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Encorafenib and binimetinib were registered in 2018 for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The results of the phase III study (Columbus) are very promising. Median PFS for patients who have received this treatment was 14.9 months, and the median OS was 33.6 months. The reduction of toxicity is the reason for the unique pharmacokinetic profile of this therapy. Knowledge about the adverse evets is important in the context of optimizing and individualizing treatment.

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses encorafenib (Braftovi), 75 mg oral capsules in combination with binimetinib (Mektovi), 15 mg oral tablets. Indications: Braftovi (encorafenib) is indicated, in combination with binimetinib, for the treatment of patients with unresectable metastatic melanoma with a BRAF V600 mutation, as detected by a validated test. Mektovi (binimetinib) is indicated, in combination with encorafenib, for the treatment of patients with unresectable metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.

Despite the increasing role of immunotherapy, BRAF/MEK inhibitor combinations have still a central role in the treatment of BRAF V600-mutant melanoma. Encorafenib-binimetinib is the third BRAF-MEK inhibitor combination approved for the metastatic melanoma with BRAF V600 mutation. Data from phase III trial demonstrated high antitumor efficacy and good tolerability of encorafenib-binimetinib. Compared to other combinations (dabrafenib-trametinib, vemurafenib-cobimetinib) the new combination showed favourable results in terms of the low rates of pyrexia and photosensitivity. Trials with triplet regimens that combine encorafenib-binimetinib with immunotherapy or a third targeted agent in an effort to overcome mechanisms of resistance to BRAF/MEK inhibition are ongoing.

BACKGROUND: The diagnosis and treatment of Bethesda III thyroid nodules has always been controversial. Our aim is to study the value of puncture feeling combined with BRAF V600E mutation detection in the diagnosis of Bethesda III thyroid nodules in repeat fine needle aspiration (FNA). METHODS: From January 1, 2017 to December 31, 2021, a total of 1,114 thyroid nodules were included, of which Bethesda III thyroid nodules accounted for 12.1%. We analyzed the correlation between puncture feeling and postoperative pathology. Then, the diagnostic value of puncture feeling in Bethesda III thyroid nodules and the mutation rate of BRAF V600E in repeated FNA and its correlation with puncture feeling were analyzed. RESULTS: The results showed that there was a significant correlation between puncture feeling and postoperative pathology in the 1114 thyroid nodules (P

Simple Summary The incidence of cutaneous malignant melanoma is increasing worldwide. Despite available modern therapeutical options, long-term survival of patients in advanced stages of the disease remains rather limited until now. Detailed insights into etiopathogenesis and mechanisms of tumour progression enable physicians to manipulate distinct molecular structures and pathways therapeutically and so treat the tumour. Unfortunately, the acquisition of therapeutic resistance frequently terminates these therapeutical interventions. The presented special issue is focusing on the research and therapeutic experience of leading scientists, and it summarises the state of the art of targeted therapy of melanoma and suggests the new perspectives of the treatment of disease.

Mutations in the BRAF gene have been described to occur in two-third of melanomas. The objective of the study was to establish the frequency of BRAF V600E/K/R mutation in a series of melanomas from Indian origin and to correlate mutation status with clinicopathological features. Seventy melanoma cases were evaluated for BRAF V600 mutation by pyrosequencing. Overall, BRAF mutations were detected in 30% of the patients. All mutations observed were missense type (GTG > GAG) resulting in p.V600E, while none showed V600K/R mutation. The frequency of BRAF V600E mutations were more in patients with onset age of 50 years. BRAF mutations were significantly associated with tumor site wherein more mutations were seen in tumors from head and neck and extremities region. Acral and mucosal tumor subtype showed a mutation frequency of 31% and 20%, respectively. Epithelial cell morphology tends to harbor frequent BRAF V600E mutation (36%) than other morphological subtypes. Tumors with ulceration and necrosis showed increased BRAF mutation rate (32.5% and 33%) respectively. In conclusion, this is the first study to report a mutation frequency of 30% in this cohort. Our results demonstrated that the BRAF V600E mutation is a frequent event in Indian melanomas, and represents an important molecular target for novel therapeutic approaches.

