ELV-3111 / Enliven Therapeutics - LARVOL DELTA

RAS-mutant tumor-selective inhibition of dimeric RAF by a novel Type 1 RAF inhibitor (AACR-NCI-EORTC 2025) - "Here, we characterized ELV-3111, a novel potent and selective Type 1 (αC-IN/DFG-IN) RAF inhibitor with broad activity in various RAS-MT models, both in cells and in vivo, similar to Type 2 RAF inhibitors...By paradoxically activating MAPK signaling in normal tissues, Type 1 RAF inhibitor mitigates MEK inhibitor-induced toxicities, while in RAS-MT tumors, the two drugs synergize to suppress the pathway. This tumor-selective mechanism, previously exploited in BRAF-MT cancers, can now be extended to RAS-MT-driven tumors, offering a renewed therapeutic opportunity and the potential to reshape combination strategies across a broader spectrum of MAPK-driven cancers."

Oncology • BRAF • EGFR

RAS-mutant tumor-selective inhibition of dimeric RAF by a novel Type 1 RAF inhibitor (AACR-NCI-EORTC 2025) - "Here, we characterized ELV-3111, a novel potent and selective Type 1 (αC-IN/DFG-IN) RAF inhibitor with broad activity in various RAS-MT models, both in cells and in vivo, similar to Type 2 RAF inhibitors...By paradoxically activating MAPK signaling in normal tissues, Type 1 RAF inhibitor mitigates MEK inhibitor-induced toxicities, while in RAS-MT tumors, the two drugs synergize to suppress the pathway. This tumor-selective mechanism, previously exploited in BRAF-MT cancers, can now be extended to RAS-MT-driven tumors, offering a renewed therapeutic opportunity and the potential to reshape combination strategies across a broader spectrum of MAPK-driven cancers."

Oncology • BRAF • EGFR

Mechanism of tumor-selective inhibition of dimeric RAF by a Type 1 RAF inhibitor (AACR 2025) - "However, Type 2 RAF inhibitors showed modest results as single agents, and their subsequent combination with MEK inhibitors led to increased efficacy but also enhanced toxicities due to MAPK pathway suppression in normal tissue.Here we characterized ELV-3111, a novel potent and selective Type 1 (αC-IN/DFG-IN) RAF inhibitor with broad and potent activity in various RAS-MUT models, both in cells and in vivo, similar to Type 2 RAF inhibitors...Using an array of biochemical and in-cell target engagement assays, we discovered that MAPK hyperactivation by Type 1 RAF inhibitors occurs via a RAS-dependent allosteric mechanism that is distinct from the described paradoxical activation mechanism of Type 1,5 inhibitors. Thus, the unique mechanism of action of Type 1 RAF inhibitors enables vertical MAPK-targeting combinations that are expected to be safer and more effective for patients with cancers driven by dimeric RAF, compared to current treatments."

Late-breaking abstract • Oncology • BRAF • EGFR

ELV-3111, a type 1 pan-RAF inhibitor, that safely combines with MEK inhibitors for enhanced anti-tumor activity in NRAS and BRAF mutant cancers including the most common mechanisms of BRAF inhibitor clinical resistance (AACR 2025) - "Improved tolerability is thought to result from concurrent cancelling out of the RAF inhibitor-associated pathway activation and the reversal of the MEK inhibitor pathway suppression in normal tissues.To address the limited breadth of therapeutic utility of the 1.5 inhibitors, type 2 RAF inhibitors (DFG-out, αC-helix-in) such as naporafenib, have been evaluated clinically. Finally, ELV-3111 effectively addresses the most common alterations driving resistance to the approved RAF inhibitors including BRAF alternative splice variants and co-occurring NRAS or KRAS mutations. Therefore, ELV-3111 represents a next generation RAF inhibitor with the breadth of utility of a type 2 inhibitor and the ability to safely combine with other targeted therapies like a Type 1.5 inhibitor."

Clinical • Late-breaking abstract • Oncology • BRAF • EGFR • KRAS • NRAS

Enliven Therapeutics Announces Poster Presentations at the 2025 AACR Annual Meeting (PRNewswire) - "Enliven Therapeutics...announced the Company will present five posters at the upcoming American Association for Cancer Research (AACR) Annual Meeting..."

Clinical data • Preclinical • Chronic Myeloid Leukemia • Solid Tumor