naporafenib (ERAS-254) / Novartis, Erasca - LARVOL DELTA

Off-target activation of GCN2 by BRAFV600inhibitors attenuates melanoma outgrowth (AACR 2026) - "Herein, we define an off-target effect in which several clinical BRAFV600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4...This result is mirrored in PC9 lung cancer cells treated with erlotinib, an EGFR inhibitor, that shares the same off-target activation of GCN2...We further describe the activation of GCN2 signaling in melanoma patient-derived xenograft models treated with dabrafenib and trametinib, and observe a significant decrease in disease-free survival in a cohort of human melanoma patients with altered GCN2 pathway components. Finally, we describe the benefits of combining the next-generation "paradox breaker" RAF inhibitor naporafenib with a GCN2 activator, HC-7366, in A375 melanoma cells. Thus, GCN2 is emerging as a promising cotreatment candidate in melanoma and potentially beyond."

Lung Cancer • Melanoma • Oncology • Solid Tumor • ATF4

Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov) - P2 | N=134 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2026 ➔ Feb 2027 | Trial primary completion date: Mar 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=157 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2021 ➔ May 2022 | Trial primary completion date: May 2021 ➔ May 2022

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Mar 2026 | Trial primary completion date: Oct 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=157 ➔ 105

Enrollment change • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2023 ➔ Mar 2024 | Trial primary completion date: Sep 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2024 ➔ Apr 2025 | Trial primary completion date: Dec 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ Sep 2024 | Trial primary completion date: Mar 2024 ➔ Sep 2024

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=157 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2022 ➔ Sep 2023 | Trial primary completion date: Nov 2022 ➔ Sep 2023

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=157 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ Nov 2022 | Trial primary completion date: Mar 2024 ➔ Nov 2022

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=157 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2022 ➔ Mar 2024 | Trial primary completion date: May 2022 ➔ Mar 2024

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=157 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2025 ➔ Oct 2025 | Trial primary completion date: Apr 2025 ➔ Oct 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

SEACRAFT-1: A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations (clinicaltrials.gov) - P1 | N=86 | Active, not recruiting | Sponsor: Erasca, Inc. | Trial completion date: Nov 2025 ➔ Dec 2026

Trial completion date • Oncology • Solid Tumor

A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2) (clinicaltrials.gov) - P3 | N=78 | Active, not recruiting | Sponsor: Erasca, Inc. | Recruiting ➔ Active, not recruiting | N=470 ➔ 78

Enrollment change • Enrollment closed • Monotherapy • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • NRAS

First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations. (PubMed, Eur J Cancer) - "Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation."

Journal • Metastases • P1 data • Cardiovascular • Dermatitis • Dermatology • Heart Failure • Immunology • Lung Cancer • Melanoma • Neuralgia • Non Small Cell Lung Cancer • Oncology • Pain • Pruritus • Solid Tumor • DUSP6 • KRAS • NRAS

Preliminary results from SEACRAFT-1: An open-label study of naporafenib with trametinib in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations (EORTC-NCI-AACR 2024) - P1 | "N+T in pts with solid tumors harboring RAS Q61X mutations showed acceptable preliminary safety/tolerability. TRAEs, including dermatologic TRAEs, were generally low grade and manageable. In comparison, 2 previous studies with the same dosage of the combination that did not mandate primary prophylaxis for skin toxicity reported dermatologic TRAEs in 44/84 pts (52%) with G1-2 and 30/84 pts (30%) with G3-4."

Clinical • Metastases • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • KRAS • NRAS • RAS

Phase II study of multiple LXH254 drug combinations in patients (pts) with unresectable/metastatic, BRAF V600- or NRAS-mutant melanoma (ESMO 2022) - P2 | "We explore LXH254 combined with LTT462 (ERK1/2 inhibitor), trametinib (MEK1/2 inhibitor), or ribociclib (CDK4/6 inhibitor) in previously treated, BRAF V600 or NRAS-mutant melanoma. Conclusions These combinations exhibited tolerable safety profiles; most common toxicities were cutaneous. LXH254 in combination with LTT462 or trametinib shows promising efficacy in NRAS-mutant, immuno-resistant melanoma."

Clinical • Late-breaking abstract • P2 data • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov) - P1 | N=105 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2026 ➔ Oct 2026 | Trial primary completion date: Mar 2026 ➔ Oct 2026

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Insights into RAS-driven melanoma and its therapeutic implications. (PubMed, Cancer Treat Rev) - "Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes."

IO biomarker • Journal • Review • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS • NRAS

A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer. (PubMed, Lung Cancer) - P1 | "Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect."

Journal • Metastases • P1 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • DUSP6 • KRAS • NRAS

Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study. (PubMed, J Clin Oncol) - P1 | "Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation."

Combination therapy • Journal • CNS Tumor • Dermatitis • Dermatology • Immunology • Lung Cancer • Melanoma • Neuroblastoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Steven-Johnson Syndrome • BRAF • KRAS • NRAS

A phase 1b, multicenter, open-label dose-escalation and expansion platform study of select drug combinations in adult patients with advanced or metastatic BRAF V600 colorectal cancer (AACR-NCI-EORTC 2025) - P1 | "This first-in-human, phase 1b study (NCT04294160) evaluated the safety, pharmacokinetics (PK), and preliminary antitumor activity of several rationally designed combinations in patients with BRAF V600-mutant CRC. This open-label, adaptive platform trial included a doublet backbone arm (BA: dabrafenib [DRB436; BRAF V600 inhibitor] + LTT462 [ERK1/2 inhibitor]) and 6 triplet arms (TAs): A1 (DRB436 + LTT462 + trametinib [TMT212; MEK1/2 inhibitor]), A2 (DRB436 + LTT462 + LXH254 [B/C-RAF inhibitor]), A3 (DRB436 + LTT462 + TNO155 [SHP2 inhibitor]), A4 (DRB436 + LTT462 + spartalizumab [anti–PD-1]), A5 (DRB436 + TMT212 + TNO155), and A6 (DRB436 + LTT462 + tislelizumab [anti–PD-1]). This multi-arm platform study demonstrated manageable safety across several MAPK pathway inhibitor combinations in BRAF V600-mutant CRC. Although RDs were not defined, preliminary efficacy and disease control results showed modest antitumor effect in all treatment arms."

Clinical • IO biomarker • Late-breaking abstract • Metastases • P1 data • Colorectal Cancer • Oncology • Solid Tumor • BRAF • DUSP6

Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov) - P2 | N=134 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Mar 2026 | Trial primary completion date: Oct 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF • NRAS