2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

For over four decades, KRAS was considered "undruggable" due to its smooth surface topology, picomolar affinity for GTP/GDP, and the absence of deep hydrophobic pockets suitable for small molecule inhibition. This paradigm was shattered in 2013 with the discovery of a cryptic switch-II pocket in KRASG12C, enabling the development of covalent inhibitors that irreversibly trap the oncoprotein in its inactive state. The subsequent FDA approvals of sotorasib (2021) and adagrasib (2022) for KRASG12C-mutated non-small cell lung cancer (NSCLC) represented watershed moments in precision oncology, validating that direct KRAS inhibition was not only feasible but clinically impactful. However, these first-generation agents have revealed important limitations: objective response rates of 32-44%, median progression-free survival of only 6-7 months, and the inevitable emergence of acquired resistance through on-target secondary mutations (Y96D, H95D/R, R68S) and bypass pathway activation (EGFR, HER2, MET, PI3K). Furthermore, KRASG12C mutations represent only a fraction of KRAS-driven malignancies—approximately 12% of NSCLC, 3% of colorectal cancer, and 1% of pancreatic cancer—leaving the majority of patients with other prevalent mutations (G12D in pancreatic cancer, G12V in colorectal cancer) without direct therapeutic options.

This presentation will provide a comprehensive overview of the evolving landscape of KRAS inhibitor development, with a focus on next-generation strategies designed to overcome these limitations. We will present the preclinical characterization and early clinical insights from a novel series of second-generation KRASG12C inhibitors developed through iterative structure-based drug design. The optimized lead compound, PGC-296, demonstrates substantially enhanced potency compared to first-generation agents, with biochemical IC50 of 12 nM in GDP/GTP exchange assays and sub-nanomolar cellular GI50 (0.8 nM) in NCI-H358 KRASG12C-mutant lung cancer cells. This compound exhibits >1000-fold selectivity over wild-type KRAS and other GTPases, minimizing off-target toxicity. In murine xenograft models, oral administration of PGC-296 at 30 mg/kg BID induced complete tumor regression (100% tumor growth inhibition) with sustained target engagement evidenced by >90% inhibition of p-ERK at 24 hours post-dose. Pharmacokinetic studies revealed excellent oral bioavailability (68%) and a half-life supportive of twice-daily dosing.

A first-in-human Phase Ia/Ib dose-escalation trial was initiated in patients with advanced KRASG12C-mutant solid tumors who had progressed on prior therapies. As of the January 2026 data cut-off, 42 patients have been enrolled across six dose levels. The recommended Phase II dose (RP2D) was established at 400 mg BID based on safety, tolerability, and preliminary efficacy. Among 35 evaluable patients, confirmed partial responses were observed in 11 patients (31% objective response rate), including activity in four patients who had previously progressed on sotorasib, suggesting that PGC-296 may overcome certain resistance mechanisms. The most common treatment-related adverse events were grade 1-2 transaminitis (24%), diarrhea (19%), and nausea (14%), with no grade 4/5 treatment-related adverse events observed. Pharmacodynamic analyses of paired tumor biopsies confirmed dose-dependent inhibition of ERK phosphorylation, demonstrating robust target engagement in humans.

Beyond G12C-specific inhibition, we will present preclinical data on a novel active-state KRAS inhibitor, PGC-388, designed to bind the GTP-loaded conformation of multiple KRAS mutants. This tri-complex inhibitor demonstrates potent biochemical activity against KRASG12C (IC50 5 nM), KRASG12V (IC50 18 nM), and retains activity against the KRASG12C resistance mutation Y96D. In cellular assays, PGC-388 inhibits proliferation of a broad panel of KRAS-mutant cancer cell lines, including pancreatic (MIA PaCa-2, G12C; PANC-1, G12D), colorectal (SW620, G12V), and lung (NCI-H23, G12C) models. These findings suggest a potential path toward broader KRAS mutant coverage, including the most prevalent mutations in pancreatic and colorectal cancers.

The presentation will conclude with a discussion of emerging combination strategies designed to enhance response durability and overcome resistance, including combinations with SHP2 inhibitors, SOS1 inhibitors, immune checkpoint blockade, and chemotherapy. We will also address the critical challenge of equitable access to these transformative therapies and the need for innovative clinical trial designs, including platform trials and adaptive protocols, to accelerate the evaluation of next-generation KRAS inhibitors and combination regimens.

A Phase II expansion cohort in KRASG12C-mutant NSCLC and colorectal cancer is currently enrolling, with results anticipated in late 2026. The KRAS story serves as both a landmark achievement and a roadmap for future efforts to conquer other intractable cancer targets through persistent structure-based drug design, deep biological understanding, and rapid clinical translation.