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DRUG:

belvarafenib (RG6185)

i
Other names: HM-95573, RG-6185, RG6185, RG 6185, GDC-5573, GDC 5573, HM95573, HM 95573, GDC5573
Company:
Hanmi
Drug class:
pan-RAF inhibitor
2ms
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
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BRAF (B-raf proto-oncogene)
|
Cotellic (cobimetinib) • belvarafenib (RG6185)
3ms
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
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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Cotellic (cobimetinib) • belvarafenib (RG6185)
8ms
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
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)
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BRAF mutation • NRAS mutation • RAS mutation
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belvarafenib (RG6185)
9ms
Enrollment closed • Enrollment change • Combination therapy • IO biomarker • Metastases
|
NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation
|
Opdivo (nivolumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
12ms
Trial completion date • Trial primary completion date • Combination therapy • IO biomarker • Metastases
|
NRAS (Neuroblastoma RAS viral oncogene homolog)
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NRAS mutation
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Opdivo (nivolumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
12ms
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 treatment of patients with FGFR1-fusion positive leukemias.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • FGFR1 (Fibroblast growth factor receptor 1) • RUNX1 (RUNX Family Transcription Factor 1)
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RUNX1 mutation • FGFR fusion • FGFR1 fusion • FGFR1 expression • FGFR1 rearrangement
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Mekinist (trametinib) • Iclusig (ponatinib) • Lenvima (lenvatinib) • bortezomib • Xospata (gilteritinib) • Pemazyre (pemigatinib) • Inlyta (axitinib) • fexagratinib (ABSK091) • belvarafenib (RG6185) • Recentin (cediranib) • dovitinib (TKI258)
1year
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
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • SPRY2 (Sprouty RTK Signaling Antagonist 2)
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KRAS mutation • BRAF mutation • NRAS mutation • NF1 mutation • RAS mutation
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Cotellic (cobimetinib) • belvarafenib (RG6185)
1year
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
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF V600E • NRAS mutation • BRAF V600 • BRAF wild-type • RAS mutation • NRAS wild-type
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belvarafenib (RG6185)
over1year
Trial primary completion date • Combination therapy • IO biomarker • Metastases
|
NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation
|
Opdivo (nivolumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
over1year
HM95573 in Combination With Either Cobimetinib or Cetuximab in Patients With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
P1; Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Sep 2023 --> Sep 2024
Combination therapy • Trial completion date • Trial primary completion date • Enrollment closed • Metastases
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PI3K (Phosphoinositide 3-kinases)
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EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • KRAS G13D • RAS mutation • BRAF fusion • KRAS G13 • NRAS G13
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FoundationOne® CDx
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Erbitux (cetuximab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
over1year
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)
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 • PD(L)-1 Biomarker • IO biomarker • Metastases
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation • BRAF fusion
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Cotellic (cobimetinib) • belvarafenib (RG6185)
over1year
Structure and RAF-family kinase isoform selectivity of Type II RAF inhibitors tovorafenib and naporafenib. (PubMed, J Biol Chem)
Selective inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as Pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.
Journal
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BRAF (B-raf proto-oncogene) • ARAF (A-Raf Proto-Oncogene)
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BRAF mutation
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Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • Braftovi (encorafenib) • belvarafenib (RG6185) • Ojemda (tovorafenib) • naporafenib (ERAS-254)
over1year
Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model. (PubMed, Clin Exp Metastasis)
It also significantly inhibited tumor growth in NRAS mutant SK-MEL-30 and K1735 tumor-bearing mice and synergized to enhance the antitumor activity combined with cobimetinib or atezolizumab. Most importantly, belvarafenib strongly reduced tumor burden and markedly improved survival benefits in mice intracranially implanted with A375SM melanoma. These results demonstrated that belvarafenib, which has favorable BBB permeability, and potent antitumor activity on the tumors with BRAF/NRAS mutations, may be a promising therapeutic option for patients with BRAF/NRAS mutant melanoma brain metastasis.
Preclinical • Journal • PD(L)-1 Biomarker
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NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF V600E • NRAS mutation • BRAF V600 • RAS mutation • NRAS mutation + BRAF mutation
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Tecentriq (atezolizumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
over1year
PHI-501, a novel and potent pan-RAF inhibitor in metastatic melanoma (AACR 2023)
Regardless of the therapeutic effect of class I BRAF inhibitors such as vemurafenib, dabrafenib and encorafenib, melanoma patients with BRAF non-V600/RAS mutations remain limited response...The effect of PHI-501 on anchorage independent growth and cell proliferation compared to vemurafenib or belvarafenib (pan-RAF inhibitor) were tested in A375 (BRAFV600E), C8161 (BRAFG464E) and SK-MEL-2 (NRASQ61R) melanoma cell lines by soft agar assay, western blot and FACS analysis... PHI-501, a novel pan-RAF inhibitor, has potent oral anti-tumor activity. Melanoma cells harboring BRAF non-V600/NRAS or BRAF common V600E mutations exhibited significantly reduced proliferation, increased apoptosis and inhibited migration upon treatment with PHI-501. The results of this study suggest that PHI-501 has a potential to overcome the limited response in the treatment of melanoma, and warrant evaluation of PHI-501 as a single agent to treat both BRAF-and NRAS-mutated metastatic melanoma.
PARP Biomarker • Metastases
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NRAS (Neuroblastoma RAS viral oncogene homolog) • ANXA5 (Annexin A5)
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BRAF V600E • NRAS mutation • RAS mutation • NRAS Q61 • NRAS Q61R • NRAS mutation + BRAF mutation • BRAF G464E
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Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • Braftovi (encorafenib) • belvarafenib (RG6185) • PHI-501
over1year
Enrollment change • Combination therapy • IO biomarker • Metastases
|
NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation
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Opdivo (nivolumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
almost3years
Melanoma with genetic alterations beyond the BRAFV600 mutation: management and new insights. (PubMed, Curr Opin Oncol)
As of today, no molecular-targeted therapies have shown to improve survival in patients with advanced BRAFV600 wild-type melanoma. Combinatorial strategies, involving MEK-inhibitors, RAF dimer inhibitors and CDK4/6 inhibitors, are currently under investigation and have promising activity in advanced BRAFV600 wild-type melanoma.
Journal • PD(L)-1 Biomarker • IO biomarker
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NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1)
|
BRAF mutation • NRAS mutation • BRAF V600 • BRAF wild-type • NRAS Q61 • NRAS wild-type
|
Keytruda (pembrolizumab) • Tecentriq (atezolizumab) • imatinib • Cotellic (cobimetinib) • Tasigna (nilotinib) • belvarafenib (RG6185)
3years
Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. (PubMed, Pharmacol Res)
This led to the development of sotorasib as a second-line treatment of KRAS mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
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KRAS mutation
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Lumakras (sotorasib) • Zarnestra (tipifarnib) • Krazati (adagrasib) • avutometinib (VS-6766) • pictilisib (GDC-0941) • buparlisib (AN2025) • belvarafenib (RG6185) • ulixertinib (BVD-523) • lifirafenib (BGB-283) • naporafenib (ERAS-254)
over3years
Clinical • Enrollment open • Combination therapy • IO biomarker
|
NRAS (Neuroblastoma RAS viral oncogene homolog)
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NRAS mutation
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Tecentriq (atezolizumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
over3years
ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. (PubMed, Nature)
The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.
Journal
|
BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ARAF (A-Raf Proto-Oncogene)
|
BRAF mutation • NRAS mutation • BRAF V600 • NRAS mutation + BRAF mutation
|
belvarafenib (RG6185)
over3years
Clinical • New P1 trial • Combination therapy • IO biomarker
|
NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation
|
Tecentriq (atezolizumab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
over3years
[VIRTUAL] Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models (AACR 2021)
More recently, anti-PD-(L)1 therapies such as nivolumab or pembrolizumab and atezolizumab have been approved as very useful treatments for patients with melanoma. In fact, in the NRAS G13D K1735 murine melanoma cell syngeneic mice model, the combination of belvarafenib with atezolizumab (anti-PD-L1) significantly inhibited tumor growth and effectively induced infiltration of cytotoxic T-cells into tumor tissues. These effects of belvarafenib identified in the above preclinical studies need to be immediately warranted through appropriate clinical trials.
PD(L)-1 Biomarker • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • NRAS G13 • NRAS G13D
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • belvarafenib (RG6185)
over4years
Cobimetinib and HM95573 in Patients With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
P1;N=272 --> 109 | Trial completion date: Dec 2020 --> Dec 2023 | Trial primary completion date: Jun 2018 --> Sep 2023
Trial completion date • Trial primary completion date • Enrollment change • Clinical
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PI3K (Phosphoinositide 3-kinases)
|
EGFR mutation • BRAF mutation • NRAS mutation • BRAF V600 • KRAS G13D • RAS mutation • BRAF fusion • KRAS G13 • NRAS G13
|
FoundationOne® CDx
|
Erbitux (cetuximab) • Cotellic (cobimetinib) • belvarafenib (RG6185)
over4years
Expansion Study to Evaluate the Efficacy and Safety of HM95573 in BRAF, KRAS or NRAS Mutant Solid Cancers (clinicaltrials.gov)
P1, N=65, Completed, Hanmi Pharmaceutical Company Limited | Recruiting --> Completed | N=100 --> 65 | Trial primary completion date: Apr 2019 --> Feb 2020
Clinical • Trial completion • Enrollment change • Trial primary completion date
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
KRAS mutation • BRAF mutation • NRAS mutation
|
belvarafenib (RG6185)