Revolution Medicines

The KRAS Inhibitors market is poised for significant growth driven by increasing cancer incidence, treatment access, and a robust pipeline. The market size in the 7MM was $500 million in 2023, expected to rise by 2034. KRAZATI (adagrasib) is projected to outperform LUMAKRAS (sotorasib) in revenue. The US leads in KRAS mutation cases in NSCLC, with 46% of 7MM cases. Competition in G12C NSCLC is intensifying, with Chinese biotechs entering the KRAS space. Despite G12D being the most prevalent KRAS variant, G12C is the primary target in colorectal cancer. KRAZATI is the first KRAS inhibitor approved for KRAS G12C-mutant colorectal cancer. Pancreatic cancer, with 60-90% KRAS mutations, presents a significant market opportunity. Pan-KRAS drugs, targeting multiple mutations, offer broad market potential. Key companies include Novartis, Roche, Genentech, and Mirati Therapeutics. Emerging therapies like JDQ443, Divarasib, and Avutometinib are expected to reshape the market. The KRAS inhibitor market is evolving, driven by high unmet needs, competitive drug development, and regulatory approvals.

Researchers at the Francis Crick Institute and Revolution Medicines tested a combination of KRAS G12C and SHP2 inhibitors with an immune checkpoint inhibitor in mice with lung cancer, achieving tumor shrinkage and eradication in some cases. This approach also made 'immune cold' tumors responsive to immunotherapy, suggesting potential for human application.

Researchers at the Francis Crick Institute and Revolution Medicines demonstrated that combining KRAS and SHP2 inhibitors with immunotherapy improves lung cancer treatment efficacy, particularly in resistant tumors. The triple combination in mice reduced tumor size and prevented recurrence, also sensitizing 'immune cold' tumors to immune checkpoint inhibitors. This approach aligns with ongoing studies on anti-PD-(L)1 treatments for KRAS-mutant NSCLC, though concerns about potential toxicity remain.

RMC-6236, a non-covalent pan-RAS(ON) inhibitor by Revolution Medicines, shows efficacy in 'undruggable' RAS mutant tumors via a 'tri-complex' mechanism involving cyclophilin A. AACR 2024 meeting presentation covers its discovery, preclinical profile, and clinical updates.

DelveInsight's 'Non-Small-Cell Lung Cancer Pipeline Insight 2024' covers 135+ companies and 150+ pipeline drugs, highlighting key players like BridgeBio Pharma, Daiichi Sankyo, and Merck. Prominent therapies include Trastuzumab deruxtecan, DS-1062a, and Pembrolizumab. Recent studies by Merck, AstraZeneca, and Gilead focus on Phase 3 trials for V940, Durvalumab, and Zimberelimab, respectively.

RMC-6236, a RAS-selective inhibitor for solid tumors, is projected to generate $268 mn by 2035 in the US. Revolution Medicines, developing RMC-6236, reported FY2023 revenues of $11.6 mn, with net losses of $436.4 mn. The rNPV model, accounting for drug failure risk, is available for purchase.

Novartis' HRO761, an oral allosteric WRN helicase inhibitor for MSI-high and dMMR tumors, emphasizes early HTS assay selection and medicinal chemistry strategies for optimizing LipE, TPSA, chameleonicity, and non-classical zwitterions. Discusses X-ray structure binding, differentiation from VVD-214, preclinical activity, clinical status, and chemical synthesis.

Nuvalent's NVL-520, an oral, brain-penetrant, TRK-sparing ROS1 kinase inhibitor, entered Ph. II of ARROS-1 trial for advanced ROS1-positive NSCLC, showcasing a potential best-in-class profile.