Unter Kombinationstherapie mit Cobimetinib‑/Vemurafenib zur Behandlung des BRAF-V600-positiven metastasierten Melanoms kann es zu einer symptomatischen oder asymptomatischen bilateralen serosen Retinopathie kommen, die nach Dosisreduktion oder Absetzen der Therapie in der Regel reversibel ist. Im vorgestellten Fall wird mittels optischer Koharenztomographie (OCT) der Verlauf einer bilateralen serosen Retinopathie dargestellt: Nach Absetzen der Therapie kam es zu veranderlichen Spiegeln subfovealer Flussigkeit, bis sich nach sechs Monaten die Remission einstellte.

Objective BRAF is the most common mutation in melanoma. The most common subtype is BRAF V600E, followed by V600K. Initially, the authors aimed to investigate whether clinicopathological features of melanoma are associated with BRAF mutations. We then aimed to present the relationships between the clinicopathological features and the mutated subtype (V600E vs V600K). Material and method 61 patients with metastatic malignant melanoma (affecting the lymph node or other distant sites) were selected. Patient data regarding age at the time of diagnosis, sex, metastatic site (lymph node, distant metastasis or both) and primary tumour site were obtained from the hospital's database. Tissue samples containing at least 30% tumour cells were isolated from the specimens of 61 patients (24 samples from primary tumours and 37 from metastatic foci) for BRAF analysis. Comparisons between the BRAF V600 mutation and clinicopathological and histopathological features were performed. Results BRAF V600 mutation was detected in 34 (55.7%) patients. The subtype was BRAF V600E in 22 (64.7%) patients, BRAF V600K in 11(32.4%) patients and BRAF V600R in 1(2.9%) patient. The crucial results of the present study may be summarized as follows: i) BRAF V600 mutation was more common in older patients and tumors with BRAF V600 mutation revealed necrosis and LVI more commonly than wild-type tumors, ii) BRAF V600K mutation was more common in older patients and BRAF V600K mutated tumors exhibited ulceration more commonly than tumors with BRAF V600E mutation (close to significant). Conclusion The BRAF V600 mutation may have interactions with prognostic clinicoptahological features of melanoma including necrosis and lymphovascular invasion. V600K mutation may be more common than expected and may have different associations with properties of the tumor such as tumor ulceration and patient age. Investigation of the mutated subtype of the BRAF gene may therefore reveal more detailed data about the management of melanoma and may also prevent missing of candidates for BRAF inhibitor therapies.

Introduction The use of vemurafenib in melanoma has improved the survival of patients; however, it is associated with skin toxicities. Aim To assess skin toxicities by dermoscopy in patients treated with vemurafenib. Material and methods Eight patients with BRAF V600 mutation positive metastatic melanoma were examined dermoscopically during vemurafenib treatment. All skin lesions occurring during therapy were assessed clinically and dermoscopically using a hand-held dermoscope with polarised and non-polarised light. Skin lesions suspected for malignancy appearing during therapy were totally surgically excised with consecutive histopathological examination. Results All 8 examined patients developed skin toxicity. The majority of patients (7/8) presented G1 skin toxicity according to CTCAE version 4.3. Only 1 of them had G2 skin toxicity. The most common dermoscopy findings in our study were hyperkeratotic verrucas in 5 patients (5/8) with structureless pattern. In some of them we also observed central dots, exophytic proliferation, hairpin vessels and homogeneous haemorrhage. Other findings were hyperkeratosis of the nipples (5/8) with brownish to yellowish, angular clods with a tendency to be more confluent in dermoscopy. Palmar plantar erythrodysaesthesia (3/8) showed dermoscopically a yellowish, homogeneous pattern. Four melanocytic skin lesions in 2 patients were surgically excised due to suspected malignant transformation. In most of them we observed an atypical pigmented network (abrupt cut-off, big holes), atypical globules and a homogeneous blue pattern; however, histopathological diagnosis excluded any malignancy. Conclusions Dermoscopy seems to be an easily performed and valuable method for assessment of skin toxicities during oncological therapy, at any time of the treatment.

