Diagnostic and prognostic role of long non-coding RNAs (lncRNAs) in metastatic melanoma patients with BRAF gene mutation receiving BRAF and MEK inhibitors.

Melanoma is a cancer with a high incidence rate that, despite the significant development of therapeutic options, still remains a major problem. The identification of biomarkers to select the right therapy for the right patient is one of the possibilities to improve the prognosis of patients. Potentially, the function of biomarkers could be played long non-coding RNAs (lncRNAs). The expression of selected 90 lncRNAs in serum from 30 metastatic melanoma patients with confirmed mutations in the BRAF V600 E or K gene was studied. Serum was collected prior to BRAF and MEK inhibitor therapy. The control group consisted of 16 healthy volunteers. A total of 41 lncRNAs were identified the expression of which differed statistically significantly between the patient group and the healthy volunteers. In addition, it was shown that the expression of HOXA3as (p = 0.033), PRINS (p = 0.036) and RNCR3 (p = 0.045) is higher in patients with the presence of CNS metastases, PFS inhibiting RNA (p = 0.048) is higher among patients with the presence of hepatic metastases, UCA1 (p = 0.008) expression is lower in patients with increased lactate dehydrogenase levels, while HOTAIRM1 (p = 0.044) and E2F4 antisense (p = 0.040) expression is lower in patients over 60 years of age. In addition, patients with high lincRNASFMBT2 expression showed longer median PFS (8.75 vs. 17.5 months, p = 0.0319) and OS (9.75 vs. 38 months (open observation, p = 0.0253). The obtained results require validation on a larger group of patients. If the results are confirmed, the indicated lncRNAs may play an important role as diagnostic and prognostic markers.

Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma.

BACKGROUND: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. METHODS: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. RESULTS: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. CONCLUSIONS: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.

Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study.

Background: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. Findings: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. Interpretation: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. Funding: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.

Melanoma: BRAFi Rechallenge.

Melanoma is the most aggressive type of skin cancer. Half of melanoma cases are characterized by the mutation BRAF V600. The case presented concerns a 41-year-old patient with locally advanced melanoma, being positive in mutation BRAF V600. The patient underwent surgery and received additional targeted therapy as part of a clinical study. In subsequent disease progression, immunotherapy was used. When the disease progressed again while the patient was in a good performance status, targeted therapy was administered again, and a good response was noted, making the patient reach a statistically significant overall survival, exceeding four years. Targeted therapy has proven to be an important tool in the treatment of melanoma. The use of BRAFi targeted therapy does not exclude the option of readministration at subsequent disease progression (BRAFi rechallenge). Preclinical models suggest that the resistance mechanism of cancer cells to BRAFi therapy bends, as these cell clones lose their evolutionary advantage after stopping BRAFi. Cell clones sensitive to BRAFi may then outcompete, making the treatment effective again. Therapeutical dilemmas in the management of patients with locally advanced melanoma that progresses to metastatic cancer are discussed.

Ongoing complete response after treatment cessation with dabrafenib, trametinib, and cetuximab as third-line treatment in a patient with advanced BRAFV600E mutated, microsatellite-stable colon cancer: A case report and literature review.

Metastatic BRAFV600E mutated colorectal cancer is associated with poor overall survival and modest effectiveness to standard therapies. Furthermore, survival is influenced by the microsatellite status. Patients with microsatellite-stable and BRAFV600E mutated colorectal cancer have the worst prognosis under the wide range of genetic subgroups in colorectal cancer. Herein, we present a patient case of an impressive therapeutic efficacy of dabrafenib, trametinib, and cetuximab as later-line therapy in a 52-year-old woman with advanced BRAFV600E mutated, microsatellite-stable colon cancer. This patient achieved a complete response after 1 year of triple therapy. Due to skin toxicity grade 3 and recurrent urinary tract infections due to mucosal toxicity, a therapy de-escalation to dabrafenib and trametinib was performed, and the double therapy was administered for further 41 months with ongoing complete response. For 1 year, the patient was off therapy and is still in complete remission.

