- |||||||||| Zelboraf (vemurafenib) / Roche
[VIRTUAL] Outcomes of BRAF Mutated vs. Wild Type Tumors in Melanoma Brain Metastasis (McCormick Place West, Outside Room W375) - Oct 30, 2021 - Abstract #ASTRO2021ASTRO_2208;
Further studies need to be done to determine effectiveness of treatments within each cohort, as well as to control for other patient variables such as KPS/ECOG, number of lesions, and extra-cranial metastasis. Overall Survival Outcomes for Melanoma Brain Metastasis Patients
- |||||||||| Zelboraf (vemurafenib) / Roche
Trial completion date, Trial primary completion date, Metastases: A Phase I/II Trial of Vemurafenib and Metformin to Melanoma Patients (clinicaltrials.gov) - Oct 29, 2021
P1/2, N=55, Recruiting,
Overall Survival Outcomes for Melanoma Brain Metastasis Patients Trial completion date: Jun 2019 --> Jun 2027 | Trial primary completion date: Jun 2018 --> Jun 2025
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Outcomes of BRAF Mutated vs. Wild Type Tumors in Melanoma Brain Metastasis. (Pubmed Central) - Oct 29, 2021
BRAF mutation status alone does not have a significant effect on OS or PFS in patients with MBM. Further studies need to be done to determine effectiveness of treatments within each cohort, as well as to control for other patient variables such as KPS/ECOG, number of lesions, and extra-cranial metastasis.
- |||||||||| Zelboraf (vemurafenib) / Roche
[VIRTUAL] ERDHEIM-CHESTER SYNDROME: A REPORT OF AN UNKNOWN INCIDENCE CASE () - Oct 27, 2021 - Abstract #HEMO2021HEMO_725;
Erdheim-Chester disease (CED) has approximately 1,500 known cases since 1930. It is characterized by infiltration of foamy CD68+ and CD1a- histiocytes into tissues. Activating mutations of the MAPK pathway are present in more than 80% of cases; BRAF-v600e pathway in 57% to 70% of cases; followed by MAP2K1 in 20% of cases. BRAF is one of three members of the RAF family of serine/threonine kinases (ARAF, BRAF and CRAF) whose protein products are effectors of the MAPK pathway. BRAF mutations facilitate genomic instability, increasing the power of cell differentiation and, consequently, infiltration, which enhances the process of cell differentiation and suppression of apoptosis of mutated cells. Several proto-oncogenes are part of this pathway, which can be stimulated by virtually all classical growth factors and is overactive in 30% of all human tumors. DEC, in most cases, has a high-grade course, being fatal, especially when there is multisystem involvement. The prevalence of the disease is >55 years, male with a 3:1 ratio. DEC has tropism for long bones, retroperitoneum, cardiovascular system, central nervous system and eyes, so the manifested symptoms are the most diverse. In bone manifestations, present in up to 95% of patients, an inflammatory sign is the most common, which culminates in pain in the lower limbs, the treatment is symptomatic. Cardiovascular alterations, present in 40% of cases, on MRI, aortic involvement by amorphous tissue is common, being generally asymptomatic. When infiltration occurs in the coronary arteries, in about 23% of cases, it is similar to coronary stenosis. Dx is performed by means of anatomopathological examination and biopsy immunohistochemical markers, observing Touton giant cells and CD68+, CD163+, FXIIIa+ and CD1a- markers. Treatment is with autologous hematopoietic stem cell transplantation, protocols with IFN- and with vemurafenib. The search was retrospective in the patient's electronic medical record. For example, a 52-year-old male patient, seen at a neurology clinic. Previously healthy patient, started with episodes of progressive frontoparietotemporal headache for 6 months and with associated symptoms of nausea, vomiting, vertigo, diplopia and ataxia. He denies B symptoms, but reports a weight loss of 30 kg during this period. To evolution, Broca's aphasia. No other changes. On clinical neurological examination, mydriatic and isophotoreactive pupils, horizontal nystagmus, without EOM deficit. Central paralysis of the face and soft palate on the left, with deviation of the uvula in the same direction. Positive Romberg on the right. On cranial MRI, bilateral ventricular dilatation without midline deviation. Expansive lesion on the left, at the cerebellopontine angle, extending to the foramen magnum, compressing the brainstem and adjacent structures. Biopsy of the lesion was performed. Immunohistochemistry CD68 (+) and CD1a (-). In consultancy with the institution's hematology service. Based on the findings, they indicate a proliferation of a histiocytic nature, concluding a diagnosis for Erdheim-Chester disease. The treatment administered was IFN-α / PEG-IFN-α and the chemotherapeutic agent vemurafenib. Due to the late diagnosis, the patient evolved with significant neurological worsening. Therefore, the earlier the diagnosis, the better the prognosis despite the aggressiveness of the disease. Patient remains in follow-up.