Introduction: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder associated with varied clinical presentations. Patients (pts) with advanced disease have frequent recurrences despite standard chemotherapy and a significant proportion experience long-term complications, including orthopaedic, endocrine, auditory, or neurodegenerative complications. BRAF V600 mutations have been reported in over 50% of LCH cases. The BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is approved for BRAF V600-mutation positive melanoma, NSCLC, and anaplastic thyroid cancer. Here we describe the pooled analysis of pts with LCH from two open-label phase I/II studies in pediatric pts with recurrent/refractory malignancies, treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). Results: At the data cut-off date of January 19, 2021, 13 pts with LCH had received dabrafenib monotherapy (n=2, escalation; n=11, expansion). Median age was 3 years (range, 1-11) and all pts had received prior chemotherapy (100%); one patient received prior immunoglobulin and prior anti-CD52 monoclonal antibody (8%). Median duration of exposure to dabrafenib was 51 months (range, 7-65); 7 pts continued treatment on a rollover study and 6 discontinued, due to adverse events (AE; n=2), investigator decision (n=3), or switch to combination therapy via compassionate use (n=1). All pts experienced AEs, regardless of relationship to treatment; 11 pts (85%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly vomiting (46%), increased creatinine (38%), dry skin, rash, and melanocytic naevus (each 30%). AEs led to treatment discontinuation in 2 pts (increased blood creatinine; Epstein-Barr virus associated lymphoma, not related to treatment); there were no on-treatment deaths. The overall response rate (ORR) was 77% (6 complete response [CR]; 4 regressive disease [RD]); median duration of response (DOR) was not reached (NR), the estimated 24-month DOR rate was 90% (95% CI, 40-100). Median PFS was NR; the estimated 24-month PFS rate was 90% (95% CI, 50-100). At the data cut-off date of February 10, 2021, 12 pts with LCH had received dabrafenib + trametinib combination (2, escalation; 10, expansion). Median age was 4 years (range, 2-13) and all pts had received prior chemotherapy (100%). Median duration of exposure to treatment was 22 months (range 1.8-35.9); 8 patients continued therapy on a rollover study and 4 discontinued, due to AEs (n=2), lack of efficacy (n=1), or long term CR (n=1). All pts experienced AEs; 9 pts (75%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly pyrexia (58%), diarrhoea, dry skin, decreased neutrophil count, and vomiting (each 42%). AEs led to treatment discontinuation in 2 pts (AST increased; ALT increased); there were no on-treatment deaths. The ORR was 58% (4 CR; 3 RD); median DOR was NR, the estimated 24-month DOR rate was 100% (95% CI, NR-NR). Median PFS was NR; the estimated 24-month PFS rate was 100% (95% CI, NR-NR). Conclusions: Dabrafenib, with or without trametinib, demonstrated durable efficacy in pediatric pts with relapsed/refractory BRAF V600E mutation-positive LCH, with 90-100% of responses ongoing at 24 months. Treatment was associated with acceptable tolerability and manageable toxicities; the safety profile was consistent with what has been seen in other pediatric indications and in adult studies. Disclosures Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Roughton: Novartis Pharma AG: Current Employment. Choi: Novartis Pharmaceuticals: Current Employment. Osterloh: Novartis Farmacéutica S.A. Spain: Current Employment. Russo: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hargrave: AstraZeneca; Bayer; DayOne; Janssen; Novartis; Roche: Consultancy; AstraZeneca: Research Funding; AstraZeneca; Bayer; Novartis; Roche: Honoraria; Bayer: Speakers Bureau. OffLabel Disclosure: Trametinib in combination with dabrafenib is approved for the treatment of unresectable/metastatic melanoma with BRAF V600E or V600K mutations; adjuvant treatment for melanoma with BRAF V600E or V600K mutations; metastatic non-small cell lung cancer with BRAF V600E mutation; locally advanced/metastatic anaplastic thyroid cancer with BRAF V600E mutation.

