Megan Lyle

Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma

BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation. Paired biopsies available in one of the five patients showed reduced phospho-ERK signalling and this corresponded to a metabolic response on 18F-fluorodeoxyglucose-PET scanning. Trametinib toxicity was manageable. Trametinib has antitumour activity in patients with BRAF K601E and L597Q mutation-positive metastatic melanoma.

The Nature and management of metastatic melanoma after progression on BRAF inhibitors : effects of extended BRAF inhibition

The v‐raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor (BRAFi) drugs dabrafenib and vemurafenib have high response rates in BRAF‐mutant, metastatic melanoma; however, 50% of patients progress by 7 months. In this study, the authors examined the nature and management of disease progression (PD) on BRAFi treatment, including characteristics and outcomes of patients who received continued BRAFi treatment beyond disease progression (TBP).

Diagnosis and Treatment of KIT-Mutant Metastatic Melanoma

A 52-year-old man has unresectable locally recurrent melanoma of the left foot (Fig 1) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm(2). Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High-resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation.

Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

The degree of response and the duration of survival of patients treated with mitogen‐activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown.

The role of systemic therapies in the management of melanoma brain metastases.

Purpose of review Brain metastases in metastatic melanoma are highly prevalent and are associated with significant morbidity and a poor prognosis. Local therapy (surgery or radiotherapy) has been the mainstay of treatment, due in part to the lack of efficacy of systemic therapy. This review will focus on new systemic therapies for metastatic melanoma and their evolving role in the management of brain metastases. Recent findings BRAF inhibitors have demonstrated efficacy in active (i.e. untreated or progressing) brain metastases in BRAFV600 mutated metastatic melanoma. The cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, has also shown activity, particularly in asymptomatic metastases. Studies of programmed death 1/programmed death ligand 1 checkpoint inhibitors and combination BRAF and MEK inhibitor therapy in brain metastases are planned. Emerging evidence on the molecular biology of melanoma brain metastases, particularly the role of the phosphatidylinositol 3-kinase-AKT pathway, may identify additional therapeutic targets. Summary The development of systemic therapy effective in controlling both intra-cranial and extra-cranial melanoma metastases has resulted in a change in the paradigm of management. More research is required in patients with active brain metastases to improve patient outcomes, including studies early in the development of novel therapies, and studies to determine the safe and effective combination or sequencing of local and systemic therapies.

The molecular profile of metastatic melanoma in Australia.

Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713); 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described; however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.

Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma

This study evaluated patterns of response as discerned by comprehensive metastasis‐specific analysis in metastatic melanoma patients receiving anti‐PD‐1 antibodies. Bi‐dimensional measurements of every metastasis in patients enrolled in the KEYNOTE‐001 trial at a single institution were obtained at baseline and throughout treatment. Twenty‐seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm2 versus 760 mm2, p < .01) and occurred more frequently in the lungs (65% versus 39.4%, p < .01). Response was heterogenous (new/progressing metastases alongside CR metastases) at first assessment in 4/14 patients with objective response (OR) as opposed to 7/13 patients with non‐OR. CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early heterogeneity had a poor outcome.

Chapter 5 – Brain Metastases from Melanoma

Brain metastases are common in patients with metastatic melanoma and the majority of patients who die of the disease do so as a direct result of them. Not only does the diagnosis of brain metastasis signify a very poor prognosis, but it portends a severe impact on the patient’s quality of life. The major clinical problem of melanoma brain metastases has in the past been addressed by treatment with local therapies—surgery and radiation therapy—but the results have been unimpressive, with median survival times of just a few months reported in most series, little better than the survival times of patients offered supportive care only. However, in recent times more effective and less morbid techniques for both the surgical management of brain metastases and the treatment of them using new radiation therapy methodologies have been introduced and, at last, systemic therapies that can treat melanoma brain metastases effectively have been discovered. In this chapter the range of treatments now available to treat melanoma brain metastases will be discussed, outcomes achieved by their use will be presented, and the importance of a multidisciplinary approach to management of the problem will be emphasized.