The Pattern of Progression to First-Line Treatment with Dabrafenib and Trametinib in Patients with Unresectable or Metastatic, BRAF-Mutated, Cutaneous Melanoma: Results of the Observational T-WIN Study.

In patients with B-RAF-mutated cutaneous melanoma, targeted therapies are the treatment of choice to achieve a rapid response. In this multicentric, prospective, observational study, patients with B-RAF-mutated cutaneous melanoma who were treated with dabrafenib and trametinib were categorized in two cohorts (cohort A: limited disease (n = 104) and cohort B: bulky disease (n = 97)) according to lactate dehydrogenase levels. The primary endpoint was the progression pattern; the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety data. From baseline to time of progression, there was a progression from nodal to other sites of disease in cohort A and from skin and nodal to other sites in cohort B. In both the cohorts, the number of involved organs and metastases at each location decreased. The median OS was 32.4 months (95% CI: 20.1 months (not estimable)) for cohort A, and 10.5 months (95% CI: 8.3-14.4 months) for cohort B; median PFS was 12.4 months (95% CI: 10.9-17.0 months) for cohort A, and 8.1 months (95% CI: 6.3-9.4 months) for cohort B. No new safety signals were reported. This study describes the patterns of first-line treatment progression with dabrafenib and trametinib in Italian clinical practice. The effectiveness and safety data were consistent with previous trials and extended to a real-world heterogeneous population.

Multimodal integration of image, epigenetic and clinical data to predict BRAF mutation status in melanoma.

BACKGROUND: In machine learning, multimodal classifiers can provide more generalised performance than unimodal classifiers. In clinical practice, physicians usually also rely on a range of information from different examinations for diagnosis. In this study, we used BRAF mutation status prediction in melanoma as a model system to analyse the contribution of different data types in a combined classifier because BRAF status can be determined accurately by sequencing as the current gold standard, thus nearly eliminating label noise. METHODS: We trained a deep learning-based classifier by combining individually trained random forests of image, clinical and methylation data to predict BRAF-V600 mutation status in primary and metastatic melanomas of The Cancer Genome Atlas cohort. RESULTS: With our multimodal approach, we achieved an area under the receiver operating characteristic curve of 0.80, whereas the individual classifiers yielded areas under the receiver operating characteristic curve of 0.63 (histopathologic image data), 0.66 (clinical data) and 0.66 (methylation data) on an independent data set. CONCLUSIONS: Our combined approach can predict BRAF status to some extent by identifying BRAF-V600 specific patterns at the histologic, clinical and epigenetic levels. The multimodal classifiers have improved generalisability in predicting BRAF mutation status.

Atypical metanephric adenoma: Shares similar histopathological features and molecular changes of metanephric adenoma and epithelial-predominant Wilms' tumor.

Background: Metanephric adenomas (MAs) are rare, benign renal tumors. Wilms' tumors (WTs) are malignant embryonic tumors that originated from nephrogenic blastemal cells. However, some tumors have similar morphology to both MA and epithelial-predominant WT, which makes differential diagnosis difficult. We aimed to analyze the morphological, immunophenotypic and molecular changes in overlapping cases to explore their attribution. Methods and results: Twenty MAs, ten WTs, and nine cases with MA/WT overlapping histological features were studied. Twenty tumors demonstrated the typical morphological spectrum of MA with high cellularity and were composed of tightly packed small, uniform, round acini with a lower Ki67 index. Almost all MAs (94.7%, 18/19) were detected with BRAF V600E mutation. The ten WTs were epithelial-predominant WTs with glands, rosettes and glomerular structures, which also showed a higher Ki-67 index (up to 60%), invasive growth patterns, and a lack of BRAF mutation. However, the other nine overlapping cases showed two components: typical MA-like areas and epithelial WT-like areas. The cells of the WT-like areas were tubular, columnar and showed marked cytological atypia, with a Ki-67 proliferative index of up to 30%. The immunophenotype of these overlapping lesions was not significantly different from that of typical MA and they positively expressed WT1 and CD57. The BRAF V600E mutation was detected in both WT-like and MA-like areas in nine overlapping tumors. The follow-up data of 31 patients were analyzed, with a median follow-up time of 66 months (range, 8-45 months). Even though most patients with WT underwent radiotherapy or chemotherapy after surgery, two died, and one had liver metastasis. No MA or overlapping cases showed any evidence of recurrence or metastasis after surgery. Conclusions: The molecular changes in tumors with overlapping morphological features were the same as those of typical MA; thus, we think that these tumors should be classified as MA and further called atypical MA. It is important to note that atypical MA is not a neglected subtype of MA. It possesses different histological morphology and a higher Ki-67 index but has the common imaging characteristics, immunophenotype and gene expression as typical MA, and patients usually have a good prognosis.