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 (

Incidence of melanoma has been constantly growing during the last decades. Although most of the new diagnoses are represented by thin melanomas, the number of melanoma-related deaths in 2018 was 60,712 worldwide (Global Cancer Observatory, 2019). Until 2011, no systemic therapy showed to improve survival in patients with advanced or metastatic melanoma. At that time, standard of care was chemotherapy, with very limited results. The identification of BRAF V600 mutation, and the subsequent introduction of BRAF targeting drugs, radically changed the clinical practice and dramatically improved outcomes. In this review, we will retrace the development of molecular-target drugs and the current therapeutic scenario for patients with BRAF mutated melanoma, from the introduction of BRAF inhibitors as single agents to modern clinical practice. We will also discuss the resistance mechanisms identified so far, and the future therapeutic perspectives in BRAF mutated melanoma.

e15527 Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.

Background: Determining the BRAF mutation status of patients with advanced metastatic melanoma is essential in order to assess patients' eligibility for targeted BRAF inhibitor therapy. The aim of this study was to validate the utility of immunohistochemistry (IHC) to rapidly obtain the BRAF status in the UK cancer centre setting. Methods: All samples sent for molecular testing for detection of the BRAF mutation over a 26-month period were prospectively tested using the VE1 monoclonal antibody IHC stain. Results: Two-hundred and nineteen samples from 214 patients were identified. All patients were AJCC stage III/IV, except one. There was an overall 95.0% (208/219) concordance rate, with a sensitivity of 94.4% (84/89) and a specificity of 95.4% (124/130) when using genomic assays as the gold standard. Discordance resulted from the inability of the molecular technique to detect the V600E2 mutation and an inability of the IHC staining technique to detect non-V600E mutations. Molecular testing on smaller tumour deposits was also unreliable. Conclusions: IHC staining has good sensitivity and excellent specificity for BRAF V600E mutations. BRAF IHC can be incorporated into a BRAF mutation testing algorithm for UK cancer centres to as a feasible first-line assay and identify a subset of cases that require subsequent genomic testing. It has the additional major advantages of reduced cost and rapid turnaround time.

The MAPK-ERK signaling cascade is among the most frequently mutated pathways in human cancer, with the BRAF V600 mutation being the most common alteration. FDA-approved BRAF inhibitors as well as combination therapies of BRAF and MEK inhibitors are available and provide survival benefits to patients with a BRAF V600 mutation in several indications. Yet non-V600 BRAF mutations are found in many cancers and are even more prevalent than V600 mutations in certain tumor types. As the use of NGS profiling in precision oncology is becoming more common, novel alterations in BRAF are being uncovered. This has led to the classification of BRAF mutations, which is dependent on its biochemical properties and affects it sensitivity to inhibitors. Therefore, annotation of these novel variants is crucial for assigning correct treatment. Using a high throughput method for functional annotation of MAPK activity, we profiled 151 different BRAF mutations identified in the AACR Project GENIE dataset, and their response to 4 different BRAF inhibitors- vemurafenib and 3 different exploratory 2nd generation inhibitors. The system is based on rapid synthesis of the mutations and expression of the mutated protein together with fluorescently labeled reporters in a cell-based assay. Our results show that from the 151 different BRAF mutations, ~25% were found to activate the MAPK pathway. All of the class 1 and 2 mutations tested were found to be active, providing positive validation for the method. Additionally, many novel activating mutations were identified, some outside of the known domains. When testing the response of the active mutations to different classes of BRAF inhibitors, we show that while vemurafenib efficiently inhibited V600 mutations, other types of mutations and specifically BRAF fusions were not inhibited by this drug. Alternatively, the second-generation experimental inhibitors were effective against both V600 as well as non-V600 mutations. Using this large-scale approach to characterize BRAF mutations, we were able to functionally annotate the largest number of BRAF mutations to date. Our results show that the number of activating variants is large and that they possess differential sensitivity to different types of direct inhibitors. This data can serve as a basis for rational drug design as well as more accurate treatment options for patients. Citation Format: Zohar Barbash, Dikla Haham, Liat Hafzadi, Ron Zipor, Shaul Barth, Arie Aizenman, Lior Zimmerman, Gabi Tarcic. A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1092.

