belvarafenib (RG6185) / Hanmi - LARVOL DELTA

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 (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

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

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

Belvarafenib in patients (pts) with BRAF class II or III alteration-positive tumours: TAPISTRY study (ESMO 2024) - P2 | "In this study belvarafenib did not demonstrate antitumour activity in pts whose tumours had class II or III BRAF alterations. However, a number of pts had stable disease. Further studies are needed to understand the value of BRAF inhibition in the tumour-agnostic setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF

Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma. (PubMed, Cancers (Basel)) - "Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations."

Journal • Melanoma • Oncology • Solid Tumor • BRAF

Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma. (PubMed, bioRxiv) - "Purpose: This study explores the potential of preclinical in vitro cell line response data and computational modeling in identifying optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Further, our analysis suggests the importance of drug dosing strategies to optimize synergy based on mutational context, yet highlights the real-world challenges of maintaining a narrow dose range. This approach establishes a framework for translational investigation of drug responses in the refinement of combination therapy, balancing the potential for synergy and practical feasibility in cancer treatment planning."

Journal • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

TUSPETINIB RETAINS NANOMOLAR POTENCY AGAINST AML CELLS ENGINEERED TO EXPRESS THE NRASG12D MUTATION OR SELECTED FOR RESISTANCE TO VENETOCLAX (EHA 2024) - P1/2 | "Cells with NRASG12D did not demonstrate resistance to the MCL-1inhibitor S63845; instead, modest expression of NRASG12D in clones A and C was associated with 4...4-foldhypersensitivity to the Raf inhibitor belvarafenib... NRASG12D mutation in R/R AML patients is associated with poor response. This studyindicates: 1) that the level of NRASG12D mutant protein rather than its presence alone is the key determinantof sensitivity to both TUS and VEN in the MV-4-11 FLT3-ITD model; and 2) the combination of TUS+VENovercomes any resistance to each agent. There is a strong rationale for combining TUS with VEN to treatNRASG12D AML given that: a) the drugs exhibit additivity in cytotoxic assays in both the wild type MV-4-11and the NRASG12D clones; b) low levels of NRASG12D protein do not cause resistance to either drug; c) thedevelopment of even high levels of VEN resistance does not cause resistance to TUS; and d) the previously-reported marked hypersensitivity to VEN that..."

IO biomarker • Acute Myelogenous Leukemia • Immunology • Oncology • BCL2 • FLT3 • JAK1 • JAK2 • SYK

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

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

Exploring Molecular Genetic Alterations and RAF Fusions in Melanoma: A Belvarafenib Expanded Access Program in Patients with RAS/RAF-Mutant Melanoma. (PubMed, Oncologist) - "Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib."

Journal • Melanoma • Oncology • Solid Tumor • BRAF • NRAS • RAS

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. | Recruiting ➔ Active, not recruiting | N=128 ➔ 65

Combination therapy • Enrollment change • Enrollment closed • IO biomarker • Metastases • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • NRAS

Hanmi Pharmaceutical’s Belvarafenib Receives Second Approval for Therapeutic Use for Melanoma (Business Korea) - "Hanmi Pharmaceutical has received additional approval for the therapeutic use of the anti-cancer drug candidate Belvarafenib, which was technologically transferred to global pharmaceutical company Genentech, a member of the Roche Group (RHO). According to the Ministry of Food and Drug Safety on Jan. 10, Severance Hospital of Yonsei University received approval for the therapeutic use of Belvarafenib targeting individual patients for the treatment of melanoma a day earlier. This marks the second approval for therapeutic use of Belvarafenib specifically for melanoma patients....The research on Belvarafenib, led by Genentech, commenced on May 13, 2021. The target completion date for the research is Sept. 1, 2024."

Non-US regulatory • Melanoma • Oncology • Skin Cancer • 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=128 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Sep 2024 ➔ Nov 2025 | Trial primary completion date: Nov 2023 ➔ Nov 2025

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

Hanmi Pharmaceutical's new anti-cancer drug 'belvarafenib' also kills cancer cells that metastasize to the brain. [Google translation] (Health Korea News) - "Belvarafenib, an anti-cancer new drug candidate developed by Hanmi Pharmaceutical, was found to be effective against cancer cells that have metastasized to the brain in animal tests. In general, anticancer drugs have a low blood-brain barrier (BBB) ​​passage rate, making it difficult to treat tumors when they metastasize to the brain. However, 'belvarafenib' is attracting attention as it shows the potential for development as an anticancer drug that overcomes these shortcomings...This patent application is being filed jointly by Hanmi Pharmaceutical, Genentech, and Genentech's parent company, Roche...As the mice used in the experiment were transplanted with human tumor cells, and the effects in humans can be reliably predicted through the rodent model, 'belvarafenib' is a treatment for human brain cancer and metastatic brain cancer harboring MAPK mutations."

Patent • Preclinical • Brain Cancer • CNS Tumor • Oncology • Solid Tumor

A Case of Acute Interstitial Nephritis Associated with Belvarafenib, a Novel pan-RAF Kinase Inhibitor for Metastatic NRAS Mutant Melanoma (KIDNEY WEEK 2023) - "A literature review reported no renal adverse effects associated with pan-RAF agents.Belvarafenib is a novel agent; further research and time are required to determine its adverse effects incidence. However, clinicians must remain vigilant about the potential kidney adverse effects of this agent and consider a kidney biopsy to assess AIN in patients whose AKI does not respond promptly to discontinuing Belvarafenib and supportive care."

Clinical • Metastases • Acute Kidney Injury • Fatigue • Melanoma • Nephrology • Oncology • Renal Disease • Solid Tumor • BRAF • NRAS

Anti-tumor activity of belvarafenib in combination with cobimetinib in patients with metastatic solid tumors harboring BRAF fusions or BRAF class II/III mutation (ESMO 2023) - P1 | "No new safety signals were found. Table: 661MO SC-A: BRAF fusion (N=15) SC-B: Point mutation (N=8) Best overall response CR 0 0 PR 9 (60.0) 0 SD 5 (33.3) 4 (50.0) PD 1 (6.7) 4 (50.0) ORR n (%) 9 (60.0) 0 95% CI 32.29, 83.66 0, 36.94 Disease control rate (PR+SD) n (%) 14 (93.3) 4 (50.0) 95% CI 68.05, 99.83 13.70, 78.80 mPFS month 13.7 2.1 95% CI 7.36, 18.23 1.61, 7.16 Conclusions The combination of Belva with Cobi showed promising anti-tumor activity as well as durable responses in patients with BRAF fusions regardless of cancer type."

Clinical • Combination therapy • IO biomarker • Metastases • Biliary Cancer • Biliary Tract Cancer • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • BRAF • NRAS