- |||||||||| cladribine / Generic mfg.
[VIRTUAL] ERDHEIM-CHESTER DISEASE (ECD): A RARE ETIOLOGY OF OBSTRUCTIVE ACUTE ABDOMEN IN A YOUNG PATIENT () - Oct 27, 2021 - Abstract #HEMO2021HEMO_724;
Several therapeutic options can be used to control the disease, including corticosteroids, radiotherapy, interferon-α, purine analogues (2Cda or DCF), mono/polychemotherapy, and targeted drugs such as vemurafenib and dabrafenib.Objective To report one case of atypical presentation of ECD, manifested as acute obstructive abdomen in a patient under 20 years-old.Case report An 18-year-old woman, with no previous comorbidities, sought medical service at the HC-FMUSP due to abdominal pain, abdominal distension, and stopping of the elimination of gases and feces...She started therapy with cladribine (2-Cda) 5 mg/m2, I.V., D1-D5, 30/30 days, for six cycles...Although it has a mutation that works as a target for specific therapeutic intervention (BRAF inhibitors), these drugs are unavailable in the context of the Brazilian Public Health System. Thus, our patient underwent conventional cytotoxic treatment, with manageable toxicity and excellent therapeutic response.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Braftovi (encorafenib) / Ono Pharma, Pierre Fabre, Pfizer, Zelboraf (vemurafenib) / Roche
Clinical, Journal: BRAF-inhibitor therapy related encephalitis in a patient with metastatic melanoma. (Pubmed Central) - Oct 27, 2021
Thus, our patient underwent conventional cytotoxic treatment, with manageable toxicity and excellent therapeutic response. This is the first known report of a patient who has developed encephalitis due to treatment with BRAF-inhibitors.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness. (Pubmed Central) - Oct 25, 2021
Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells' aggressiveness.
- |||||||||| Koselugo (selumetinib) / Merck (MSD), AstraZeneca, Zelboraf (vemurafenib) / Roche
Preclinical, Journal, Microsatellite instability, MSi-H Biomarker: Chemotherapeutic effects of MEK kinase inhibitor and BRAF kinase inhibitor on KRAS-mutated human colon cancer cell lines with different microsatellite instability. (Pubmed Central) - Oct 22, 2021
The underlying synergistic cytotoxic efficacy of AZD/PLX combination on KRAS-mutated colon cancer cells with different MSI status was further substantiated by markedly decreased phosphorylation of ERK in both LS74T and SW480 cell lines upon AZD and PLX treatment. Based on these collective data, we propose that MSI status should be considered when MEK kinase inhibitor or BRAF kinase inhibitor is treated for KRAS-mutated colon cancer, and that combination of both inhibitors synergistically inhibit proliferation of KRAS-mutated colon cancer cells independent of MSI status.
- |||||||||| Mekinist (trametinib) / Novartis, Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Clinical, Review, Journal: Panniculitis during BRAF inhibitor and/or MEK inhibitor therapy: A new case report and literature review (Pubmed Central) - Oct 20, 2021
When panniculitis occurs during BRAF±MEK inhibitor therapy, the causal role of the TT must be considered after full etiological investigation. It is essential to determine whether a causal relationship exists in order to avoid unwarranted cessation of treatment.
- |||||||||| [VIRTUAL] AKI with BRAF and MEK Inhibitors May Not Be a Class Effect () - Oct 17, 2021 - Abstract #KIDNEYWEEK2021KIDNEY_WEEK_1350;
This case demonstrates that renal toxicity from BRAF and MEK inhibitor may not be a class effect and may also be dose dependent. It may be possible to consider a dose reduction or switch to another medication in the same class if renal toxicity is noted.