10024 Background: Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for BRAF mutant metastatic melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens. Our aim was to better assess if BRAF mutation status has any impact on survival to combination ipilimumab/nivolumab (I/N) versus single-agent PD-1 inhibitor (PD-1i). Methods: We performed a single center, retrospective analysis on a cohort of patients diagnosed with metastatic or unresectable melanoma from 2012 to 2019 at the University of Michigan who were treated with standard I/N or PD-1i (nivolumab or pembrolizumab). A univariate analysis of progression free survival (PFS) and overall survival (OS) was stratified by treatment type and BRAF mutation status. A multivariate Cox regression of survival was used to compare the effects of the treatment groups adjusted by BRAF status, age, gender, pre-treatment LDH level, prior treatment status, and brain metastases status. Results: 323 patients were identified. 132 had BRAF V600 mutation and 191 had BRAF wildtype (WT) status. 138 patients received I/N and 185 patients received PD-1i. In our univariate analysis, there was no difference in PFS [HR: 0.72, 95% CI, 0.46 – 1.13] or OS [HR: 0.78, 0.44 – 1.38] with I/N versus PD-1i in the BRAF mutant cohort, but there was improved PFS [HR: 0.55, 0.35 – 0.88) and OS [HR: 0.52, 0.28 – 0.95] with I/N compared to PD-1i in the BRAF WT group. In the multivariate analysis, the BRAF WT group continued to show PFS benefit with I/N compared to PD-1i [HR: 0.57, 95% CI, 0.35 – 0.95], but the OS benefit no longer achieved statistical significance [HR: 0.54, 0.28 – 1.03]. Conclusions: Our study results were discordant with the observation in the landmark CheckMate 067 trial, which noted improved PFS and OS with I/N compared to nivolumab alone in the BRAF mutant group and no difference in the BRAF WT group. In our real-world retrospective analysis, I/N over PD-1i should be considered as initial immunotherapy for metastatic melanoma patients regardless of BRAF mutation status, but even more favorably in BRAF WT.

e22028 Background: The drug combination of BRAF inhibitors with MEK inhibitors delays the onset of resistance and enhances apoptosis. Objectives: The main objective was to evaluate the percentage of long responders to the combination therapy. Methods: Participants were patients with advanced melanoma harboring a BRAF V600 mutation, who received Cobimetinib + Vemurafenib as first line, and who started treatment at least 12 months before inclusion. Patients were classified as long responders (patients who have reached at least 12 months of objective response -complete response CR/ partial response PR- to the treatment) or non-responders. Sociodemographic, anthropometric, clinical characteristics, baseline tumor characteristics and treatment dose modification were compared between long responders and non-responders. HADS scale, WPAI-GH and SMAQ questionnaires were used to evaluate the anxiety and depression, productivity and treatment compliance respectively, in patients under active treatment at the moment of the study visit. Results: 41 patients were evaluated. Mean (±SD) age was 57.8 (14.0) years. 56.1% were male. Almost one third of the population (29,3%) was classified as long responder. There were no statistically significant differences in the baseline tumor characteristics, demographic data nor in the clinical characteristics neither in treatment dose modification. CR was the best response achieved by 29.3% of patients, 46.3% achieved PR and 12.2% SD (stable disease). Mean of time to response was 6.9 months for CR patient, and 3.3 and 2.2 months for PR and SD patients respectively. Mean of duration of response was 9.4 months for CR patients, and 10.1 and 9.5 months for PR and SD patients respectively. 42.5% of Adverse Events (AEs) were related with the combination treatment. In the 68.5% of AEs the severity was mild, and in 19.4% moderate. In most cases no action was taken (74.9%) and the outcome was recovered (83.4%). Conclusions: Vemurafenib and Cobimetinib have an important impact in long term survival, leading to a steady complete response in one third of the patients.

