- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Novel natural inhibitors targeting B-RAF(V600E) by computational study. (Pubmed Central) - Dec 16, 2021
Two novel natural compounds (ZINC000100168592 and ZINC000049784088) from ZINC15 database were found binding to B-RAF(V600E) with more favorable interaction energy in comparison with the reference drug Vemurafenib...The result of this study shows that ZINC000100168592 and ZINC000049784088 are ideal leading potential compounds to inhibit B-RAF(V600E). The findings of this study and these selected drug candidates greatly contributed to the medication design and improvement of B-RAF(V600E) and other proteins.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition. (Pubmed Central) - Dec 16, 2021
Ferrochelatase overexpression protected kidney tubular epithelial cells and conversely ferrochelatase knockdown increased the sensitivity to vemurafenib-induced kidney toxicity. Thus, our studies suggest that vemurafenib-associated kidney tubular epithelial cell dysfunction and kidney toxicity is BRAF-independent and caused, in part, by off-target ferrochelatase inhibition.
- |||||||||| Zelboraf (vemurafenib) / Roche
Biomarker, Review, Journal, IO biomarker: Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy. (Pubmed Central) - Dec 16, 2021
Collectively, these mechanisms confer melanoma resistance to apoptotic stimuli delivered by T cells despite a fully functional and effective antitumor immune response. Identification of biomarkers, combination treatment, and the use of CAR T cells are among the approaches that can potentially circumvent melanoma's resistance to immunotherapy.
- |||||||||| Journal, IO biomarker: BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation. (Pubmed Central) - Dec 16, 2021
The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Unexpected cause of vemurafenib-induced nephrotoxicity: ferrochelatase. (Pubmed Central) - Dec 16, 2021
reported that vemurafenib-induced nephrotoxicity is not directly caused by viral oncogene homolog B1 inhibition but is partly caused by ferrochelatase inhibition in renal tubular epithelial cells. Because several other protein kinase inhibitors are also known to cause ferrochelatase inhibition, further studies are needed to elucidate the role of ferrochelatase in renal function and injury.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
Clinical, Journal, PD(L)-1 Biomarker, IO biomarker: EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT) (Pubmed Central) - Dec 14, 2021
Currently, the targeted therapy with low molecular weight selective inhibitors of mutant BRAF (vemurafenib, dabrafenib) and immune checkpoint blockers (nivolumab, pembrolizumab) is generally recommended for unresectable skin melanoma patients bearing BRAF mutations. Despite this dual treatment strategy, the use of even one nivolumab (in monoregimen), showed complete regression of both - the local recurrence and multiple lung metastases in the case of a positive BRAF mutation and substantially improved the survival of inoperable cancer patient.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Journal, Tumor Mutational Burden: Branching clonal evolution patterns predominate mutational landscape in multiple myeloma. (Pubmed Central) - Dec 10, 2021
A few drivers such as FAT4, IGLL5 and CDKN1A retained consistent distribution patterns at two time points. These findings are clinically relevant and point at consideration of evaluating multi time point subclonal mutational landscapes for designing better risk stratification strategies and tailoring time to time risk adapted combination therapies in future.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Enrollment closed, Trial completion date, Trial primary completion date: To Evaluate the Efficacy Beyond Progression of Vemurafenib+Cobimetinib Associated With Local Treatment Compared to Second-line Treatment in Patients With BRAFV600+ Metastatic Melanoma in Focal Progression With First-line+Vemurafenib+Cobimetinib. (clinicaltrials.gov) - Dec 2, 2021
P2, N=120, Active, not recruiting,
The combination treatment with vemurafenib/cobimetinib results in an important impact on long-term survival, leading to a steady CR in one-third of the patients. Recruiting --> Active, not recruiting | Trial completion date: Apr 2021 --> Apr 2023 | Trial primary completion date: Apr 2021 --> Apr 2023
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma. (Pubmed Central) - Dec 2, 2021
Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.
- |||||||||| Mekinist (trametinib) / Novartis, Opdivo (nivolumab) / Ono Pharma, BMS, Tafinlar (dabrafenib) / Novartis
Journal, HEOR, Combination therapy, PD(L)-1 Biomarker, IO biomarker: Cost-Effectiveness of the Dabrafenib Schedule in Combination With Trametinib Compared With Other Targeted Therapies, Immunotherapy, and Dacarbazine for the Treatment of Unresectable or Metastatic Melanoma With BRAFV600 Mutation in Colombia. (Pubmed Central) - Dec 2, 2021
The combined scheme could be a cost-effective and even a cost-saving alternative to vemurafenib + cobimetinib, nivolumab, and pembrolizumab if the costs associated with the use of other medications are taken into account after progression to the first line of treatment. Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay.
