Encorafenib (Braftovi) in Combination With Binimetinib (Mektovi)

CADTH recommends that Braftovi in combination with Mektovi should be reimbursed by public drug plans for the treatment of unresectable or metastatic melanoma with a BRAF V600 mutation if certain conditions are met. Braftovi and Mektovi should only be reimbursed if used in combination and prescribed and monitored by clinicians with expertise in diagnosis and management of melanoma who are familiar with the toxicity profile associated with the Braftovi with Mektovi regimen and if it does not cost more than the least costly BRAF inhibitor and MEK inhibitor (BRAFi/MEKi) combination treatment. Braftovi with Mektovi should only be covered to treat adult patients with advanced or metastatic melanoma who have a BRAF V600 gene mutation that has been identified through a validated test. Patients who have not received previous treatment and patients whose disease has progressed after first-line immunotherapy are eligible for coverage.

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First-line treatment of NRAS-mutated metastatic melanoma with a MEK inhibitor

Journal of Cancer Research and Therapeutics ◽

10.4103/jcrt.jcrt_50_18 ◽

2019 ◽

Vol 0 (0) ◽

pp. 0

Author(s):

Marco Siano ◽

Angelika Bickel ◽

Stefan Diem ◽

Lukas Flatz ◽

Björn Stinn

Keyword(s):

Metastatic Melanoma ◽

Mek Inhibitor ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Encorafenib, binimetinib and cetuximab combined therapy for patients with BRAFV600E mutant metastatic colorectal cancer

Future Oncology ◽

10.2217/fon-2019-0748 ◽

2020 ◽

Vol 16 (6) ◽

pp. 161-173 ◽

Cited By ~ 3

Author(s):

Sanne CFA Huijberts ◽

Robin MJM van Geel ◽

Rene Bernards ◽

Jos H Beijnen ◽

Neeltje Steeghs

Keyword(s):

Growth Promotion ◽

Combined Therapy ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Current Treatment ◽

The Novel ◽

Efficacy And Safety ◽

First Line ◽

Metastatic Setting ◽

Mitogen Activated Protein

Approximately 10–15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.

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Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy

Case Reports in Oncological Medicine ◽

10.1155/2020/4392562 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Caitlyn N. Myrdal ◽

Srinath Sundararajan

Keyword(s):

Targeted Therapy ◽

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Objective Response ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Optimal Sequencing ◽

The Right

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.

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Association of concomitant use of acid reducing agents in full-dose vemurafenib users with risk of progression in BRAF V600 mutation-positive unresectable or metastatic melanoma patients: A retrospective cohort study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9540 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9540-9540

Author(s):

Lotte Marieke Knapen ◽

Rutger H.T. Koornstra ◽

Johanna H.M. Driessen ◽

Bas Van Vlijmen ◽

Sander Croes ◽

...

Keyword(s):

Cohort Study ◽

Metastatic Melanoma ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

First Line ◽

Full Dose ◽

Reduced Dose ◽

Increased Risk ◽

Risk Of Progression ◽

Braf V600 Mutation

9540 Background: Vemurafenib is used for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The approved fixed vemurafenib dose of 960 mg twice daily may result in overexposure. Concomitant use of acid reducing agents (ARAs) may result in underexposure. Both situations are likely to affect treatment outcome. Therefore, the aim of this study was to determine the association between the use of vemurafenib (full-dose versus reduced dose) and/or concomitant ARA use (yes versus no) and the risk of disease progression. Methods: A retrospective cohort study was conducted using data from the electronic health record software of the Radboudumc pharmacy and medical records of the Radboudumc (March 17th 2012 to March 17th 2016). Patients (N = 112) using vemurafenib as first line treatment for melanoma were included. Multivariable cox regression estimated adjusted hazard ratios (HRa) and 95% confidence intervals (CI) of progression in vemurafenib users (full-dose N = 67 versus reduced dose N = 45) and/or concomitant ARA users (N = 38). Adjustments were made for age and sex. Results: The mean follow-up time was 3.5 months and 41 patients (36.6%) developed progression on first line vemurafenib. Co-treatment of ARAs in patients using full-dose vemurafenib was associated with a 4.6-fold increased risk of progression (HRa 4.56; 95% CI 1.51-13.75) as compared to full-dose vemurafenib users not co-treated with ARAs. No increased risk was found for users of vemurafenib in a reduced dose, regardless of concomitant ARA use. Conclusions: Concomitant use of ARAs in full-dose vemurafenib users was associated with an increased risk of progression. Physicians should be cautious to prescribe ARAs to patients tolerating full-dose vemurafenib. The presence of considerable confounding by disease severity, the small number of events and the hypothesis generating character of this study emphasize the need to prospective validate these results.

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Abstract 422: Sequential targeted therapy and immunotherapy of a BRAF positive metastatic melanoma patient with BRAF inhibitor vemurafenib, MEK inhibitor cobimetnib and a novel PD-1 antibody Sintilimab

10.1158/1538-7445.am2021-422 ◽

2021 ◽

Author(s):

Yu Zhang ◽

Xiaomo Li ◽

Tonghui Ma ◽

Baoshan Cao

Keyword(s):

Targeted Therapy ◽

Metastatic Melanoma ◽

Melanoma Patient ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Metastatic Melanoma Patient

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PROCLAIM-001: A first-in-human trial to assess tolerability of the protease-activatable anti-PD-L1 Probody CX-072 in solid tumors and lymphomas.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3107 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3107-TPS3107 ◽

Cited By ~ 1

Author(s):

Alexander I. Spira ◽

Mark R. Middleton ◽

Aung Naing ◽

Karen A. Autio ◽

John J. Nemunaitis ◽

...

