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

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

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

The absorption, distribution, metabolism, excretion, and pharmacokinetic properties of the pan-rapidly accelerated fibrosarcoma (RAF) inhibitor naporafenib in healthy subjects: An absolute bioavailability and mass balance study. (PubMed, Drug Metab Dispos) - "SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the pharmacokinetics, disposition, and metabolism of naporafenib after oral and microtracer intravenous administration in healthy participants. This knowledge will guide future nonclinical and clinical studies evaluating drug-drug interactions, organ dysfunction, and safety of metabolites."

Journal • PK/PD data • Fibrosarcoma • Oncology • Sarcoma • Solid Tumor

Unexpected remission of Darier disease in a melanoma patient treated with trametinib and naporafenib. (PubMed, JAAD Case Rep) - No abstract available

Journal • Melanoma • Oncology • Solid Tumor

Dermatologic Toxicities Associated With Novel Pan-RAS/RAF Inhibitors. (PubMed, J Cutan Pathol) - "Treatment with novel pan-RAS/RAF inhibitors exhibits a spectrum of DTs that exhibit some overlap with small molecule inhibitors that target the MAPK pathway."

Journal • Colorectal Cancer • Dermatology • Dermatopathology • Immunology • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor

Understanding and overcoming innate and acquired MAPK inhibition resistance in anaplastic thyroid cancer. (PubMed, Cell Rep Med) - "Although patients with the BRAFV600E alteration respond to the type I RAF inhibitor (RAFi) dabrafenib with trametinib, most rapidly develop adaptive or acquired resistance. Finally, we describe a mechanism of acquired resistance to naporafenib through compensatory mutations in MAST1. Taken together, our work rationalizes the clinical investigation of type II RAFi in the setting of thyroid cancer."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

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

Targeting pancreatic cancer with combined inhibition of EGFR and RAF. (PubMed, PLoS One) - "Building on these findings, we investigated the therapeutic benefit of combining the EGFR inhibitor erlotinib with the novel pan-RAF inhibitor LXH-254. hese results contrast with previous reports of efficacy from monotherapies in xenograft models, highlighting the limitations of current preclinical approaches. Our findings underscore the need to develop more effective pathway-targeted inhibitors, and preclinical models that predict clinical outcomes more accurately."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • KRAS

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

Understanding and overcoming innate and acquired resistance to type I and II RAF inhibitors in anaplastic thyroid cancer using translational functional genomics (AACR 2024) - "We further demonstrate that naporafenib in combination with MEKi trametinib can durably and robustly overcome both innate and acquired treatment resistance to dabrafenib and trametinib using ATC cell lines and patient-derived xenograft models, including in a PDX model from an ATC patient who developed acquired resistance to dabrafenib and trametinib. Finally, we describe a novel mechanism of acquired resistance to type II RAF inhibitor and MEK inhibitor through compensatory mutations in MAST1. Taken together, our work using translational and functional genomics have unraveled the differential mechanisms of treatment resistance to type I and type II RAFi in combination with trametinib, and rationalizes the clinical investigation of type II RAFi in the setting of thyroid cancer."

Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers (AACR 2024) - "Here, we demonstrate that the 3rd generation of pan-RAF inhibitors LY3009120, LXH254, and Belvarafenib inhibit ARAF, BRAF, CRAF, BRAF(V600E), and CRAF(R391W) kinase activity in biochemical HotSpotTM assay. Furthermore, our results show these inhibitors can block the downstream ERK phosphorylation in cellular HTRF assay and induce caspase-3/7 activation in Western blot assay in the triple negative breast cancer MDA-MB-231 cells. Taken together, our results indicate the biochemical HotSpotTM kinase activity assay, and NanoBRETTM target engagement and NanoBITTM cellular assays can serve as great platforms to facilitate RAF drug discovery against human cancers."

Breast Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • ARAF • BRAF • CASP3 • CASP7 • KRAS

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