encorafenib and Skin-Neoplasms

Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI. In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time.. Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Despite the significant progress in the treatment of unresectable or metastatic. Targeted therapy, including BRAF- and MEK-inhibitors, and immunotherapies have greatly contributed to advances in the treatment of

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Skin Neoplasms; Sulfonamides

The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA).. A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted.. A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints.. This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Network Meta-Analysis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

Approximately 40-50% of patients with cutaneous melanoma harbor point mutations in. Encorafenib, a highly selective BRAF inhibitor, was developed in combination with binimetinib, a potent, selective allosteric MEK1/2 inhibitor, to improve efficacy and tolerability over other approved combo-targeted therapies. This novel combination shows peculiar pharmacodynamic properties which translate in a higher on-target potency and paradox index. Consistent survival improvements for encorafenib and binimetinib in. the favorable survival results and the attractive toxicity profile suggest that encorafenib and binimetinib combination is an intriguing standard option when targeted therapies are considered as first line treatment in BRAF mutated melanoma patients. In the near future, results from ongoing clinical trials will provide information on the use of this novel combination in specific situation, including as adjuvant treatment or as a combination strategy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Point Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Survival Rate

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Disease-Free Survival; Humans; Melanoma; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

This year again, several breaking news were published in our field of oncodermatology, especially in the domain of immunotherapy. Many works have reported results on predictive biomarker identification. Concerning melanoma treatment, we were disappointed by the negative results of the phase III trial evaluating the IDO1 inhibitor epacadostat + pembrolizumab versus pembrolizumab. However, many promising preliminary results involving the combinations of anti-PD1 and innate immunity activators have been published. We also have a new anti-BRAF + anti-MEK combination: encorafenib + binimetinib with a good benefit/risk ratio and a particularly favorable safety profile as compared with existing similar combinations. Major steps forward were obtained for locally advanced Merkel cell carcinoma and squamous cell carcinoma with anti-PDL-1 avelumab and anti-PD1 cemiplimab respectively.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Benzimidazoles; Biomarkers, Tumor; Carbamates; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Dermatology; Humans; Melanoma; Skin Neoplasms; Sulfonamides; Survival Analysis

Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT. Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.

Topics: Benzamides; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-kit; Pyridines; Skin Neoplasms; Sulfonamides; Thiazoles

Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for. A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged.. Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Prospective Studies; Proto-Oncogene Proteins B-raf; Skin Neoplasms

In COLUMBUS part 1, patients with advanced. In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety.. COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced. Patients with locally advanced unresectable or metastatic. Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.. In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lactate Dehydrogenases; Melanoma; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented.. COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma. In PART-I, 577 patients were randomised (1:1:1) to encorafenib plus binimetinib, encorafenib or vemurafenib. The primary objective was to assess progression-free survival. As a secondary objective, HRQoL was assessed by the EQ-5D, the EORTC QLQ-C30 and the FACT-M questionnaires. Furthermore, time to definitive 10% deterioration was estimated with a Kaplan-Meier analysis and differences in mean scores between groups were calculated with a mixed-effect model for repeated measures. Hospitalisation rate and the impact of hospitalisation on HRQoL were also assessed.. Patients receiving the combination treatment showed improvement of their FACT-M and EORTC QLQ-C30 global health status scores, compared to those receiving vemurafenib (post-baseline score differences: 3.03 [p < 0.0001] for FACT M and 5.28 [p = 0.0042] for EORTC QLQ-C30), indicative of a meaningful change in patient's status. Furthermore, a delay in the deterioration of QoL was observed in non-hospitalised patients compared to hospitalised patients (hazard ratio [95% CI]: 1.16 [0.80; 1.68] for EORTC QLQ-C30 and 1.27 [0.81; 1.99] for FACT-M) and a risk reduction of 10% deterioration, favoured the combination in both groups.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Quality of Life; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up.. In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups.. At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM.. Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Diarrhea; Disease-Free Survival; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Nausea; Outcome Assessment, Health Care; Prognosis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib; Vomiting

Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib.. Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated.. The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event.. Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies.. ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Fatigue; Female; Humans; Incidence; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Nausea; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib; Vomiting

Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF. COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator.. Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.. Array BioPharma, Novartis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Female; Humans; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Time Factors; Vemurafenib; Young Adult

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF. COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.. The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF. Array BioPharma, Novartis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Male; Melanoma; Middle Aged; Mutation; Phenotype; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Time Factors; Vemurafenib; Young Adult

