zoldonrasib (RMC-9805)

P1, N=604, Recruiting, Revolution Medicines, Inc. | N=444 --> 604

Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations...RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC.

We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRASG12D cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).

While FDA-approved mutation-specific and pan-KRAS inhibitors show limited efficacy in PDAC, emerging agents (MRTX1133 and RMC-9805) have demonstrated preclinical promise. The molecular basis of KRAS-driven PDAC, current inhibitors, resistance mechanisms, and innovative strategies are discussed herein to address treatment barriers. Opportunities to improve clinical outcomes are underscored in this challenging malignancy by integrating insights from preclinical and clinical research.

P1/2, N=133, Recruiting, Tango Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1/2, N=133, Not yet recruiting, Tango Therapeutics, Inc.

P1/2, N=1130, Recruiting, Revolution Medicines, Inc. | N=406 --> 1130

P1, N=444, Recruiting, Revolution Medicines, Inc. | N=290 --> 444 | Trial completion date: Jul 2026 --> Apr 2027 | Trial primary completion date: Aug 2025 --> Apr 2026

P1, N=290, Recruiting, Revolution Medicines, Inc.

TCR sequencing of T cells from tumors and blood harvested from treated mice revealed a significant increase in T cell diversity, as well as an increase in the number of shared TCR clones among all KRASG12D(ON) inhibitor-treated samples, suggesting cancer-associated antigen recognition.Overall, in these preclinical experiments, RMC-9805 exhibited direct anti-tumor effects and indirectly transformed the TME through inhibition of cancer cell-intrinsic KRASG12D oncogenic signaling. The increased antigen presentation, recognition, and T cell infiltration induced by inhibition of mutant KRAS may permit a more favorable environment for immune-directed ‘companion’ therapies, such as checkpoint inhibitors, cellular therapies, and/or vaccines.[1] Timar, J. et al, 2020 [2] Hamarsheh, S. et al, 2020 [3] Sumimoto, H. et al, 2016

Furthermore, RMC-9805 combination therapies drove regressions in CRC models relatively less responsive to monotherapy. Supported by these findings, RMC-9805 is currently in IND-enabling development to permit clinical evaluation of single agent and combination strategies in patients with KRASG12D tumors.