- |||||||||| Zelboraf (vemurafenib) / Roche
[VIRTUAL] Role of Off-Target Ferrochelatase Inhibition in Vemurafenib Nephrotoxicity (Simulive) - Oct 17, 2021 - Abstract #KIDNEYWEEK2021KIDNEY_WEEK_840;
Furthermore, these findings suggest that along with vemurafenib, other drugs that inhibit FECH activity might cause nephrotoxicity. Together, the present study describes the development of novel experimental models of vemurafenib nephrotoxicity and reveals the underlying off-target mechanisms that contribute to renal injury.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Journal: Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition. (Pubmed Central) - Oct 14, 2021
Conditioned media obtained from healthy dermal fibroblasts or CAFs modulated the MM cell's response differently to the treatment: while supernatants from healthy fibroblasts potentialized the efficiency of drugs on MM, those from CAFs tended to increase cell survival. Our data indicate that the secretory profiles of fibroblasts influence MM sensitivity to the combined vemurafenib and cobimetinib treatment and highlight the need for 3D in vitro cocultures representing the complex crosstalk between melanoma and CAFs during preclinical studies of drugs.
- |||||||||| Zelboraf (vemurafenib) / Roche, Yervoy (ipilimumab) / Ono Pharma, BMS
Journal: Current Advancements and Novel Strategies in the Treatment of Metastatic Melanoma. (Pubmed Central) - Oct 13, 2021
Thus, this review attempts to evaluate the therapeutic efficacy of current advancements in metastatic melanoma treatment by surveying new research into the molecular and cellular basis of treatments along with their clinical efficacy. In addition, this review aims to elucidate novel strategies that are currently being used and have the potential to be used in the future.
- |||||||||| Journal, PD(L)-1 Biomarker: BRAF L597K mutation: an opportunity to treat. (Pubmed Central) - Oct 9, 2021
Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab...In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018...Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.
- |||||||||| BLZ-945 / Novartis, BMS, Zelboraf (vemurafenib) / Roche
Journal: Epithelioid glioblastoma with microglia features: Potential for novel therapy. (Pubmed Central) - Oct 8, 2021
Treating E-GBM-derived tumor cells with the BRAF-V600E inhibitor, PLX4032 (vemurafenib), resulted in a dose-dependent reduction in cell viability that was amplified by addition of the CSF-1R inhibitor, BLZ945. The present case provides insight into the cellular nature of E-GBM and introduces several possibilities for effective targeted therapy for these patients.
- |||||||||| Mekinist (trametinib) / Novartis, Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Journal: Single-cell trajectories of melanoma cell resistance to targeted treatment. (Pubmed Central) - Oct 1, 2021
The single-cell transcriptomic analyses reported here employed a spectrum of bioinformatics methods to identify mechanisms of melanoma resistance to single- and double-agent treatments. This study deepens our understanding of treatment-induced cellular reprogramming and plasticity in melanoma cells and identifies targets of potential relevance to the management of treatment resistance.
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen, Zelboraf (vemurafenib) / Roche
Enrollment closed: A Phase II Study of the BRAF Inhibitor, Vemurafenib, Plus Obinutuzumab in Patients With Previously Untreated Classical Hairy Cell Leukemia (clinicaltrials.gov) - Sep 27, 2021
P2, N=30, Active, not recruiting,
This study deepens our understanding of treatment-induced cellular reprogramming and plasticity in melanoma cells and identifies targets of potential relevance to the management of treatment resistance. Recruiting --> Active, not recruiting
- |||||||||| karonudib (TH1579) / Oxcia, Helleday Foundation
Journal: AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma. (Pubmed Central) - Sep 24, 2021
Finally, TH1579 in combination with BRAF inhibitor exhibited a more potent cell killing effect in BRAF mutant cells both in vitro and in vivo. In summary, we show that TH1579-mediated efficacy is independent of BRAF/NRAS mutational status but dependent on the expression of AXL and CAV-1.