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.

BACKGROUND: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. METHODS: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. RESULTS: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively. CONCLUSIONS: This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.

Case Report: Rechallenge With BRAF and MEK Inhibitors in Metastatic Melanoma: A Further Therapeutic Option in Salvage Setting?

BACKGROUND: The combination of BRAF and MEK inhibitors represents the standard of care treatment for patients with metastatic BRAF-mutated melanoma, notwithstanding the high frequency of emergent resistance. Moreover, therapeutic options outside clinical trials are scarce when patients have progressed after both targeted therapy and therapy with immune checkpoint inhibitors. In this article, we report our experience with targeted therapy rechallenging with BRAF and MEK inhibitors in patients with metastatic BRAF-mutated melanoma after progression with kinase inhibitors and immunotherapy. METHODS: Four patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitors after progression with targeted therapy and subsequent immunotherapy (checkpoint inhibitors). RESULTS: Two patients (one of them was heavily pretreated) had partial response over 36 months (with local treatment on oligoprogression disease) and 10 months, respectively. A third patient with multisite visceral disease and high serum levels of lactate dehydrogenase had a short-lived clinical benefit rapidly followed by massive progression of disease (early progressor). The fourth patient, currently on treatment with BRAF/MEK inhibitors, is showing a clinical benefit and radiological stable disease over 3 months of therapy. Adverse events were manageable, similar to those reported during the first targeted therapy; the treatment was better tolerated at rechallenge compared with the first treatment by two out of four patients.

Targeted Therapies for Melanoma.

The incidence of cutaneous malignant melanoma (CMM) is significantly increasing worldwide.[...].

Clinical Development of BRAF plus MEK Inhibitor Combinations.

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.

Matrix metalloproteinases MMP-1, MMP-2, and MMP-13 are overexpressed in primary nodular melanoma.

BACKGROUND: The spread and invasion of malignant melanoma cells involve degradation and reorganization of the extracellular matrix by the activation of several matrix metalloproteinases (MMPs). This study analyzed the expression of MMP-1, MMP-2, and MMP-13 proteins in primary nodular melanoma (NM) and dysplastic nevi (DN) as a significant risk factor for melanoma development. The secondary goal was to analyze the correlation of MMPs protein expression in NM with tumor invasion, BRAF V600 mutation status, and overall survival. METHODS: Immunohistochemistry for MMP-1, MMP-2, and MMP-13 was performed on nodular melanoma (n = 52) and dysplastic nevi (n = 28) on tissue microarray (TMA). BRAF V600 mutation analysis on NM samples was performed by the Sanger sequencing method. RESULTS: A high level of MMPs expression in NM samples (>30%) compared with DN (<8%) was statistically significant (P < 0.001). BRAF V600 mutations were detected in 15 of 39 (38.5%) NM samples. This study revealed an interesting finding that MMP-1 and MMP-13 protein expression in the BRAF V600 mutated melanomas were significantly lower than in the BRAF V600 wild type (P < 0.05). CONCLUSION: Cox analysis revealed that Clark categories, Breslow thickness, and MMP-1 high protein expression are predictive factors for shorter overall survival (P < 0.05).

Encorafenib and binimetinib for the treatment of BRAF V600E/K-mutated melanoma.

