Abbisko Therapeutics Opens ABSK141 Clinical Trial, Joining a Crowded Race to Drug KRAS G12D
For decades, the KRAS G12D mutation sat at the top of oncology's most-wanted list — prevalent, lethal, and stubbornly resistant to pharmacological intervention. Now Abbisko Therapeutics, a Shanghai-based biotech listed on the Hong Kong exchange (HKEX: 2256), has registered a first-in-human Phase I/II study of its oral small-molecule KRAS G12D inhibitor, ABSK141, in patients with advanced solid tumors. The ABSK141 Phase I first-in-human trial (NCT07417189), designated ABSK141-101, was posted on ClinicalTrials.gov in February 2026, with dosing planned to begin in March at Fudan University Shanghai Cancer Center. It enters a field where at least ten other direct KRAS G12D inhibitors are already in clinical testing — and where the first efficacy readouts from competitors are beginning to reshape expectations for what targeted therapy can achieve in pancreatic, colorectal, and lung cancers.
What the Abbisko ABSK141-101 Trial Is Designed to Do
The study is structured in three sequential stages: dose escalation, dose expansion, and a Phase II efficacy evaluation. In the escalation portion, adults aged 18 and older with histologically confirmed, locally advanced or metastatic solid tumors harboring the KRAS G12D mutation will receive ABSK141 tablets orally once daily at 400 mg, 800 mg, or 1200 mg. A single-dose run-in period on Day −3 precedes continuous daily dosing, allowing investigators to characterize the pharmacokinetic profile of each dose level before steady-state exposure. Primary endpoints for this phase are the incidence and severity of adverse events, serious adverse events, and dose-limiting toxicities observed from the run-in through Day 28.
Backfill and expansion cohorts will focus on three tumor types — colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC) — along with a basket for other KRAS G12D-mutant solid tumors. These patients must have at least one measurable lesion by RECIST 1.1 and an ECOG performance status of 0 or 1. The Phase II portion will administer the recommended Phase 2 dose (RP2D) and evaluate secondary endpoints including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), all assessed over up to 24 months. Pharmacokinetic parameters — Cmax, AUC, t½, tmax, and apparent oral clearance — are collected across all stages. The planned enrollment of 401 patients signals an intent to generate enough statistical power for tumor-specific efficacy signals, not merely a safety dataset.
Abbisko received IND clearance from the US FDA on December 2, 2025, and from China's NMPA on December 24, 2025. The trial is currently listed as "not yet recruiting," with primary completion estimated for Q4 2028 and full study completion in Q3 2029.
Why KRAS G12D Has Taken So Long to Target
The biology underlying the Abbisko Therapeutics KRAS G12D program explains both the excitement and the difficulty. KRAS functions as a molecular switch in the RAS-MAPK-ERK signaling cascade, cycling between an active GTP-bound state and an inactive GDP-bound state. Oncogenic mutations at codon 12 lock the protein in its active conformation, driving constitutive proliferative signaling. The G12C variant, in which a cysteine residue replaces glycine, offered a chemical handle: covalent inhibitors such as Amgen's sotorasib and Mirati/BMS's adagrasib could form irreversible bonds with that cysteine. The G12D variant substitutes aspartate for glycine, eliminating the reactive thiol and requiring an entirely different binding strategy — typically non-covalent, high-affinity engagement of the mutant protein's switch II pocket or adjacent allosteric sites.
KRAS G12D is the most common KRAS mutation across human cancers. It occurs in roughly 30–40% of KRAS-mutant pancreatic cancers (where KRAS itself is altered in approximately 90% of cases), 25–30% of KRAS-mutant CRC, and 15–20% of KRAS-mutant NSCLC. No KRAS G12D targeted therapy has been approved by any regulatory authority. Patients carrying this mutation are treated with conventional chemotherapy, anti-angiogenic agents, or checkpoint inhibitors — none of which address the oncogenic driver itself. In PDAC, where five-year survival for metastatic disease remains below 5%, the absence of a targeted option for the dominant driver mutation is a defining gap in the treatment landscape.
A Competitive Landscape That Has Expanded Rapidly
ABSK141 does not arrive in an empty field. The KRAS G12D inhibitor space for solid tumors has grown from a single clinical candidate in 2023 to more than a dozen programs in early-phase testing by early 2026.
Revolution Medicines has two molecules in the space. RMC-9805 (zidesamtinib), a tri-complex inhibitor that co-opts cyclophilin A to bind KRAS G12D in its active state, is in Phase I/II (NCT06040541) and has reported early responses in PDAC. RMC-6236 (breasafitinib), a pan-RAS(ON) inhibitor active against G12D along with G12V, G12R, and other variants, has generated the most attention in pancreatic cancer and received breakthrough therapy designation from the FDA for PDAC.
Bristol-Myers Squibb, through its acquisition of Mirati Therapeutics, controls MRTX1133 — the first selective KRAS G12D inhibitor to enter clinical testing. Originally an intravenous compound, an oral formulation is in development. Eli Lilly's LY3962673 is being evaluated in the Phase I MOONRAY-01 trial (NCT number via AllSci), which is already recruiting and plans to enroll up to 630 patients across PDAC, NSCLC, and CRC. Verastem's VS-7375 is in a Phase I/II study that includes combination cohorts with cetuximab. Boehringer Ingelheim (BI 3706674), Astellas (ASP3082, a degrader approach), BridgeBio (BBO-8520), and several China-based developers — Hengrui (HRS-4642), Jacobio (JAB-23000 series), Qilu (QLC1101), and Hansoh (HS-10529) — are all running or preparing early-phase studies in overlapping patient populations.