rineterkib (LTT462) / Novartis - LARVOL DELTA

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

Medicinal chemistry approaches and synthetic routes toward ERK inhibitor LTT462 (ACS-Fall 2025) - "Herein, we present the medicinal chemistry approaches used and synthetic routes towards the development of LTT462, a potent and orally bioavailable small molecule inhibitor of ERK1/2. LTT462 has shown efficacy in a wide range of MAPK pathway-driven human cancer cell lines and in vivo tumors."

BRAF

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; Sponsor Decision

Trial termination • Myelofibrosis

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

ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. (PubMed, Blood Adv) - P1/2 | "Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821."

Journal • Hematological Disorders • Myelofibrosis • Neutropenia • Thrombocytopenia • GDF15

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

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

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

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

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 primary completion date: Aug 2024 ➔ Nov 2024

Metastases • Trial primary 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 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2024 ➔ Jan 2025 | Trial primary completion date: Oct 2024 ➔ Jan 2025

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

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Myelofibrosis

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 (Lung Cancer) - P1b | N=241 | NCT02974725 | Sponsor: Novartis Pharmaceuticals | "Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36)....Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAFnon-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5 % and 76.1 % with naporafenib plus rineterkib or trametinib, respectively."

P1 data • Non Small Cell Lung Cancer

A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov) - P1 | N=241 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business reasons

Metastases • Trial termination • Cutaneous Melanoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • 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: Apr 2024 ➔ Jul 2024

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 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2024 ➔ Sep 2024 | Trial primary completion date: May 2024 ➔ Sep 2024

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

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ Jul 2024

Trial completion date • Myelofibrosis

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: Jan 2024 ➔ Apr 2024 | Trial primary completion date: Jan 2024 ➔ Apr 2024

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

A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov) - P1 | N=242 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2023 ➔ Apr 2024 | Trial primary completion date: Dec 2023 ➔ Apr 2024

Metastases • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • DUSP6 • 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 primary completion date: Oct 2023 ➔ Jan 2024

Metastases • Trial primary completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF • 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: Jul 2023 ➔ Oct 2023 | Trial primary completion date: May 2023 ➔ Oct 2023

Metastases • Trial completion date • Trial primary 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 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=350 ➔ 122

Enrollment change • Enrollment closed • Metastases • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • DUSP6