BRAF is a constituent of the mitogen-activated protein kinase (MAPK) signaling pathway, which serves to activate downstream MEK, and is one of the most commonly mutated oncogenes in human tumors. Indeed, BRAF V600 mutations are present in approximately 40% of metastatic melanoma tumors. Encorafenib (LGX-818, Braftovi) and binimetinib (MEK-162, Mektovi) are small-molecule inhibitors of BRAF and MEK, respectively. BRAF and MEK inhibitors have been shown to improve overall and progression-free survival among patients with metastatic melanoma. Of these inhibitors, encorafenib and binimetinib are the newest combination, which received approval by the Food and Drug Administration (FDA) for the treatment of BRAF V600E/K-mutated melanoma in June 2018. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of encorafenib and binimetinib in BRAF V600-mutated melanoma.

Low BRAF V600 mutation prevalence in primary skin nodular melanoma in Indonesia: a real-time PCR detection among Javanese patients.

BACKGROUND: Cutaneous melanoma is a rare, aggressive skin malignancy with a high mortality rate. Although only contributing 7.6% of the cases worldwide, Asia is responsible for 18.6% of deaths from cutaneous melanoma. BRAF V600 mutation presents a potential prognostic predictor in melanoma. Unfortunately, studies on that mutation in melanoma, particularly nodular subtype, in Indonesia are still scarce. This research aimed to investigate the prevalence of BRAF V600 mutation in primary skin nodular melanoma in Yogyakarta and Central Java, Indonesia. Its association with clinicopathological parameters was also analyzed. METHODS: Forty paraffin-embedded tissue samples from primary skin nodular melanoma cases in 2011-2018 were collected from the two biggest referral hospitals in Yogyakarta and Central Java, Indonesia. The BRAF V600 mutation status was assessed using qualitative real-time PCR and its associations with age, sex, anatomic location, lymph node metastasis, tumor thickness, ulceration, mitotic index, necrosis, lymphovascular invasion, and tumor-infiltrating lymphocytes were analyzed. RESULTS: BRAF V600 mutations were found in 4 (10%) samples. These mutations were significantly associated with the central (non-extremity) region (p = 0.013) and presence of lymphovascular invasion (p = 0.005). However, it was not associated with any other variables analyzed in this study. CONCLUSION: The prevalence of BRAF V600 mutation in Indonesian primary skin nodular melanoma cases is low and significantly associated with anatomic location and lymphovascular invasion. It is lower than prevalences in other Asian populations as well as in Caucasian populations and suggests that melanoma cases in Javanese people may have distinct clinicopathological characteristics from other Asian ethnicities.

An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system.

BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.

[Cobimetinib/vemurafenib-associated bilateral serous retinopathy: a case report]. / Cobimetinib­/Vemurafenib-assoziierte bilaterale seröse Retinopathie: ein Fallbericht.

Under a combination therapy with cobimetinib/vemurafenib for the treatment of BRAF-V600 positive metastatic melanoma, symptomatic or asymptomatic bilateral serous retinopathy can occur, which is reversible after dose reduction or treatment discontinuation. In the case presented the progress of bilateral serous retinopathy was documented by optical coherence tomography (OCT). After therapy discontinuation, subfoveal fluid levels varied until remission was reached six months later.

Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis.

BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety. METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months). RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAFV600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals.

Acute encephalopathy with combination dabrafenib/trametinib therapy.

Biomarkers have improved the clinical application of numerous targeted agents used to treat solid tumors. In melanoma, the finding that approximately 60% of tumor cells harbor specific Val600 mutations of BRAF has increased the likelihood of response to certain agents aimed at inhibiting the mutant kinase. While dabrafenib is an effective anti-tumor agent with acceptable tolerability in patients with BRAF-mutated melanoma, we report the development (and outcome) of a previously unpublished acute toxic reaction observed in a patient receiving the drug.

Dabrafenib in metastatic melanoma: a monocentric 'real life' experience.

Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3-4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts.