK activation, including durable inhibition of p-ERK, p-AKT and p-S6, reflecting robust and long-lasting control of both MAPK and PI3K pathways. Mechanistic studies confirmed that the potential resistance mechanisms were heterogeneous across models, with RAF-MEK-ERK inhibitors retaining anti-proliferative activity in some cell lines.
About GFH375/VS-7375
GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated dose-dependent inhibition in models bearing KRAS G12D mutation; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel 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 I trial. Verastem selected GFH375/VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, as its lead program from the collaboration, in December 2023 and the license for GFH375 that was exercised in January 2025 is the first one from this collaboration. The licenses would give Verastem development and commercialization rights outside of China while GenFleet would retain rights inside of China.
Forward-looking Statements
Specific information in this press release may contain or constitute forward-looking words that are not historical facts. They can be identified by using forward-looking terminology, such as "predict", "believe", "plan", "predict", "expect", "will", "may", "should" and other words of similar meanings.Based on the management's current beliefs, plans, estimates and expectations of the company's operation and market trends subject to changes beyond control, the forward-looking terminology reflects GenFleet Therapeutics' beliefs, plans, estimates and expectations of future development. Actual outcome in the future may differ significantly from forward-looking words owing to market, policy, and R&D uncertainties, among others.Subject to the above-mentioned uncertainties, GenFleet Therapeutics makes no expressed or implied guarantee as to the accuracy, completeness or feasibility of this presentation, and you are cautioned not to solely rely on such forward-looking words.Neither the company nor any of its directors, officers, employees, shareholders, agents, related parties, consultants or representatives will be liable to you or any other person for consequences resulting from using this presentation. Investors are advised to exercise due diligence with reference to the company's official disclosures for decision-making.