- |||||||||| Mekinist (trametinib) / Novartis, Zelboraf (vemurafenib) / Roche
[VIRTUAL] HORMAD1 Contributes to the Development of Squamous Cell Carcinomas in Melanoma Patients () - Sep 21, 2021 - Abstract #ESDR2021ESDR_492;
Our results suggest that HORMAD1 likely plays a key role in the development of SCCs by increasing genomic instability and proliferation in normal keratinocytes following BRAFi monotreatment. The increased risk of SCC formation is attenuated by dampening HORMAD1 levels with the co-administration of the MEKi, trametinib.
- |||||||||| All good things come in threes - only with the 3rd targeted combination system therapy with BRAF / MEK inhibition free of skin symptoms - case report (Stream 6) - Sep 20, 2021 - Abstract #ADO2021ADO_272;
Because of the resulting pulmonary metastasis, the patient switched to targeted therapy with dabrafenib (BRAF inhibitor / BRAFi) and trametinib (MEK inhibitor / MEKi) for BRAF-positive malignant melanoma...Since the symptoms recurred despite halving the dose, the targeted therapy was switched to vemurafenib (BRAFi) and cobimetinib (MEKi)...Therapy with encorafenib (BRAFi) and binimetinib (MEKi) was therefore initiated...Therapy with encorafenib (BRAFi) and binimetinib (MEKi) was therefore initiated...Therapy with encorafenib (BRAFi) and binimetinib (MEKi) was therefore initiated...The most common forms of acneiform or maculopapular rash, benign and malignant epithelial tumors and plantar hyperkeratoses. However, the characteristics and severity of the side effects - including those affecting the skin - differ for the various BRAF and MEK inhibitors, so that (also) a (multiple) change to another combination can be effective.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
Deep remission of a metastatic V600E-mutated melanoma despite therapeutic toxicity thanks to optimized sequential therapy (Stream 3) - Sep 20, 2021 - Abstract #ADO2021ADO_237;
Background : Targeted therapies with BRAF and MEK inhibitors for metastatic malignant melanoma with evidence of a BRAF mutation, as well as the combined immune checkpoint blockade (ICI) with the CTLA-4 antibody ipilimumab and the PD-1 antibody nivolumab, are an integral part of the therapeutic spectrum with a characteristic side effect profile...Therapy with vemurafenib / cobimetinib was well tolerated after dose reduction in diarrhea and conjunctivitis...This led to another substance class change - a therapy with encorafenib / binimetinib...Conclusion : With a sequential therapeutic approach and switching between targeted therapy and combined ICI, a long-lasting and deep remission can be achieved and at the same time compromising toxicity can be avoided. The right time to change therapy and the order of the sequence remain to be discussed.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
Side effect management in SJS / TEN overlap syndrome after BRAF / MEK inhibition in metastatic melanoma (Stream 3) - Sep 20, 2021 - Abstract #ADO2021ADO_231;
The patient had received ipilimumab and nivolumab immediately before a challenge with vemurafenib and cobimetinib...It remains to be seen whether our patient reacted directly to the BRAF / MEK inhibition or whether such a severe reaction was only possible after sensitization through the anti-CTLA-4 / PD-1 antibody therapy. The case presented here also shows
- |||||||||| The combined BRAF and MEK therapy as a new therapeutic approach for NRAS-mutated melanoma (Stream 4) - Sep 20, 2021 - Abstract #ADO2021ADO_110;
In summary, these results show that the combination with a BRAFi enhances the moderate antiproliferative and pro-apoptotic properties of the MEKi in NRAS mutated mellanoma cell lines. The results thus represent a promising new therapeutic approach that should be investigated in further in vitro experiments and clinical studies.
- |||||||||| Xalkori (crizotinib) / Pfizer, Nexavar (sorafenib) / Bayer, Amgen, Zelboraf (vemurafenib) / Roche
Clinical, Journal: Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers. (Pubmed Central) - Sep 19, 2021
These results dissect the role of the miR-211-DUSP6-ERK5 axis in melanoma tumor growth and suggest a mechanism for the development of drug-resistant tumors and a target for overcoming resistance. Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.
- |||||||||| Enrollment open: NeoACTIVATE: Vemurafenib, Cobimetinib, Atezolizumab, and Tiragolumab in Treating Patients With High-Risk Stage III Melanoma (clinicaltrials.gov) - Sep 16, 2021
P2, N=30, Recruiting,
Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors. Suspended --> Recruiting
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