PURPOSE To study whether BRAF V600 mutations in non–small-cell lung cancer (NSCLC) may indicate sensitivity to the BRAF inhibitor vemurafenib, we included a cohort of patients with NSCLC in the vemurafenib basket (VE-BASKET) study. On the basis of observed early clinical activity, we expanded the cohort of patients with NSCLC. We present results from this cohort. METHODS This open-label, histology-independent, phase II study included six prespecified cohorts, including patients with NSCLC, and a seventh all-comers cohort. Patients received vemurafenib (960 mg two times per day) until disease progression or unacceptable toxicity. The primary end point of the final analysis was objective response rate (Response Evaluation Criteria in Solid Tumors, version 1.1). Secondary end points included progression-free survival, overall survival, and safety. Because the prespecified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. RESULTS Sixty-two patients with BRAF V600–mutant NSCLC were enrolled and treated: 13% (n = 8) had received no prior systemic therapy, and 87% (n = 54) had received prior therapies. The objective response rate was 37.1% (95% CI, 25.2% to 50.3%) overall, 37.5% (95% CI, 8.5% to 75.5%) in previously untreated patients, and 37.0% (24.3% to 51.3%) in previously treated patients. Median progression-free survival was 6.5 months (95% CI, 5.2 to 9.0 months), and median overall survival was 15.4 months (95% CI, 9.6 to 22.8 months). The most common all-grade adverse event was nausea (40%). The safety profile of vemurafenib was similar to that observed in melanoma studies. CONCLUSION Vemurafenib showed promising activity in patients with NSCLC harboring BRAF V600 mutations. The safety profile of vemurafenib was similar to previous observations in patients with melanoma. Our results suggest a role for single-agent BRAF inhibition in patients with NSCLC and BRAF V600 mutations.

As reported by Auliac et al., patients with BRAF-mutated non-small-cell lung cancer (NSCLC) have particular clinicopathologic features and prognosis. [...]

2i/v every 3 weeks. Mathematical modelling underlies this study. As a result it has been demonstrated that the use of vemurafenib strategy in treatment of metastatic melanoma in patients with BRAF V600 mutation had better progression-free survival (PFS) rate throughout the entire modelling horizon. The use of vemurafenib in treatment of metastatic and inoperable melanoma in patients with BRAF V600 mutation is economically advisable taking into account the data on effectiveness (PFS). The use of vemurafenib in patients with BRAF V600 mutation is an absolutely innovative medical technology which currently does not have any alternative. Vemurafenib may be indicated for inclusion in reimbursement lists for treatment of patients with this mutation.

Among brain tumors, the BRAF V600E mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF V600 mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (

Background: The genetic basis of melanoma affects its clinicopathologic characteristics and increasingly influences its management. B-Raf proto-oncogene, serine/threonine kinase gene (BRAF)-mutated melanoma may present with specific dermoscopic features. Objectives: To identify the dermoscopic features associated with BRAF mutation in cutaneous melanoma and to evaluate a model capable of predicting BRAF mutations on the basis of dermoscopic and clinicopathologic features that are easily accessible in normal clinical practice. Methods: A prospective, cross-sectional, observational, and descriptive study was performed. A total of 93 cutaneous melanomas with dermoscopic images from 93 patients were included. BRAF mutational status was determined by genetic analysis using 2 methods: cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Pleasanton, CA) and Sanger sequencing. Clinicopathologic data were collected; dermoscopic images were analyzed by 2 independent blind observers. Results: Blue-white veil in dermoscopy was significantly associated with BRAF mutations (odds ratio, 4.3; 95% confidence interval, 1.6-11.5; P=.003). Patients with BRAF-mutated melanomas were significantly younger than those with wild-type melanomas (odds ratio, 0.96; 95% confidence interval, 0.93-0.99; P=.008). On the basis of these 2 variables, it was possible to predict BRAF mutational status in melanoma with 73% accuracy. Limitations: Histologic data were obtained from pathology reports. The accuracy of the predictive model has not been tested with a new data set. Conclusions: Blue-white veil in dermoscopy is associated with BRAF mutations in cutaneous melanoma.