Topics: Carbamates; Cetuximab; Humans; Nevus, Pigmented; Skin Neoplasms

Immune checkpoint inhibitors (ICIs) and targeted treatments have improved the health outcomes of patients with advanced melanoma. However, due to the high cost of novel therapies, it is crucial to evaluate their value by considering both effectiveness and cost. To compare the cost-effectiveness of these novel agents (atezolizumab-vemurafenib-cobimetinib, vemurafenib-plus-cobimetinib, dabrafenib-plus-trametinib, and encorafenib-plus-binimetinib) for first-line treatment of metastatic melanoma with the BRAF. A patient-level model was developed to project the health outcomes of 4 strategies for patients with advanced melanoma. We estimated transition probabilities from the IMspire150 (ClinicalTrials.gov, NCT02908672), COMBI-AD (NCT01682083), and COLUMBUS (NCT01909453) trials using a parametric survival model. All health outcomes, including direct cost, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER), were estimated from the US payer perspective. Lifetime cost, QALYs, life-years (LYs), and ICERs were calculated. Univariable and probabilistic sensitivity analyses were performed to test model robustness, along with multiple scenario analyses.. Of the 4 competing strategies, atezolizumab-vemurafenib-cobimetinib produced the best health outcomes, and the vemurafenib-cobimetinib strategy was the least expensive option. Atezolizumab-vemurafenib-cobimetinib, dabrafenib-plus-trametinib, and vemurafenib-cobimetinib formed the cost-effective frontier, indicating that the ordered ICERs were $325,113/QALYs for dabrafenib-plus-trametinib vs. vemurafenib-cobimetinib strategies and $2,247,500/QALYs for atezolizumab-vemurafenib-cobimetinib vs. dabrafenib-plus-trametinib strategies. Encorafenib-plus-binimetinib was dominated by the other 3 competing strategies. The drug price and first-line utility significantly influenced the model utcomes.. For BRAF-mutant advanced melanoma, the vemurafenib-cobimetinib strategy could be considered the most cost-effective treatment at the willingness-to-pay threshold of $150,000.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Humans; Immune Checkpoint Inhibitors; Melanoma; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Lactate Dehydrogenases; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides

Encorafenib is a BRAF inhibitor increasingly used as a second-line treatment for metastatic melanoma and colorectal cancer. BRAF inhibitors have been reported to be associated with new and changing melanocytic lesions, including eruptive naevi. We describe two cases of eruptive naevi secondary to encorafenib used for the treatment of BRAF-mutant metastatic colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbamates; Colonic Neoplasms; Exanthema; Humans; Mutation; Nevus, Pigmented; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; Skin Neoplasms; Sulfonamides

Malignant melanoma is a malignant tumor with a poor prognosis. From 2010 the discovery of mutation of BRAF and the development of drugs against this target significantly improved the survival of these patients. The best results were achieved with the double inhibition of the MAPK pathway. There are 3 approved targeted therapies: vemurafenib and cobimetinib, dabrafenib and trametinib, encorafenib and binimetinib. They have similar efficacy, but different toxicity profiles. In this article, is critically review the case of a patient with metastatic melanoma treated with the combination encorafenib and binimetinib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

The efficacy of encorafenib plus binimetinib (E + B) combination therapy for BRAF-mutated advanced melanoma as second-line therapy and beyond is still unknown. In this report, we investigated 22 cases of BRAF-mutated advanced melanoma treated with E + B combination therapy. The objective response rate (ORR) for the total cohort was 68.4%. Notably, the ORR for the second-line and beyond cohort was 73.3%, suggesting that the therapeutic effect of E + B combination therapy is comparable with that of first-line targeted therapy. In contrast, overall survival and progress-free survival in our present cohort was worse than that in a previous clinical trial. Notably, although the incidence rate of severe adverse events was higher than that in a previous report, our present study suggested that E + B combination therapy is a well-tolerated antimelanoma regimen. Our present study suggested that the efficacy and safety profile of E + B combination therapy as a second-line therapy and beyond is comparable with that of first-line targeted therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Communicable Disease Control; COVID-19; Dose-Response Relationship, Drug; Drug Monitoring; Drug Overdose; Humans; Liver Function Tests; Long QT Syndrome; Male; Medication Therapy Management; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vomiting

Combination treatment with BRAF plus MEK inhibitors is a standard of care in patients with BRAF-mutant advanced melanoma. In addition to dabrafenib+trametinib and vemurafenib+cobimetinib, a new combination of BRAF and MEK inhibitors, encorafenib and binimetinib, was recently introduced into clinical practice. Encorafenib plus binimetinib achieved similar efficacy to that observed with previously available combinations, but incidence of some toxicities such as pyrexia and photosensitivity, which have a relevant impact on patients quality of life, is lower. In this article, the case of a patient who received encorafenib and binimetinib within the phase 3 trial COLUMBUS is presented and discussed, with a focus on the clinical management during the pandemic caused by SARS-CoV-2 virus.

