Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.

BACKGROUND: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. METHODS: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. RESULTS: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32). CONCLUSION: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

Which adjuvant treatment for patients with BRAFV600-mutant cutaneous melanoma?

Treatment of patients with melanoma has considerably improved over the past decade and more recently with adjuvant therapies for patients with American Joint Committee on Cancer (AJCC) stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma, in order to prevent recurrence. In the adjuvant setting, two options are available to patients with BRAFV600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib). In the absence of comparative studies, it is difficult to determine which of these options is best. Our aim was to review published studies focusing on the management of patients with BRAFV600-mutant melanoma in the adjuvant setting. We also reviewed the main clinical trials of BRAF plus MEK inhibitors and immunotherapy in advanced (i.e. unresectable metastatic) BRAF-mutant melanoma in an attempt to identify results potentially affecting the management of patients on adjuvants. More adverse events are observed with targeted therapy, but all resolve rapidly upon drug discontinuation, whereas with immune checkpoint blockers some adverse events may persist. New therapeutic strategies are emerging, notably neoadjuvant therapies for stage III patients and adjuvant therapies for stage II patients; the place of the adjuvant strategy amidst all these options will soon be re-evaluated. The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings. This review will lead clinicians to a better understanding of the different adjuvant treatments available for patients with totally resected AJCC stage III and IV BRAFV600-mutant melanoma before considering subsequent treatment strategies.

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance.

BACKGROUND: Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. METHODS: Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression. RESULTS: We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects. CONCLUSION: PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib.

[Nodular cutaneous amyloidosis associated with Sjögren's syndrome]. / Amylose cutanée nodulaire et syndrome de Gougerot-Sjögren.

BACKGROUND: Cutaneous nodular amyloidosis is rare, and association with Sjögren's syndrome has been reported. We discuss the possible link between these two diseases based on a case we saw. PATIENTS AND METHODS: A 78-year-old woman with Sjögren's syndrome ongoing for 17 years presented for evaluation of a waxy infiltrated lesion on her left leg that had appeared 6 months earlier. Histopathological examination revealed a deposit of homogenous eosinophilic material throughout the dermis consistent with amyloidosis. Immunohistochemical study showed these deposits to be AL immunoglobin light chains. DISCUSSION: The association of cutaneous nodular amyloidosis and Sjögren's syndrome appears to be a distinct disease entity reflecting the polymorphic clinical spectrum of lymphoproliferative diseases related to Sjögren's syndrome.

[Auto-immune thyroiditis and drug reaction with eosinophilia and systemic symptoms (DRESS) associated with HHV-6 viral reactivation]. / Thyroïdite auto-immune et syndrome d'hypersensibilité médicamenteuse (DRESS) associés à une réactivation virale HHV6.

INTRODUCTION: DRESS syndrome is a severe adverse drug reaction with visceral involvement. Its physiopathology includes immunological disorders associated with human herpes virus (HHV) reactivation. We report two cases of auto-immune thyroiditis occurring in the context of DRESS syndrome associated with HHV-6 reactivation. OBSERVATIONS: Case 1 : A 39-year-old woman presented DRESS syndrome with HHV-6 reactivation, cutaneous, lymph node, hepatic and renal disorders treated with systemic corticosteroids for 10 months. Following discontinuation of the corticosteroids, she developed Graves's disease, which was stabilized with carbimazole and a beta-blocker. CASE 2: A 31-year-old woman was hospitalized for DRESS syndrome with delayed HHV-6 reactivation and severe hepatic involvement. She was successfully treated by topical steroids. Six weeks later, she presented De Quervain thyroiditis associated with moderate relapsing DRESS, which were treated by sodium levothyroxine and topical steroids. DISCUSSION: There is currently debate about the implication of viral reactivation, in particular HHV-6, in chronic DRESS, relapse and development of auto-immune diseases. These observations highlight the potential risk of patients developing auto-immune diseases and underline the need for prolonged clinical and laboratory follow-up of patients with DRESS.