belvarafenib (RG6185) / Hanmi - LARVOL DELTA

Phase Ib study of belvarafenib in combination with cobimetinib in advanced solid tumors: Clinical activity in NRAS-mutant melanoma supporting further development (KSMO 2026) - No abstract available

Clinical • Combination therapy • Metastases • P1 data • Melanoma • Oncology • Solid Tumor

A Study to Evaluate the Safety and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-mutant Advanced Melanoma. (clinicaltrials.gov) - P1 | N=65 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jun 2027 ➔ Dec 2026 | Trial primary completion date: Jun 2027 ➔ Dec 2026

IO biomarker • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • NRAS

Hanmi Pharmaceutical…said on the 10th that phase 2 of a domestic clinical trial of the oral targeted anticancer drug "Belvarafenib," which targets NRAS gene mutation melanoma with no available treatments, is proceeding smoothly. (Chosun Biz) - "The company plans to finish patient enrollment by 2027 and apply for conditional approval in Korea in 2028...The domestic phase 2 is a multicenter, single-arm study evaluating the efficacy and safety of Belvarafenib in combination with the MEK inhibitor 'cobimetinib.' The company expects that this combination will complement the limitations of existing BRAF inhibitor plus MEK inhibitor regimens and improve treatment effects in a broader range of patients with genetic mutations."

Korea filing • Trial status • Melanoma

Belvarafenib for CNS Efficacy in Patients With BRAF-Altered Solid Tumors (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Samsung Medical Center

New P2 trial • Brain Cancer • Oncology • Solid Tumor • BRAF

Tumor-agnostic Precision Immuno-oncology and Somatic Targeting Rational for You (TAPISTRY) Platform Study (clinicaltrials.gov) - P2 | N=920 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • IO biomarker • Pan tumor • Tumor mutational burden • Lung Cancer • Lymphoma • Oncology • Solid Tumor • BRAF

mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway. (PubMed, Cell Death Dis) - "Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy."

Journal • Melanoma • Oncology • Solid Tumor • ATF4 • MTHFD2 • NF1 • NRAS

Characterization of intrinsic and acquired resistance to KRASG12C inhibitors across a broad collection of cancer cell line models (AACR 2026) - "Although PTEN loss was restricted to OV56, both OV56 and SW1573 were resistant to inhibitors of various MAPK pathway components, including RAF (tovorafenib, belvarafenib), MEK (trametinib), and ERK (ulixertinib), suggesting MAPK pathway independence. Cross-resistance to adagrasib, sotorasib and divarasib was also observed in the acquired resistant models.Intrinsically KRASG12C inhibitor-resistant cell lines, along with acquired resistant models, represent valuable systems for evaluating next-generation KRAS inhibitors and identifying new drug combinations to optimize therapeutic benefit of KRASG12C inhibitors in patients."

Preclinical • Oncology • KRAS • PTEN

PHI-501 is a novel potent next-generation pan-RAF/DDRs inhibitor, and overcomes resistance to RAF or MEK inhibitor in melanoma via dual inhibition of RAF and DDR1/2 signaling (AACR 2024) - "In this study, we evaluated the ability of PHI-501 to overcome drug-resistance to RAF or MEK inhibitors in melanoma harboring NRAS or BRAF mutations. Three drug-resistant cell lines were established by long-term treatment of belvarafenib in SK-MEL-2 (SK-MEL2BR) and each of dabrafenib and trametinib in SK-MEL-3 (SK-MEL3DR and SK-MEL3TR, respectively). Novel pan-RAF/DDR dual inhibitor PHI-501 has greater anti-tumor activity in RAF or MEK inhibitor-resistant melanoma, which is through downregulation of MAPK signaling and EMT-related genesets and promoting apoptosis. These data support that the clinical development of PHI-501 for melanoma refractory to MAPK inhibitors."

Melanoma • Oncology • Solid Tumor • BRAF • DDR1 • IL6 • KRAS • NRAS • TNFA

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (AACR 2025) - P3 | "The combination of avutometinib with the focal adhesion kinase (FAK) inhibitor defactinib has shown clinical activity for patients with low-grade serous ovarian cancer and is currently being investigated in a Phase 3 confirmatory study (RAMP 301; NCT06072781)...In contrast to the tumor regressions induced by avutometinib plus exarafenib in this ME9518 model, the combination of the MEK-only inhibitor binimetinib with exarafenib caused substantial body weight loss and failed to show tumor regression. Strong tumor regressions in all mice were also observed with the combination of avutometinib and the pan-RAFi belvarafenib in an NRAS mutant xenograft model (SKMEL2). Mechanistically, the deep tumor regressions observed with the combination of avutometinib plus exarafenib corresponded with virtually complete elimination of MAPK pathway markers such as pMEK, DUSP4 and pS6 in the tumors relative to avutometinib or exarafenib alone which conferred less complete inhibition...."

Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • DUSP4 • KRAS • NRAS

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

Unraveling Kiaa1549-Braf driven brain tumors: From modeling to therapy (AACR 2025) - "Furthermore, targeting the robust MAPK pathway activation in these KB-driven tumor models with Belvarafenib significantly reduced ERK phosphorylation and tumor growth, and significantly increased the survival of treated mice.These findings demonstrate that KB promotes tumor initiation and progression, and highlight the therapeutic potential of Belvarafenib targeting this oncogenic event. Thus, our KB-DLGNTs model emerges as a valuable tool to evaluate the efficacy of novel pre-clinical BRAF inhibitors."

Astrocytoma • Brain Cancer • CNS Tumor • Glioneuronal Tumor • Oncology • Pilocytic Astrocytoma • Solid Tumor • BRAF • KIAA1549

Belvarafenib in Combination With Cobimetinib in Patients With Locally Advanced or Metastatic NRAS-Mutant Melanoma (clinicaltrials.gov) - P2 | N=45 | Recruiting | Sponsor: Hanmi Pharmaceutical Company Limited

New P2 trial • Melanoma • Oncology • Solid Tumor • NRAS

Hanmi Pharmaceutical has initiated patient dosing in a domestic Phase 2 clinical trial of its oral targeted anticancer candidate belvarafenib for the treatment of malignant melanoma. (Korea IT Times) - "The multicenter, single-arm Phase 2 study will enroll 45 patients to evaluate the efficacy and safety of belvarafenib in combination with the MEK inhibitor cobimetinib."

Trial status • Melanoma

A Study to Evaluate the Safety and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-mutant Advanced Melanoma. (clinicaltrials.gov) - P1 | N=65 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Dec 2025 ➔ Jun 2027 | Trial primary completion date: Dec 2025 ➔ Jun 2027

IO biomarker • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • NRAS

Hanmi Pharmaceutical, the core operating subsidiary of Hanmi Science, announced on January 8 that it had received approval on January 5 from the Ministry of Food and Drug Safety for the Phase 2 clinical trial plan of belvarafenib, a targeted anticancer agent developed in-house. (Korea IT Times) - "The Phase 2 study will be conducted as a multicenter, single-arm trial in patients with locally advanced or metastatic melanoma harboring NRAS mutations. The trial aims to evaluate the efficacy and safety of belvarafenib in combination with the MEK inhibitor cobimetinib...Belvarafenib has also been selected for the Ministry of Food and Drug Safety’s 'Giljabi' program, which provides comprehensive support for innovative products from clinical design through regulatory approval. The drug is currently being administered on a limited basis to some patients under treatment-use approval, and Hanmi plans to continue research and development with the goals of early commercialization and expanded indications."

New P2 trial • Non-US regulatory • Melanoma

Efficacy of Belvarafenib with and without Cobimetinib in Preclinical Models of Ras Pathway-Mutant AML (ASH 2023) - "Mechanistically, we identified distinct biochemical and transcriptional effects of RAF dimer and MEK inhibition in AML cells. We are characterizing these further and pursuing causes of resistance in primary Nras- and ­Kras-mutant mouse AMLs that relapsed after an initial response to treatment."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • BRAF • KRAS • NF1 • NRAS • SPRY2

Belvarafenib Inhibits the Growth of RAS-Mutant Acute Myeloid Leukemia Cell Lines in Vitro and Drives Adaptive Resistance In Vivo (ASH 2024) - "OCI-AML3 cells were lentivirally transduced with doxycycline-inducible vectors containing constitutively active MEK-DD, a MEK mutation that confers resistance to allosteric MEK inhibitors (L115P), or candidate MEK resistance mutations and cell viability was determined by CellTiter-Glo...NRAS-mutant OCI-AML3 cells expressing MEK-DD were resistant to belvarafenib and sensitive to cobimetinib...We are characterizing candidate resistance mutations in addition to Mapk21 K57T that emerged during belvarafenib treatment. Altogether, our data support further investigation of belvarafenib monotherapy and rational drug combinations in AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF • EIF4EBP1 • KRAS • MAP2K1 • MAPK1 • NRAS

Ex Vivo Drug Sensitivity Evaluation of a ZMYM2: : FGFR1 Fusion-Positive 8p11 Myeloproliferative Syndrome (EMS) Leukemia (ASH 2023) - "Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the..."

Preclinical • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • FGFR1 • FLT3 • RUNX1 • ZMYM2

Small Molecule Modulation of Inactive-to-Active State Transitions of RAS:RAF-Family Complexes (AACR-NCI-EORTC 2025) - "AGLUE-1 notably increased MEK:ARAF interaction without affecting other RAF isoforms and led to elevated MEK phosphorylation without a corresponding increase in ERK phosphorylation, suggesting a distinct mode of action compared to known MEK inhibitors such as Avutometinib and Trametinib. Moreover, AGLUE1 exhibited synergistic anti-proliferative effects with the RAF inhibitor belvarafenib in cancer cell lines. Our data demonstrate that AGLUE1 enhances endogenous ARAF-MEK interactions and selectively increases MEK phosphorylation, with minimal impact on ERK activity... Our data demonstrate that AGLUE1 enhances endogenous ARAF-MEK interactions and selectively increases MEK phosphorylation, with minimal impact on ERK activity. These findings suggest a unique mode of action and potential for AGLUE1 to synergize with existing RAF inhibitors. This work supports the development of ARAF-targeted chemical tools to explore its pharmacological role in cancer and highlights the..."