Topics: Aged; Benzimidazoles; Carbamates; COVID-19; Drug Combinations; Female; Humans; Melanoma; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome

Topics: Acrylonitrile; Adult; Aniline Compounds; Carbamates; Extracellular Signal-Regulated MAP Kinases; Fluorescein Angiography; Fundus Oculi; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Mitogen-Activated Protein Kinases; Retina; Retinal Diseases; Skin Neoplasms; Subretinal Fluid; Sulfonamides; Tomography, Optical Coherence

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

Metastatic melanoma is often accompanied by the development of brain metastases, at presentation or during the course of therapy. Local therapies such as surgery and radiation have been considered standard treatments for intracranial disease. However, the emergence of systemic therapies has been changing the treatment paradigm for the management of brain metastases. In patients with BRAF-mutated melanoma, combined BRAF and MEK inhibition has been found to elicit significant clinical responses. Patients who develop resistance to MAP kinase (MAPK) targeted therapy can achieve significant responses upon rechallenge. In this case, a 68-year-old woman with metastatic melanoma who had received multiple treatment courses including combination immunotherapy and combination MAPK-targeted therapy presented with a brainstem metastasis and demonstrated a complete response upon initiation of encorafenib and binimetinib, thereby obviating the need for stereotactic radiosurgery.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Brain Neoplasms; Carbamates; Female; Humans; Melanoma; Proto-Oncogene Proteins B-raf; Radiosurgery; Skin Neoplasms; Sulfonamides

Type I hypersensitivity reactions (HSR) to dabrafenib are rare but have been previously described. We present a case where a 72-year-old woman with recurrent, metastatic BRAF-mutated melanoma developed a type I HSR to dabrafenib. We, therefore, developed a desensitization protocol with encorafenib, a similar class agent, to allow the patient to continue with treatment. Patients with a history of HSR to dabrafenib may be considered for encorafenib desensitization when other therapeutic options are limited.

Topics: Aged; Carbamates; Female; Humans; Melanoma; Neoplasm Recurrence, Local; Skin Neoplasms; Sulfonamides

Topics: Aged; Androstadienes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Carbamates; Female; Humans; Mastectomy; Mastectomy, Segmental; Melanoma; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neoplasms, Unknown Primary; Radiotherapy; Skin Neoplasms; Sulfonamides

Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen-activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well-known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab-resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C-X-C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult-onset Still's disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug Resistance, Neoplasm; Female; Fever; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Nivolumab; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Treatment Outcome

Nearly 50% of patients with metastatic melanoma harbor a BRAFV600-mutation, which can be targeted with the use of BRAF and MEK inhibitors, either in the front-line or treatment-refractory setting. Encorafenib is the newest BRAF-inhibitor to have received FDA-approval in combination with the MEK inhibitor binimetinib.. The authors provide an overview of the preclinical development and the clinical trials that led to the use of encorafenib in BRAFV600-mutant melanoma. They also give discussion on its current use in clinical practice, providing their expert perspectives on the subject.. Preclinical research has provided strong rationale for upgrading encorafenib investigation into clinical development/testing. However, there is not yet enough data to determine where encorafenib may fit in comparison to other drugs in the same class, and ongoing trials will further define its role in the treatment of melanoma. Of note, there are ongoing studies that further explore the role of encorafenib + binimetinib such as in combination regimens with immunotherapy drugs, and in brain metastases.

Topics: Animals; Carbamates; Drug Development; Drug Discovery; Drug Evaluation, Preclinical; Humans; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

Topics: Acute Disease; Benzimidazoles; Carbamates; Female; Humans; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Tumor Lysis Syndrome

The advent of BRAF and MEK inhibitors changed the landscape of the management of BRAF mutated melanoma patients. In this article, we report the case of a 51-year-old man with BRAF mutated locally advanced cutaneous melanoma of the head who demonstrated a limited response to initial anti-BRAF monotherapy followed by extensive surgery. Anti-PD1 therapy failed to reverse the disease progression. However, subsequent double inhibition of the BRAF and MEK pathways induced a fast and remarkable tumour response.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug Resistance, Neoplasm; Humans; Lymph Node Excision; Male; MAP Kinase Kinase 1; Margins of Excision; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Inhibitors of BRAF, a gene coding a protein called B-raf, with or without inhibitors of MEK (MAPK/extracellular signal-regulated kinase) are often used as palliative treatment in BRAF-mutated metastatic melanoma. Recent data show improved progression-free survival with encorafenib with binimetinib, a newer BRAF/MEK inhibitor combination, compared with older agents, but there have been no reports of this treatment in the setting of renal and liver failure. We report a patient with disease-induced transaminitis and renal failure requiring dialysis who was successfully treated with encorafenib and binimetinib. His transaminitis improved and he was able to stop dialysis without any significant adverse effects during treatment, suggesting encorafenib with binimetinib may be used safely and effectively even in patients with end organ damage.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Liver Neoplasms; Male; Melanoma; Middle Aged; Proto-Oncogene Proteins B-raf; Renal Insufficiency; Skin Neoplasms; Sulfonamides

B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib).. The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib.. Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature.. The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%).. Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.

