The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma.

Abstract Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (…

Differential influence of vemurafenib and dabrafenib on patient lymphocytes despite similar clinical efficacy in melanoma

Background: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts’ immune system. Patients and methods: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. Results: Progression-free survival (PFS) as well as overall survival (O…

Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.

BackgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance.MethodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing.ResultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS o…

Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition.

Abstract Background Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results Among 173 BRAFV600-mutant …

Gebrauch von Komplementärmedizin bei Patienten mit metastasierendem Melanom unter Therapie mit Ipilimumab innerhalb einer klinischen Studie

Zusammenfassung Hintergrund und Ziel In Deutschland wenden 40–90 % aller Krebspatienten Methoden der komplementaren and alternativen Medizin (KAM) an. Bis dato gibt es kein Datenmaterial zum Einsatz der KAM bei Melanompatienten. Das Ziel unserer Studie war es, Daten uber den Gebrauch, die Informationsquellen und Ziele von Patienten mit metastasierendem Melanom zu erfassen. Patienten und Methoden Einhundertsechsundfunfzig Patienten aus 25 Studienzentren nahmen an der DecOG-MM-PAL Multibasket Studie teil. Die beteiligten Personen wurden auch gebeten, an einer Nebenstudie teilzunehmen, die ihren Gebrauch von KAM erfassen sollte. Dazu wurde wahrend der Behandlung ein standardisierter Fragebogen…

Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy.

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidence…

Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety.

Summary Background Even though progress has been made, the detection of melanoma still poses a challenge. In light of this situation, the Nevisense electrical impedance spectroscopy (EIS) system (SciBase AB, Stockholm, Sweden) was designed and shown to have the potential to be used as an adjunct diagnostic tool for melanoma detection. Objectives To assess the effectiveness and safety of the Nevisense system in the distinction of benign lesions of the skin from melanoma with electrical impedance spectroscopy. Methods This multicentre, prospective, and blinded clinical study was conducted at five American and 17 European investigational sites. All eligible skin lesions in the study were exami…

Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG

BackgroundImmune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment.MethodsThis multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted …

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival

Background: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. Patients and methods: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. Results: A total of 300 patients from 14 centers were included into this study with a median follow-up t…

A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy

Background: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. Objective: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean …

Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study

BackgroundCheckpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.MethodsMGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB–IV melanoma patients (discovery cohort: n=53, confirmation…

Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy – A multicentre study of 90 patients from the German Dermatooncology Group

Abstract Aim Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. Patients and methods Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. Results We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1–181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of I…

The genetic landscape of clinical resistance to RAF inhibition in melanoma.

11009 Background: Although single-agent RAF inhibition has proved effective in metastatic BRAFV600-mutant melanoma, most patients relapse and some are intrinsically resistant. While several genetic resistance effectors have been identified, a comprehensive assessment of the genetic resistance spectrum in a large patient cohort may further inform resistance patterns and treatment strategies. Methods: Pre-treatment and post-relapse biopsies were obtained from BRAFV600melanoma patients treated with vemurafenib or dabrafenib. Whole exome sequencing of tumor and normal samples was performed to identify exome-wide mutations, insertion/deletions, and chromosomal copy number alterations. Since som…

Hematological immune related adverse events after treatment with immune checkpoint inhibitors

Abstract Introduction With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes. Patients and methods Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres. Results In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amou…

Erythema nodosum-like lesions during BRAF inhibitor therapy: Report on 16 new cases and review of the literature.

Importance BRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation. Objective To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management. Design and Setting Retrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature. Results Sixteen patients were identified who developed erythema nodosum-…

1122P Real-world analysis of dabrafenib plus trametinib in patients with BRAFV600-mutated melanoma brain metastases

Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients

Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi). Results: The median duration of BRAFi treatment interruption prior to radiothera…

Electrical impedance spectroscopy as a potential adjunct diagnostic tool for cutaneous melanoma.

Background Previous studies have shown statistically significant differences in electrical impedance between various cutaneous lesions. Electrical impedance spectroscopy (EIS) may therefore be able to aid clinicians in differentiating between benign and malignant skin lesions. Objectives The aim of the study was to develop a classification algorithm to distinguish between melanoma and benign lesions of the skin with a sensitivity of at least 98% and a specificity approximately 20 per cent higher than the diagnostic accuracy of dermatologists. Patients/Methods A total of 1300 lesions were collected in a multicentre, prospective, non-randomized clinical trial from 19 centres around Europe. Al…