GenFleet Therapeutics (Shanghai) Inc. (HKEX: 02595) has initiated a three-arm Phase II study testing two novel combination regimens against GFH375 monotherapy in pretreated KRAS G12D-mutant pancreatic cancer — a move that extends the company's combination strategy well beyond the cytotoxic backbones that currently dominate second-line treatment.
The open-label, randomized, parallel-controlled trial will enroll patients with locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC) who have progressed on or were intolerant of at least one prior systemic therapy. It is being conducted across tens of sites in China, with Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine as the lead site. The two experimental arms pair GFS202A — a GDF15/IL-6 bispecific antibody targeting cancer cachexia — and GFH276, an oral Pan RAS (ON) inhibitor, each against GFH375 alone. The study will assess antitumor activity, safety, and cachexia-related symptom improvements for each combination.
GFH375 is an oral, non-covalent small-molecule inhibitor targeting both the GTP-bound (ON) and GDP-bound (OFF) states of mutant KRAS G12D, blocking downstream RAS/MAPK signaling and inhibiting tumor proliferation. The compound has received China's Breakthrough Therapy Designation for KRAS G12D-mutant metastatic pancreatic cancer monotherapy and holds US FDA Fast Track Designation for the same indication. It is already enrolled in a registrational Phase III monotherapy study in pancreatic cancer — the first for any oral KRAS G12D inhibitor.
The rationale for the GFS202A arm draws on the high cachexia burden in this population: GenFleet reports that over 60% of pancreatic cancer patients develop cachexia, the highest prevalence among all malignancies. GDF15 and IL-6 are both implicated in the pathway linking tumor burden to muscle wasting and reduced treatment tolerability. GFS202A, described by the company as the world's first cachexia-targeted bispecific antibody, entered clinical testing in 2025. Preliminary data presented as a poster at the 2026 ASCO Annual Meeting showed a favorable safety profile, improvements in appetite, and dose-dependent increases in body weight and skeletal muscle volume, though specific numerical values were not disclosed.
The rationale for combining GFH375 with GFH276 is mechanistic differentiation. GFH375 targets KRAS G12D via the switch-II pocket (SIIP), inhibiting both ON and OFF states; GFH276 is a molecular-glue Pan RAS (ON) inhibitor that hijacks cyclophilin A to target GTP-bound RAS proteins across wild-type and mutant subtypes. GenFleet argues that pairing inhibitors with distinct mechanisms may permit dose optimization of GFH276 to reduce rash — a common adverse event with pan-RAS agents — while maintaining or improving antitumor activity relative to combining two SIIP-based inhibitors.