| Popis: |
Background: KRAS mutations (mt) are found in ~30% of non-small cell lung cancers (NSCLC). Despite the approval and development of KRAS G12C and KRAS G12D inhibitors respectively, mechanisms of resistance to MAPK pathway inhibitors are emerging and combination strategies are needed for patients with KRAS mt NSCLC . Avutometinib (VS-6766) is a unique RAF/MEK clamp that inhibits MEK kinase activity and blocks RAF-mediated phosphorylation of MEK. We studied the preclinical and clinical activity of the combination of avutometinib with the mTOR inhibitor everolimus in KRAS mt NSCLC. Methods: A panel of KRAS mt NSCLC cell lines were treated for 1 hour with clinically relevant concentrations of avutometinib and everolimus and changes in phosphoproteins were measured using an antibody array. We then tested for synergy of avutometinib and everolimus in 3D proliferation assays and in the H441 NSCLC xenograft model. A clinical trial is ongoing (NCT02407509) testing the combination of 3.2 mg avutometinib with 5 mg of everolimus administered twice weekly 3 weeks on/1 week off in 28-day cycles (previously defined as the recommended phase 2 dose) in a cohort of patients with KRAS mt NSCLC. Results: Avutometinib inhibited the MAPK pathway (p-MEK, p-ERK, p-90RSK) with an increase in p-PRAS40, suggesting activation of the PI3K pathway as an adaptive resistance mechanism. Everolimus inhibited the PI3K pathway (p-p70S6K and p-RPS6). Among a panel of KRAS mt NSCLC cell lines, avutometinib + everolimus showed synergistic anti-proliferative activity across KRAS G12C, G12V and G12D variants (mean synergy score of ~18). In the H441 KRAS G12V NSCLC xenograft model, there was a significant reduction in tumor volume and increase in survival with the combination of avutometinib and everolimus (87% TGI; 66 days vs 36.5 days in control group) compared to control. In the clinical trial expansion, 16 patients with KRAS mt NSCLC have been treated so far with avutometinib and everolimus (5 G12V, 3 Q61H, 2 G12C, 2 G12A, 2 G12D, 1 G13A, 1 G13D; median prior lines = 2). The current objective response rate (ORR) among the 14 patients who have at least one post assessment scan is 3/14 (21%; 1 G12V, 1 G12A, 1 G13A) with 11/14 showing a reduction in tumor size as best response. The current progression free survival (PFS) is 5.3 months (95% CI 2.8-7.4 months) with 4 patients still on study. Updated data on the planned cohort size of 20 patients will be presented. Conclusion: The combination of avutometinib and everolimus overcomes the activation of the PI3K/AKT/mTOR pathway which is an adaptive resistance mechanism to MAPK pathway inhibition. We have shown that avutometinib and everolimus induce synergistic anti-tumor effects preclinically, and preliminary data suggest clinically meaningful ORR and PFS in patients with KRAS mt NSCLC including non-G12C variants. Citation Format: Simon Rodney, Adam R. Stewart, Victoria Sanchez Perez, Cienne Morton, Lisa A. Pickard, Taleen Shakouri, Toby Prout, Mona Parmar, Alison J. Turner, Silvia Coma, Jonathan Pachter, Laura Finneran, Emma Hall, James Spicer, Anna Minchom, Udai Banerji. Preclinical and clinical evaluation of the RAF/MEK clamp avutometinib (VS-6766) in combination with the mTOR inhibitor everolimus for the treatment of KRAS mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3461. |
