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

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

LXH254 hybrid with adamantane: synthesis and in vitro evaluation of 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety as a novel B-RAF inhibitor. (PubMed, Bioorg Med Chem Lett) - "It was worth noting that the adamantane alcohol of Z-001 was very suitable for matching the cavities near the solvent exposed region, which was filled with adamantyl moiety and effectively utilized in the docking model. The binding mode between Z-001 and B-RAF kinase provided a reasonable explanation for Z-001 as a potential B-RAF kinase inhibitor."

Journal • Preclinical • BRAF

Advanced Thyroid Cancer with Brain Metastases: A Case Series. (ATA 2025) - "Despite multiple treatments—including chemotherapy (docetaxel and doxorubicin), pembrolizumab, trametenib, everolimus, lenvatinib, and eventually starting sapanisertib, he passed away shortly after.One patient with PDTC had progression of disease, complicated with intracranial bleeding while on lenvatinib. Another with BRAFV600E-mutated PTC, failed multiple therapeutic targets including lenvatinib, sorafenib, dabrafenib, trametinib and pembrolizumab. With ongoing disease progression, initiated therapy with encorafenib and binimetinib...The other patient with NRAS-mutated FTC initially did not tolerate naporafenib, showed stable disease after redifferentiation therapy with trametinib...Radiation, including stereotactic surgery, has a pivotal role in managing brain metastasis and achieving local control2. Little is known about the evolution of mutations in brain metastases in the context of advanced thyroid carcinoma3, and therefore more data is needed to understand the..."

Clinical • Late-breaking abstract • Metastases • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • AXIN1 • MSH2 • NF1 • NRAS • PTEN • RB1 • SETD2 • TP53

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 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: Jul 2025 ➔ Oct 2025 | Trial primary completion date: Jun 2025 ➔ Oct 2025

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

Outcomes with targeted therapy for NRAS-mutated melanoma: A systematic review and meta-analysis. (ASCO 2025) - "The targeted therapies investigated included Binimetinib (n = 299; 56.7%), Naporafenib plus Rineterkib (n = 29; 5%), Naporafenib plus Trametinib (n = 24; 4.5%), Trametinib (n = 17; 3.2%), Naporafenib plus Ribociclib (n = 15; 2.8%), and Binimetinib plus Bocodepsin (n = 9; 1.7%). Targeted therapies in NRAS-mutated melanoma show modest efficacy with frequent adverse effects. Innovative approaches, including novel therapeutic agents with different mechanisms of action, are urgently needed to improve clinical outcomes and address this unmet medical need."

IO biomarker • Retrospective data • Review • Dermatitis • Dermatology • Immunology • Melanoma • 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. | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Solid Tumor

Targeting the MAPK Pathway for NRAS Mutant Melanoma: From Mechanism to Clinic. (PubMed, Br J Dermatol) - "In recent years, significant clinical advancements have been achieved by targeting the NRAS-MAPK pathway, with novel therapies such as the MEK inhibitor tunlametinib and the combination therapy of the pan-RAF inhibitor naporafenib with trametinib leading the way. In this review, we will systematically summarize the recent advances in the direct targeting of mutant NRAS proteins and their downstream RAF and MEK proteins, as well as targeting the MAPK pathway in combination with other therapeutic targets, including the immunotherapy, to treat NRAS mutant melanoma. Additionally, we will further discuss the current issues and emerging countermeasures related to targeted therapy for NRAS mutant melanoma."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • NRAS

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

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 2025 ➔ Jul 2025 | Trial primary completion date: Feb 2025 ➔ Jun 2025

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

Erasca Reports Fourth Quarter and Full Year 2024 Business Updates and Financial Results (GlobeNewswire) - "SEACRAFT-2: Randomized pivotal Phase 3 trial for naporafenib plus trametinib in patients with NRASm melanoma...Phase 3 Stage 1 randomized dose optimization data expected in H2 2025"

P3 data • Cutaneous Melanoma

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

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: Dec 2024 ➔ Mar 2025

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

A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov) - P1 | N=122 | Terminated | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2025 ➔ Sep 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2025 ➔ Sep 2024; The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.

Trial completion date • Trial primary completion date • Trial termination • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Erasca Reports Third Quarter 2024 Business Updates and Financial Results (GlobeNewswire) - "Key Upcoming Milestones: (i) SEACRAFT-2: Randomized pivotal Phase 3 trial for naporafenib plus trametinib in patients with NRASm melanoma - Phase 3 Stage 1 randomized dose optimization data expected to be reported in 2025."

P3 data • Melanoma

Dermatologic Toxicities Associated with Novel PanRAS/RAF Small Molecule Inhibitors (ASDP 2024) - "Dermatologic toxicities (DTs) to newer panRAS (RMC-6236) and panRAF (LXH254) are not well studied...Combination therapy with MEK/ERK (trametinib or LTT462) Nibs was recorded in two of the six patients...In this cohort of patients treated with panRAS/RAF Nibs, folliculitis and DHR were the two most common histomorphologic types of DTs. These novel panRAS/RAF Nibs exhibit overlap of DTs with other Nibs (e.g., receptor tyrosine kinases) that target the MAPK pathway illustrating that disruption of this cell signaling pathway appears to promote an off-target pro-inflammatory response in susceptible patients."

Atopic Dermatitis • Dermatology • Endocrine Cancer • Immunology • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Vasculitis • KRAS

Naporafenib Program Update (GlobeNewswire) - P3 | N=470 | SEACRAFT-2 (NCT06346067) | Sponsor: Erasca, Inc. | "40% (4/10) response rate observed in the melanoma cohort, including three confirmed partial responses (cPR) and one unconfirmed partial response (uPR)...70% (7/10) of patients were on treatment as of the data cutoff, including all four responders...Results suggest that mandatory primary rash prophylaxis helped reduce frequency and severity of dermatological toxicities, reduced drug discontinuation rate due to adverse events...Randomized dose optimization data from Stage 1 of the SEACRAFT-2 Phase 3 trial expected in 2025."

P3 data • Melanoma • Oncology • Solid Tumor