- |||||||||| tunlametinib (HL-085) / Tianjin Binjiang Pharma
Trial completion date, Trial primary completion date, Metastases: A PhaseI Study of HL-085 Plus Vemurafenib in Solid Tumor With BRAF V600 Mutation (clinicaltrials.gov) - Dec 1, 2021
P1, N=45, Recruiting,
Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay. Trial completion date: Aug 2021 --> Aug 2022 | Trial primary completion date: Aug 2021 --> Aug 2022
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells. (Pubmed Central) - Nov 29, 2021
Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Wound healing with topical BRAF inhibitor therapy in a diabetic model suggests tissue regenerative effects. (Pubmed Central) - Nov 21, 2021
We previously found that paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway via topical administration of the BRAF inhibitor vemurafenib accelerates wound healing by activating keratinocyte proliferation and reepithelialization pathways in healthy mice...Hair follicles expressing Sox-9 and K15 surrounded by CD34+ stroma were found in wounds of diabetic and non-diabetic mice, and their formation can be prevented by blocking downstream MEK signaling. Thus, topically applied BRAF inhibitors may accelerate wound healing, and promote the restoration of improved skin architecture in both normal and impaired wounds.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: eIF4B enhances ATF4 expression and contributes to cellular adaptation to asparagine limitation in BRAF-mutated A375 melanoma. (Pubmed Central) - Nov 21, 2021
BRAF inhibitors, such as vemurafenib, induce ATF4 in BRAF-mutated melanoma cells, but the mechanisms of ATF4 induction are not fully elucidated...Interestingly, eIF4B supported cellular proliferation under asparagine-limited conditions, possibly through the eIF4B-ATF4 pathway. Our findings indicate that eIF4B can regulate ATF4 expression, thereby contributing to cellular stress adaptation, which could be targeted as a therapeutic approach against malignancies, including melanoma.
- |||||||||| Zelboraf (vemurafenib) / Roche
Clinical, Journal: Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers. (Pubmed Central) - Nov 17, 2021
Responses were observed in 13 unique cancer types, including historically treatment-refractory tumors such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Journal: Loss of ACK1 Upregulates EGFR and Mediates Resistance to BRAF inhibition. (Pubmed Central) - Nov 17, 2021
Vemurafenib resistance mediated by ACK1 inhibition can be reversed by EGFR inhibitor gefitinib. Our data indicate that ACK1 loss may be a post-transcriptional mechanism that increases EGFR signaling and contributes to drug resistance.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
Outcomes of treatment modalities for melanoma metastatic to the gastrointestinal tract ([VIRTUAL]) - Nov 16, 2021 - Abstract #NCRI2021NCRI_193;
Over the last 10 years, immunotherapy with checkpoint inhibitors (ipilimumab, pembrolizumab and nivolumab), and targeted therapy with BRAF (vemurafenib, dabrafenib and encorafenib) and MEK inhibitors (trametinib and binimetinib) has improved the survival of patients with metastatic melanoma...From the time of first treatment, patients had longer median survival if they had surgery or immunotherapy (median survival not reached) than if they had targeted therapy (median survival =8.8 months, p=0.018) or best supportive care (including 1 patient who had dacarbazine: median survival =2.0 months, p=0.001)...Patients with resectable GI metastases are likely to have a prolonged survival even in the presence of other metastases, and warrant consideration of surgery. Impact statement Research may benefit from further investigation into how systemic treatment improves prognosis of melanoma patients with GI metastasis.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche, XL888 / Exelixis, Merck (MSD)
Trial completion date: XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - Nov 16, 2021
P1, N=26, Active, not recruiting,
Impact statement Research may benefit from further investigation into how systemic treatment improves prognosis of melanoma patients with GI metastasis. Trial completion date: Dec 2021 --> Apr 2022
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Multi-sample measurement of hyperpolarized pyruvate-to-lactate flux in melanoma cells. (Pubmed Central) - Nov 16, 2021
There was a significant reduction of k in BRAF cells following 24 and 48 hours of treatment with 2 μM vemurafenib (P ≤ .05)...BRAF inhibition had no significant effect on the metabolic flux of BRAF cells. These data demonstrate a 6-8-fold increase in efficiency for the measurement of k in cell suspension samples compared with traditional hyperpolarized in vitro methods.
- |||||||||| Braftovi (encorafenib) / Ono Pharma, Pierre Fabre, Pfizer, Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Clinical, P3 data, Journal, HEOR: Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). (Pubmed Central) - Nov 12, 2021
P3
The improved efficacy of encorafenib plus binimetinib compared to vemurafenib, translates into a positive impact on the perceived health status as assessed by the HRQoL questionnaires. The study is registered with ClinicalTrials.gov, number NCT01909453 and EudraCT number 2013-001176-38.
- |||||||||| Tafinlar (dabrafenib) / Novartis, bafetinib (INNO-406) / CytRx, Zelboraf (vemurafenib) / Roche
Journal: Development and Validation of a Five-RNA-Based Signature and Identification of Candidate Drugs for Neuroblastoma. (Pubmed Central) - Nov 10, 2021
The potential mechanisms of the five RNAs were also explored via gene set enrichment analysis, and candidate drugs targeting the five genes, including dabrafenib, vemurafenib, and bafetinib, were screened. In conclusion, we constructed a five-RNA-based signature to predict the survival of NBL and screened candidate agents against NBL.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Clinical, Journal, Combination therapy, IO biomarker: A novel C-terminal Hsp90 inhibitor KU758 synergizes efficacy in combination with BRAF or MEK inhibitors and targets drug-resistant pathways in BRAF-mutant melanomas. (Pubmed Central) - Nov 10, 2021
Using in vitro proliferation and protein-based Western Blot analyses, our novel inhibitor, KU758, potently inhibited melanoma cell proliferation (without induction of the heat shock response) in vitro and synergized with both BRAF and MEK inhibitors in inhibition of cell migration and protein expression from resistance pathways. Overall, our work provides early support for further translation of C-terminal Hsp90 inhibitor and mitogen-activated protein kinase pathway inhibitor combinations as a novel therapeutic strategy for BRAF-mutant melanomas.
- |||||||||| Enrollment open, Tumor mutational burden: CRAFT: the NCT-PMO-1602 Phase II Trial (clinicaltrials.gov) - Nov 10, 2021
P2, N=175, Recruiting,
Overall, our work provides early support for further translation of C-terminal Hsp90 inhibitor and mitogen-activated protein kinase pathway inhibitor combinations as a novel therapeutic strategy for BRAF-mutant melanomas. Not yet recruiting --> Recruiting
- |||||||||| Trial completion date, Trial primary completion date, Tumor mutational burden: Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR) (clinicaltrials.gov) - Nov 9, 2021
P2, N=720, Recruiting,
Not yet recruiting --> Recruiting Trial completion date: Sep 2021 --> Sep 2023 | Trial primary completion date: Sep 2021 --> Sep 2022
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells. (Pubmed Central) - Nov 6, 2021
In this work, we showed that SAMMSON is rapidly induced upon inhibition of ERK signaling, and SAMMSON overexpression conferred resistance to vemurafenib-induced cytotoxicity in melanoma cells...In summary, these findings suggest that SAMMSON may function as a new mediator of adaptive resistance to RAF inhibitors in melanoma by modulating CARF-p53 signaling. SIGNIFICANCE: This study highlights the role of a SAMMSON/CARF/p53 signaling axis in modulating the adaptive resistance of mutant BRAF melanoma to RAF inhibitors.
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen
Purine Analogues Increase the Risk of Lethal and/or Prolonged COVID19 While Obinutuzumab Increases the Risk of Prolonged but Not Lethal Infection in Patients Treated for Lymphoid Malignancies –a Study of Krohem, the Croatian Group for Hematologic Diseases (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_5240;
Treatment regimens were divided into those containing purine analogues (PA), mainly bendamustine and fludarabine, standard-dose chemotherapy without PA (e.g. CHOP, CVP, chlorambucil, etc.), high-dose chemotherapy without PA (e.g. DHAP, ICE, etc.), B-cell receptor inhibitors (iBCR) and venetoclax...All of the 7 patients who received neither cytotoxic agents nor iBCR (4 were on rituximab monotherapy, 2 on cyclosporine and 1 on vemurafenib) recovered, none had prolonged infection...These drugs should probably be avoided in patients with indolent NHL and CLL, diseases for whom other effective treatments are available, during the current pandemia. Anti-CD20 monoclonal antibodies seem to have a smaller effect on mortality, with obinutuzumab increasing the risk of prolonged disease, but not of death, in comparison to rituximab.
- |||||||||| Zelboraf (vemurafenib) / Roche
Trial completion date, Trial primary completion date, Metastases: Vemurafenib Neoadjuvant Trial in Locally Advanced Thyroid Cancer (clinicaltrials.gov) - Nov 5, 2021
P2, N=24, Active, not recruiting,
While we have not observed any relapse to date, a longer follow-up is needed to assess durability of remission compared to purine nucleoside-treated cohorts. Trial completion date: Nov 2020 --> Sep 2023 | Trial primary completion date: Nov 2020 --> Sep 2022
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal, IO biomarker: Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance. (Pubmed Central) - Nov 4, 2021
Inhibiting exportin-1 or overexpressing Polκ increased the abundance of nuclear-localized Polκ, particularly in response to the BRAF-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAF melanoma cells...However, we found that the increased expression of Polκ was not excessively mutagenic, indicating that noncatalytic or other functions of Polκ could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Polκ might prevent drug resistance in some cancer cells.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ. (Pubmed Central) - Nov 4, 2021
Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib...In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition.
- |||||||||| Zelboraf (vemurafenib) / Roche
Enrollment open, Combination therapy, Metastases: Phase II Trial of Vemurafenib and Sorafenib in Pancreatic Cancer (clinicaltrials.gov) - Nov 2, 2021
P2, N=12, Recruiting,
To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition. Not yet recruiting --> Recruiting
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Clinical, FDA event, Review, Journal: Mini review: The FDA-approved prescription drugs that target the MAPK signaling pathway in women with breast cancer. (Pubmed Central) - Oct 31, 2021
The most common breast cancer drugs that regulate or inhibit the MAPK pathway may include Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide. In this review, we will discuss the roles of the MAPK/RAS/RAF/MEK/ERK pathway in BC and summarize the FDA-approved prescription drugs that target the MAPK signaling pathway in women with BC.
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