Keyword(s):

Solid Tumors ◽

Checkpoint Inhibitor ◽

Phase 1 ◽

Recombinant Antibody ◽

Braf Inhibitor ◽

Previous Treatment ◽

Mek Inhibitor ◽

Eligibility Criteria ◽

Part C ◽

Normal Tissues

TPS3107 Background: CX-072 is a novel Probody therapeutic (PbTx) targeting PD-L1. PbTxs are fully recombinant antibody prodrugs designed to be converted to active antibodies by tumor-associated proteases that are highly expressed malignant tissue; the PbTx remains largely inactive in normal tissues. In pre-clinical tumor models, a PD-L1-directed PbTx provided comparable anti-tumor efficacy to its parental anti-PD-L1 antibody, but displayed reduced auto-immunity in a model of Type 1 diabetes. Based on these pre-clinical data, CX-072 has the potential to enable combination therapies that are otherwise poorly tolerated. This Phase 1/2 study (PROCLAIM-001 (PRObody CLinical Assessment In Man) assesses the tolerability and antitumor activity of CX-072 in humans with an emphasis on immune-related adverse events, particularly in combinations. CX-072 will be administered as monotherapy (Part A), in combination with 2 schedules of ipilimumab (Parts B1 and B2) and in combination with vemurafenib (Part C). The expansion cohort (Part D) will include CX-072 monotherapy in PD-L1 responsive tumor types. Methods: Key eligibility criteria are as follows: Parts A and B1: checkpoint inhibitor-naive patients with advanced, refractory solid tumor or lymphoma (unmeasurable disease allowed) for whom approved PD agents are not available. Part B2: advanced, refractory solid tumors or lymphomas with measurable disease who have progressed on a previous treatment with a PD-(L)1 inhibitor, but did not discontinue due to toxicity. Part C: checkpoint inhibitor, BRAF-inhibitor and MEK-inhibitor-naïve metastatic V600E BRAF-mutated melanoma. Patients without an active autoimmune disease, ongoing infection, and ECOG PS 0-1 may be eligible to participate in the study. Dose escalation follows the 3+3 design in all arms. Ipilimumab (Parts B1 and B2) is dosed at the approved 3 mg/kg every 3 weeks x 4. The dose of vemurafenib (Part C) is 960 mg/kg twice daily. Exploratory biomarkers are used to characterize tumor protease activity, inflammatory changes within the tumor, and CX-072 activation in tumor versus peripheral blood. Clinical trial information: NCT03013491.

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P.022 Myasthenia gravis following dabrafenib and trametinib for metastatic melanoma

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.122 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S19 ◽

Cited By ~ 1

Author(s):

A Zaloum ◽

JR Falet ◽

A Elkrief ◽

C Chalk

Keyword(s):

Protein Kinase ◽

Myasthenia Gravis ◽

Metastatic Melanoma ◽

Mapk Pathway ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Proximal Muscle Weakness ◽

Proximal Muscle ◽

Mitogen Activated Protein

Background: Inhibitors of BRAF and MEK, enzymes in the mitogen-activated protein kinase (MAPK) pathway, are now widely used in the treatment of metastatic melanoma. We report a case of acetylcholine receptor (AChR) antibody-positive myasthenia gravis developing after exposure to dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Methods: A 68-year-old man presented with dysarthria, dysphagia, cough, dyspnea, and fever. Examination revealed fatigable ptosis and proximal muscle weakness. He had started dabrafenib and trametinib for metastatic melanoma two weeks prior. He was diagnosed with myasthenia gravis and superimposed aspiration pneumonia. AChR antibodies were positive. Dabrafenib and trametinib were stopped. He improved rapidly with pyridostigmine alone, and remained free of myasthenic symptoms for the next two months. Another course of dabrafenib and trametinib was given, and seven weeks later, his myasthenic symptoms recurred. Pyridostigmine produced only partial improvement, and treatment with intravenous immunoglobulin and prednisone was initiated. Results: We are unaware of prior reports of an association between BRAF/MEK inhibitors and seropositive myasthenia gravis. The development of myasthenic symptoms twice after BRAF/MEK inhibitor exposure suggests that the association is more than coincidental. Conclusions: Myasthenia gravis may be a complication of treatment of melanoma with dabrafenib and trametinib. The mechanism by which this occurs is unknown.

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Cobimetinib- and vemurafenib-induced granulomatous dermatitis and erythema induratum: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x19847358 ◽

2019 ◽

Vol 7 ◽

pp. 2050313X1984735 ◽

Cited By ~ 1

Author(s):

Marco AJ Iafolla ◽

Jennifer Ramsay ◽

Judy Wismer ◽

Elaine McWhirter

Keyword(s):

Case Report ◽

Side Effects ◽

Metastatic Melanoma ◽

Clinical Features ◽

Braf Inhibitor ◽

Mek Inhibitor ◽

Mek Inhibition ◽

Granulomatous Dermatitis ◽

Cutaneous Toxicities

Metastatic melanoma is an aggressive malignancy. Survival can be increased with the combination of BRAF and MEK inhibition. BRAF inhibitor-induced cutaneous toxicities can be attenuated with MEK inhibition. Here, we describe the first reported case of a patient with metastatic melanoma who developed granulomatous dermatitis and erythema induratum when treated with combination BRAF (vemurafenib) and MEK inhibitor (cobimetinib) therapy and discuss the clinical features and management of dermatologic side-effects secondary to BRAF +/– MEK inhibition.

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Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

Cancers ◽

10.3390/cancers11121950 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1950 ◽

Cited By ~ 8

Author(s):

Austin Greco ◽

Danish Safi ◽

Umang Swami ◽

Tim Ginader ◽

Mohammed Milhem ◽

...

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Randomized Clinical Trials ◽

Objective Response ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Braf Inhibitors ◽

Braf Mutations ◽

Mek Inhibitors

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens.

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