Topics: Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Drug Eruptions; Female; Hand-Foot Syndrome; Humans; Keratosis; Male; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

Topics: Adult; Carbamates; Humans; Male; Melanoma; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin; Skin Aging; Skin Neoplasms; Sulfonamides

Patients with advanced melanoma have a poor prognosis. Since the discovery of BRAF mutations in cutaneous melanoma, new pharmacological agents have been developed to inhibit this target. Although the survival of patients with advanced melanoma has improved with BRAF inhibitors, the emergence of drug resistance and the high incidence of cutaneous side effects represent important limitations. The aim of our study was to compare the incidence of cutaneous side effects between BRAF inhibitor monotherapy and BRAF and MEK inhibitor combination therapy in our cohort of patients. This study was a longitudinal prospective observational study. The study population comprised 83 patients with advanced cutaneous melanoma presenting with BRAF V600 mutation. The inclusion criteria included: age above 18 years, metastatic cutaneous melanoma or melanoma with high risk of metastasis, the presence of BRAF V600 mutation, and treatment with BRAF inhibitors or a combination of BRAF and MEK inhibitors. The majority of patients developed skin toxicity during treatment. The most common cutaneous side effects were localized hyperkeratosis and verrucous keratosis. Other cutaneous side effects observed were photosensitivity, squamous cell carcinoma, and keratoacanthoma. Our results indicate that cutaneous side effects are generally observed during BRAF inhibitor monotherapy and are significantly different from those observed in patients treated with combination therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinases; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Oximes; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Diseases; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Adult; Antineoplastic Agents; Carbamates; Drug Substitution; Humans; Imidazoles; Indoles; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.

Topics: Apoptosis; Carbamates; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Enzyme Activation; Heterocyclic Compounds, 2-Ring; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

LGX818 is a new-generation BRAF inhibitor (BRAFi) that is currently undergoing phase 3 trials for the treatment of BRAF mutant metastatic melanoma patients (NCT01909453). Cutaneous toxicities associated with the administration of BRAF inhibitors are considered to be induced by the paradoxical activation of the mitogen-activated protein kinase pathway in wild-type BRAF cells. Changes in naevi, including new naevi, hyperpigmentation and fading of existing naevi, have also been reported. In addition, some patients receiving these therapies have developed second primary melanomas. As a consequence, the importance of sequential digital dermoscopy in all patients treated with a BRAFi to detect new primary melanomas has been emphasized. A 61-year-old man with BRAF mutant stage IV metastatic melanoma was commenced on the phase 1 trial of LGX818 at 300 mg daily in 2013. After 2 months of therapy, the patient was noted to have developed eruptive naevi, fading of existing naevi and darkening of other naevi. Excision of a new pigmented lesion from the back indicated a compound naevus. Immunohistochemistry showed that the naevus cells lacked a BRAF V600E mutation. This is the first reported case of eruptive naevi in a patient treated with LGX818. The absence of the BRAF V600E mutation within a changing naevus supports the theory that BRAFi stimulates the proliferation of wild-type BRAF cells. Close dermatological surveillance is important for all patients treated with any type of BRAFi.

Topics: Antineoplastic Agents; Carbamates; Dermatology; Dermoscopy; Humans; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Nevus, Pigmented; Pigmentation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides

Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy.. Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials. Ten and 150 days after treatment start respectively, the patients developed painful nodules on the legs. In addition, one patient developed symmetrical articulation pain and intermittent fever episodes.. Based on the clinical and histological presentation, erythema nodosum-like panniculitis was diagnosed in both cases. No other aetiology could be found. After receiving topical or oral steroid treatment and anti-inflammatory analgesics, the painful nodular lesions disappeared several weeks later. In one case, a rebound of the painful nodules was observed when the combination treatment (dabrafenib and trametinib) was resumed after a 1-week unscheduled treatment interruption.. Panniculitis has previously been described in association with BRAF inhibitor treatment, but not MEK inhibitor treatment. Combination treatment is usually associated with a lower incidence of cutaneous adverse events (AEs), as compared to monotherapy. Panniculitis was observed in two patients during combined BRAF and MEK inhibitor treatment. These cases illustrate the need for further research in a larger patient population to identify a possible link between combined BRAF and MEK inhibitor treatment and the incidence of panniculitis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinases; Oximes; Panniculitis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides