^
    5ms
    Tunlametinib: First Approval. (PubMed, Drugs)
    In March 2024, tunlametinib was granted conditional approval in China (based on surrogate endpoints) for use in patients with NRAS-mutated advanced melanoma who have failed anti-PD-1/PD-L1 treatment. This article summarizes the milestones in the development of tunlametinib leading to this first approval for the treatment of solid tumours with RAS and RAF mutations.
    Review • Journal • PD(L)-1 Biomarker • IO biomarker
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1)
    |
    tunlametinib (HL-085)
    6ms
    Comparing Tunlametinib Capsules and Combination Chemotherapy in Advanced NRAS-mutant Melanoma (clinicaltrials.gov)
    P3, N=165, Recruiting, Shanghai Kechow Pharma, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • IO biomarker • Metastases
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    cisplatin • carboplatin • paclitaxel • temozolomide • dacarbazine • tunlametinib (HL-085)
    6ms
    Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study. (PubMed, Exp Hematol Oncol)
    Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID.
    P1 data • Journal • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    9ms
    A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma. (PubMed, Eur J Cancer)
    Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.
    Clinical • P2 data • Journal • IO biomarker • Metastases
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • NRAS Q61 • NRAS G12 • NRAS G13
    |
    tunlametinib (HL-085)
    1year
    Preclinical characterization of tunlametinib, a novel, potent, and selective MEK inhibitor. (PubMed, Front Pharmacol)
    In vitro, tunlametinib demonstrated high selectivity with approximately 19-fold greater potency against MEK kinase than MEK162, and nearly 10-100-fold greater potency against RAS/RAF mutant cell lines than AZD6244...Furthermore, tunlametinib combined with BRAF/KRAS/SHP2 inhibitors or docetaxel showed synergistically enhanced response and marked tumor inhibition. Tunlametinib exhibited a promising approach for treating RAS/RAF mutant cancers alone or as combination therapies, supporting the evaluation in clinical trials. Currently, the first-in-human phase 1 study and pivotal clinical trial of tunlametinib as monotherapy have been completed and pivotal trials as combination therapy are ongoing.
    Preclinical • Journal
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • BRAF mutation • KRAS wild-type • RAS mutation
    |
    docetaxel • Koselugo (selumetinib) • Mektovi (binimetinib) • tunlametinib (HL-085)
    over1year
    Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer (clinicaltrials.gov)
    P3, N=165, Not yet recruiting, Shanghai Kechow Pharma, Inc.
    New P3 trial • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600
    |
    Avastin (bevacizumab) • Erbitux (cetuximab) • Zelboraf (vemurafenib) • tunlametinib (HL-085)
    over1year
    Comparing Tunlametinib Capsules and Combination Chemotherapy in Advanced NRAS-mutant Melanoma (clinicaltrials.gov)
    P3, N=165, Not yet recruiting, Shanghai Kechow Pharma, Inc.
    New P3 trial • IO biomarker • Metastases
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    cisplatin • carboplatin • paclitaxel • temozolomide • dacarbazine • tunlametinib (HL-085)
    over1year
    Efficacy and safety of tunlametinib (HL-085) combined with vemurafenib in patients with advanced BRAF V600-mutated solid tumors: A multicenter, phase I study (ESMO 2023)
    Conclusions Tunlametinib in combination with vemurafenib showed promising antitumor activity and manageable safety profile in pts with BRAF V600-mutated solid tumors. Further studies are ongoing.
    Clinical • P1 data • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    over1year
    Efficacy and Safety of HL-085 Combined With Vemurafenib in BRAF V600E Patients With Non-small Cell Lung Cancer: a Phase II Clinical Study (clinicaltrials.gov)
    P2, N=75, Not yet recruiting, Shanghai Kechow Pharma, Inc.
    New P2 trial • Metastases
    |
    PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    over1year
    A PhaseI Study of HL-085 Plus Vemurafenib in Solid Tumor With BRAF V600 Mutation (clinicaltrials.gov)
    P1, N=45, Recruiting, Shanghai Kechow Pharma, Inc. | Trial completion date: Aug 2022 --> Dec 2023 | Trial primary completion date: Aug 2022 --> Dec 2023
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    over1year
    Study of HL-085 and Vemurafinib in Metastatic Colorectal Cancer (mCRC) (clinicaltrials.gov)
    P2, N=186, Recruiting, Shanghai Kechow Pharma, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    over1year
    HL-085 in NRAS-mutated Advanced Melanoma (clinicaltrials.gov)
    P2, N=100, Completed, Shanghai Kechow Pharma, Inc. | Recruiting --> Completed | Trial completion date: Nov 2022 --> Feb 2023 | Trial primary completion date: Apr 2022 --> Feb 2023
    Trial completion • Trial completion date • Trial primary completion date • Metastases
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    tunlametinib (HL-085)
    over1year
    Study of HL-085 in NRAS Mutant Advanced Melanoma (clinicaltrials.gov)
    P1/2, N=42, Completed, Shanghai Kechow Pharma, Inc. | Recruiting --> Completed
    Trial completion • Metastases
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    tunlametinib (HL-085)
    almost2years
    First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations. (PubMed, BMC Med)
    The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.
    P1 data • Journal • Metastases
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    tunlametinib (HL-085)
    over2years
    HL-085 in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (clinicaltrials.gov)
    P2, N=70, Recruiting, Shanghai Kechow Pharma, Inc.
    New P2 trial
    |
    NF1 (Neurofibromin 1)
    |
    NF1 mutation
    |
    tunlametinib (HL-085)
    almost3years
    HL-085+Vemurafenib to Treat Advanced Melanoma Patients With BRAF V600E/K Mutation (clinicaltrials.gov)
    P2, N=104, Recruiting, Shanghai Kechow Pharma, Inc.
    New P2 trial
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600 • BRAF V600K
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    almost3years
    Study of HL-085 and Vemurafinib in Metastatic Colorectal Cancer (mCRC) (clinicaltrials.gov)
    P2, N=186, Not yet recruiting, Shanghai Kechow Pharma, Inc.
    New P2 trial
    |
    BRAF (B-raf proto-oncogene)
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    almost3years
    HL-085 in NRAS-mutated Advanced Melanoma (clinicaltrials.gov)
    P2, N=100, Recruiting, Shanghai Kechow Pharma, Inc.
    New P2 trial
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    tunlametinib (HL-085)
    3years
    Study of HL-085 Plus Docetaxel in Patients With KRAS Mutant NSCLC (clinicaltrials.gov)
    P1, N=2, Terminated, Shanghai Kechow Pharma, Inc. | N=27 --> 2 | Trial completion date: Dec 2022 --> Jul 2021 | Not yet recruiting --> Terminated | Trial primary completion date: Dec 2022 --> Jul 2021; drug development strategy adjustment
    Clinical • Enrollment change • Trial completion date • Trial termination • Trial primary completion date • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation
    |
    docetaxel • tunlametinib (HL-085)
    3years
    A PhaseI Study of HL-085 Plus Vemurafenib in Solid Tumor With BRAF V600 Mutation (clinicaltrials.gov)
    P1, N=45, Recruiting, Shanghai Kechow Pharma, Inc. | Trial completion date: Aug 2021 --> Aug 2022 | Trial primary completion date: Aug 2021 --> Aug 2022
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    4years
    A PhaseI Study of HL-085 Plus Vemurafenib in Solid Tumor With BRAF V600 Mutation (clinicaltrials.gov)
    P1, N=45, Recruiting, Shanghai Kechow Pharma, Inc. | Trial completion date: Aug 2020 --> Aug 2021 | Trial primary completion date: Aug 2019 --> Aug 2021
    Clinical • Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • tunlametinib (HL-085)
    4years
    Study of HL-085 Plus Docetaxel in Patients With KRAS Mutant NSCLC (clinicaltrials.gov)
    P1, N=27, Not yet recruiting, Shanghai Kechow Pharma, Inc. | Trial completion date: Aug 2021 --> Dec 2022 | Trial primary completion date: Aug 2020 --> Dec 2022
    Clinical • Trial completion date • Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation
    |
    docetaxel • tunlametinib (HL-085)
    4years
    Study of HL-085 in NRAS Mutant Advanced Melanoma (clinicaltrials.gov)
    P1/2, N=54, Recruiting, Shanghai Kechow Pharma, Inc. | Trial completion date: Mar 2021 --> Mar 2022 | Trial primary completion date: Mar 2020 --> Mar 2022
    Clinical • Trial completion date • Trial primary completion date
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    tunlametinib (HL-085)
    almost5years
    [VIRTUAL] A first-in-human phase I/II study of HL-085, a MEK Inhibitor, in Chinese patients with NRASm advanced melanoma. (ASCO 2020)
    Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Research Funding: Shanghai KeChow Pharma
    Clinical • P1/2 data
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • NRAS Q61K • NRAS Q61 • NRAS Q61R • NRAS G12D • NRAS Q61L • NRAS G13R • NRAS G12S
    |
    tunlametinib (HL-085)