January 26, 2026
For more than forty years, KRAS was widely considered undruggable. Despite KRAS mutations driving approximately one quarter of all cancers, approved therapies to date have been limited to G12C-selective inhibitors, addressing only a narrow subset of patients. This gap is particularly stark in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer, where non-G12C KRAS mutations dominate.
The current wave of clinical activity marks a clear transition into a second era of KRAS drug development. This phase is defined by two parallel strategies: selective inhibition or degradation of KRAS G12D, and broader pan-KRAS approaches designed to cover multiple mutant alleles within a single therapeutic asset. Recent licensing and acquisition activity, including high-profile transactions involving pan-KRAS programs, underscores sustained strategic interest across both approaches.
Early Clinical Development Remains Largely Exploratory
Across the KRAS landscape, most clinical-stage programs remain in early development. The majority of both G12D-selective and pan-KRAS assets are currently in Phase 1 or Phase 1/2 studies, frequently using basket trial designs that enroll patients across multiple advanced solid tumors. At this stage, development priorities center on safety, dose optimization, pharmacokinetics, and demonstration of target engagement rather than tumor-specific efficacy.
This early-stage concentration reflects the technical complexity of KRAS inhibition. Programs from large pharmaceutical companies and specialized oncology biotechs alike are still validating whether sufficient potency, selectivity, and tolerability can be achieved to justify later-stage expansion.
KRAS G12D Programs Begin to Narrow Toward Pancreatic Cancer
Within the KRAS G12D subset, a small but notable shift is underway. While most G12D programs continue to operate in basket designs, a limited number have progressed into pancreatic cancer–focused development, signaling increasing clinical and strategic confidence in this indication.
GenFleet and Verastem’s KRAS G12D inhibitor has advanced into pancreatic cancer–specific studies and received FDA Fast Track designation in 2025. This represents an important inflection point, as it explicitly positions KRAS G12D inhibition as a potential therapeutic strategy in PDAC rather than a purely exploratory oncology concept.
Hengrui’s KRAS G12D program has progressed further still, advancing into a pivotal Phase 3 trial in pancreatic cancer. Early Phase 1/2 data presented in 2025 showed encouraging activity when combined with standard chemotherapy, providing the clinical justification for registrational testing. At present, this program stands out as one of the most developmentally advanced KRAS G12D efforts in a tumor-specific setting.
Pan-KRAS Approaches Prioritize Breadth Over Early Indication Focus
In contrast, pan-KRAS strategies are largely oriented toward breadth and long-term scalability. Rather than targeting a single allele, these programs aim to inhibit or degrade multiple KRAS variants while sparing NRAS and HRAS, addressing historical toxicity concerns associated with earlier pan-RAS approaches.
Multiple pan-KRAS assets are currently in Phase 1 studies across solid tumors, reflecting a deliberate focus on mutation coverage and pharmacologic feasibility. Companies pursuing this approach are attempting to balance selectivity and scope, with the long-term objective of enabling use across multiple tumor types rather than committing early to a single indication.
This strategy introduces different risks and rewards compared with mutation-specific programs. While pan-KRAS assets may face higher early technical hurdles, successful execution could reduce the commercial fragmentation inherent in allele-specific development.
A Field Defined by Divergence Rather Than Convergence
Taken together, the KRAS landscape is no longer moving along a single axis. KRAS G12D–selective programs are increasingly testing whether direct KRAS inhibition can alter outcomes in pancreatic cancer, one of the highest unmet needs in oncology. Pan-KRAS programs, meanwhile, are positioning for broader applicability, aiming to define a more scalable role for KRAS-targeted therapy across solid tumors.
This divergence reflects a maturing field. Rather than attempting to solve KRAS in one stroke, developers are segmenting risk across precision-driven and breadth-driven strategies. The coming years will determine whether these paths converge clinically or continue to serve distinct roles within oncology drug development.