Oncology • ARAF • BRAF • KRAS

Development of efficient manufacturing processes for GDC-9545 (Giredestrant) and GDC-5573 (Belvarafenib) (ACS-Fall 2025) - "They also highlight the impact that high-throughput experimentation can have on facilitating expedient identification of metal-catalyzed reaction conditions. Finally, this presentation will describe some of the challenges associated with the development of chemical processes towards an HHC Category 3B API with particularly poor physical properties at multiple stages of the synthetic sequence, including the API itself."

Targeted Treatment of Solid Tumors with BRAF Fusions (EACR 2025) - "The targeted therapies used were varied, with MEK inhibitors being used in most patients, selumetinib (n = 36, 32%), followed by trametinib (n = 34, 30%), as well as, binimetinib and cobimetinib. BRAF and pan-RAF inhibitors used included dabrafenib, vemurafenib, tovorafenib and belvarafenib... In conclusion, there is limited data on the efficacy of targeted therapy in solid tumors with a BRAF fusion, with most evidence coming from case reports/series, alongside a few phase I/II trials. While BRAF fusion-positive cancers show varying yet promising responses to BRAF and/or MEK inhibitors, the effectiveness may vary with histology. Given the rarity of these fusions, there is a clear need for international collaboration and innovative trial designs, such as basket and platform trials, to assess targeted treatment strategies more effectively and improve outcomes for these patients."

Astrocytoma • Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pilocytic Astrocytoma • Sarcoma • Solid Tumor • AGK • BRAF • KIAA1549

Exploring the efficacy and mechanism of action of combined pan-Raf and MEK inhibition in halting the growth of non-V600 BRAF mutated tumors. (ASCO 2025) - P2 | "Encorafenib (Enco; BRAF monomer inhibitor) + Binimetinib (Bini; MEK inhibitor) elicit responses in <15% of patients with non-V600E BRAF mutations (NCT03839342). We hypothesized that Belvarafenib (Belva), a novel pan-RAF dimer inhibitor, is more potent than Enco in inhibiting the growth of Class 2 & 3 non-V600 BRAF mutated tumors... These results from 10 preclinical models, tested so far, put forward combined Pan-Raf and MEK inhibition as a potential effective treatment choice for patients with non-V600 BRAF mutated tumors to be investigated in clinical trials. In parallel, they unravel novel insights into the mechanism of action of this therapeutic approach and in return the druggable vulnerabilities of the non-V600 BRAF mutated tumors, a notion we are further investigating in the outlined models."

Clinical • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • BRAF

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (Businesswire) - "Verastem Oncology announces multiple presentations focused on RAS/MAPK pathway inhibition at AACR Annual Meeting 2025....Abstract #: 4393....Combining avutometinib with a pan-RAF inhibitor (exarafenib or belvarafenib) led to strong tumor regressions in multiple NRAS- and BRAF-driven tumor models corresponding with nearly complete inhibition of RAS/MAPK pathway signaling."

Preclinical • Solid Tumor

Preclinical investigation of a novel brain penetrant combination therapy targeting RAF and MEK for melanoma brain metastasis (SNO 2024) - "Current BRAF/MEK inhibitors, such as dabrafenib and vemurafenib, have shown responses on the order of 50-60% in patients with BRAF-mutant melanoma; however, responses are not durable... In mice, the brain-to-plasma unbound partition coefficients (Kpuu) of KIN-7136 and KIN-8391 were 0.67 and 0.7 respectively, higher than the comparators binimetinib and belvarafenib, demonstrating improved brain exposure.The IC50s of KIN-7136/ KIN-8391 in melanoma cell lines were 27.0/36.5 nM in A375 (BRAF V600E), 78.6/35.4 nM in HMV2 (BRAF G469V), 183.0/699.0 nM in SK-MEL-2 (NRAS Q61R), and 53.9/110.0 nM in SK-MEL30 (BRAF D287H and E275K), respectively... These preclinical data confirm the synergistic effect of KIN-7136 and KIN-8391 in BRAF-mutant melanoma brain metastases models, supporting further research to advance its clinical translation."

Combination therapy • Preclinical • Melanoma • Oncology • Solid Tumor • NRAS

Overloading And unpacKing (OAK) - droplet-based combinatorial indexing for ultra-high throughput single-cell multiomic profiling. (PubMed, Nat Commun) - "Finally, we examine transcriptomic responses of over 400,000 melanoma cells to a RAF inhibitor, belvarafenib, discovering a rare resistant cell population (0.12%). OAK's ultra-high throughput, broad compatibility, high sensitivity, and simplified procedures make it a powerful tool for large-scale molecular analysis, even for rare cells."

Journal • Melanoma • Oncology • Solid Tumor