China Merchants Securities has released a research report identifying a true inflection point for the RAS drug development pathway. The analysis focuses on "validated global benchmarks, Chinese assets approaching registration, and biomarker-driven combination opportunities." On a global scale, Revolution Medicines has established a clinical benchmark for pan-RAS(ON) inhibitors with its drug daraxonrasib, demonstrating a survival benefit in a Phase 3 clinical trial for second-line metastatic pancreatic ductal adenocarcinoma (mPDAC). The company is now accelerating its expansion into first-line PDAC, perioperative settings, and non-small cell lung cancer (NSCLC). In China, the progression of registration studies for HRS-4642 and GFH375 provides near-term value anchors, while GFH276, JAB-23E73, and other novel pan-RAS/pan-KRAS mechanism assets offer medium-to-long-term valuation upside.
The brokerage believes the core value shift in the RAS field over the next three years will first come from the validation of single-agent efficacy in second-line PDAC expanding into first-line and early-stage disease, the registration of G12D inhibitors, and the continued optimization of the therapeutic window for broad-spectrum inhibitors. The synthetic lethality combination of MTAP deletion and PRMT5 provides additional upside for RAS inhibitors to evolve into a precision combination backbone.
From 'Druggable' to 'Survival-Altering': RAS Therapies Reach a True Clinical Inflection Point
RAS was once considered an 'undruggable' target due to the lack of a traditional small-molecule binding pocket on its surface. The approval of the first KRAS G12C inhibitor in 2021 marked a breakthrough from zero to one for direct RAS inhibition. In 2026, Revolution Medicines' daraxonrasib achieved a median overall survival (mOS) of 13.2 months in the Phase 3 RASolute 302 trial for second-line mPDAC with RAS G12 mutations, nearly doubling the 6.6 months seen in the chemotherapy group (HR=0.40), alongside significant improvements in progression-free survival (PFS) and objective response rate (ORR). This result signifies a shift in the value proposition for the RAS field from 'whether a mutation can be inhibited' to 'whether a significant survival benefit can be achieved in RAS-addicted tumors,' marking the transition of broad-spectrum RAS(ON) inhibition from mechanistic innovation to clinical validation.
PDAC as the First Core Market to be Realized, with Competition Creating a Multi-Layered Ecosystem by Mutation, Tumor Type, Line of Therapy, and Combination
Over 90% of PDAC patients carry KRAS mutations, with non-G12C subtypes like G12D, G12V, and G12R accounting for the vast majority, forming the patient base for both broad-spectrum RAS inhibition and precise G12D targeting. Daraxonrasib has already confirmed a survival benefit in second-line PDAC, and subsequent competition will accelerate its move into first-line, perioperative, and combination regimens. G12D is emerging as the most attractive niche in first-line pancreatic cancer. Notably, MTAP deletion offers the first precision combination direction for RAS inhibitors with high clinical response validation: vopimetostat, by exploiting the synthetic lethality dependency of MTAP-deleted tumors on PRMT5, creates a dual-biomarker synergy when combined with RAS(ON) inhibitors. In combination with daraxonrasib, vopimetostat has achieved a 92% ORR and a 90% six-month PFS rate in previously treated, MTAP-deleted, RAS-mutated PDAC, suggesting that PDAC treatment could progress from 'broad-coverage RAS targeting' to 'deep remission under molecular stratification.'
China Emerges as the Second Pole of Global RAS Innovation, with Clinical Progress and Mechanism Innovation Accelerating in Tandem
Chinese companies have completed the first phase of commercialization for G12C inhibitors and are demonstrating stronger global competitiveness with next-generation assets. GenFleet Therapeutics has led GFH375 into Phase 3 clinical trials for oral G12D inhibitors and is also developing GFH276, a pan-RAS(ON) molecular glue. Jacobio Pharmaceuticals is advancing JAB-23E73, a dual-state pan-KRAS ON/OFF inhibitor, globally, with its authorization to AstraZeneca providing validation. Hengrui Medicine is advancing HRS-4642 into Phase 3 studies for first-line G12D-mutated PDAC and has built a full-pathway matrix covering G12D, G12C, pan-RAS, and pan-KRAS inhibitors. Other pharmaceutical companies like Betta Pharmaceuticals and BeiGene are also enriching the pipeline through pan-RAS molecular glues, KRAS degraders, and brain-penetrant RAS(ON) inhibitors. From the second half of 2026 through 2028, key data readouts for G12D, pan-RAS, and first-line PDAC are expected to be dense, and Chinese assets could continue to contribute clinical catalysts and valuation re-rating to the global RAS field.
Risk reminder: Risks include new drug research and development falling short of expectations, and policy risks.
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