Systemic Therapy For Metastatic Melanoma Research Articles

Fertility, teratogenicity, and contraception during therapy with BRAF/MEK inhibitors

Targeted mutation-based therapy with BRAF and MEK inhibitors has become an integral part of systemic therapy for metastatic melanoma in the advanced setting and for the adjuvant therapy of melanoma in stageIII after complete resection. Due to the increased chances of survival and early use in the adjuvant situation, fertility preservation as well as aspects of teratogenicity and pregnancy are increasingly relevant in patients who are often still young. To communicate the published and study-based information on fertility preservation, teratogenicity and pregnancy under therapy with BRAF and MEK inhibitors. Summaries of product characteristics as well as studies and case reports on BRAF and MEK inhibitors published in PubMed were used as sources of information. There are no specific preclinical studies or experience in humans on fertility, teratogenicity, and contraception with targeted therapy. Recommendations can only be derived from toxicity studies and individual case reports. Patients should be offered counseling on the options for fertility-protective measures before starting targeted therapy. Due to unclear teratogenicity, adjuvant melanoma therapy with dabrafenib and trametinib should not be initiated in pregnant patients. In the advanced metastatic situation, BRAF and MEK inhibitors should only be given after extensive interdisciplinary education and counselling of the pregnant patient and her partner. Patients should be informed about the need for adequate contraception during targeted therapy.

Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort

Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied. To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP). Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed. Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type. No record of standard diagnostic criteria of MUP used in the participating centers. Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies.

Health Care Utilization and Costs in Systemic Therapies for Metastatic Melanoma from 2016 to 2020.

Widespread implementation of immune checkpoint inhibitors (ICI) and targeted therapies for metastatic melanoma has led to a decline in melanoma-related mortality but increased healthcare costs. We aimed to determine how healthcare utilization varied by systemic, non-adjuvant melanoma treatment from 2016 to 2020. Adults with presumed stage IV metastatic melanoma receiving systemic therapy from 2016 to 2020 were identified in Optum, a nationwide commercial claims database. Treatment groups were nivolumab, pembrolizumab, ipilimumab+nivolumab (combination-ICI), or BRAF+MEK inhibitor (BRAFi+MEKi) therapy. Outcomes included hospitalizations, days hospitalized, emergency room (ER) visits, outpatient visits, and healthcare costs per patient per month (pppm). Multivariable regression models were used to analyze whether cost and utilization outcomes varied by treatment group, with nivolumab as reference. Among 2018 adult patients with metastatic melanoma identified, mean (SD) age was 67 (15) years. From 2016 to 2020, nivolumab surpassed pembrolizumab as the most prescribed systemic melanoma therapy while combination-ICI and BRAFi+MEKi therapies remained stable. Relative to nivolumab, all other therapies were associated with increased total healthcare costs (combination-ICI: β = $47 600 pppm, 95%CI $42 200-$53 100; BRAFi+MEKi: β = $3810, 95%CI $365-$7260; pembrolizumab: β = $6450, 95%CI $4420-$8480). Combination-ICI and BRAFi+MEKi therapies were associated with more inpatient hospital days. Amid the evolving landscape of systemic therapy for advanced melanoma, nivolumab monotherapy emerged as the most used and least costly systemic treatment from 2016 to 2020. Its sharp increase in use in 2018 and lower costs relative to pembrolizumab may in part be due to earlier adoption of less frequent dosing intervals.

Efficacy and tolerance of systemic therapies in metastatic melanoma of unknown primary versus known cutaneous: A multicenter retrospective study from the MelBase French Cohort.

9556 Background: Melanoma of unknown primary (MUP) account for 3% of all melanomas. Clinical outcome of advanced MUP in the era of novel therapies including immunotherapies (ICI) and targeted therapies (TT) have been only scarcely studied, whereas a possibly different biologic background might introduce changes in its management. Recent retrospective studies suggested that patients with advanced MUP could benefit at least as much from novel therapies as patients with known primary cutaneous melanoma (cMKP). Methods: Based on the nationwide MelBase prospective database (NCT02828202) this retrospective study included patients with advanced melanoma treated with first-line ICI, TT or CT. MUP was defined by upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. Patients with primary mucosal or ocular melanoma were excluded. Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary variables in MUP vs cMKP, stratified by treatment subset (ICI vs TT vs CT vs whole cohort). Secondary variable was treatment-related toxicity. Multivariate analyses and propensity score analysis were performed. Objective: To investigate the efficacy and safety of systemic treatments (ICI, TT and chemotherapy (CT)) in patients with advanced MUP comparatively to stage-matched cMKP. Results: A total of 1882 patients were analyzed, including 265 (14.1%) MUP. Most patients were treated with first-line ICI. Median follow-up was 16 months. Patients in the MUP cohort more often displayed unfavorable initial prognostic factors (Table). PFS and OS did not significantly differ in MUP compared to MKP patients (p=0.73 and p=0.93 respectively). Stratification of cohorts by treatment type and application of propensity score did not lead to data modification. Treatment-related toxicity rate and severity did not differ between MUP and MKP, regardless of treatment type. Conclusions: Our results suggest that advanced MUP should be managed with similar strategies as advanced MKP. In our cohort, MUP patients benefited from novel therapies as much as MKP patients despite less favorable baseline prognostic factors. Exploratory studies investigating mutational burden and host immunity are needed to identify the underlying mechanisms. [Table: see text]

Recurrence patterns in patients with Stage II melanoma: The evolving role of routine imaging for surveillance.

The relatively recent availability of effective systemic therapies for metastatic melanoma necessitates reconsideration of current surveillance patterns. Evidence supporting surveillance guidelines for resected Stage II melanoma is lacking. Prior reports note routine imaging detects only 21% of recurrent disease. This study aims to define recurrence patterns for Stage II melanoma to inform future surveillance guidelines. This is a retrospective study of patients with Stage II melanoma. We analyzed risk factors for recurrence and methods of recurrence detection. We also assessed survival. Yearly hazards of recurrence were visualized. With a median follow-up of 4.9 years, 158 per 580 patients (27.2%) recurred. Overall, most recurrences were patient-detected (60.7%) or imaging-detected (27.3%). Routine imaging was important in detecting recurrence in patients with distant recurrences (adjusted rate 43.1% vs. 9.4% for local/in-transit; p = .04) and with Stage IIC melanoma (42.5% vs. 18.5% for IIA; p = .01). Male patients also self-detected recurrent disease less than females (52.1% vs. 76.8%; p < .01). Routine imaging surveillance played a larger role in detecting recurrent disease for select groups in this cohort than noted in prior studies. In an era of effective systemic therapy, routine imaging should be considered for detection of asymptomatic relapse for select, high-risk patient groups.

Does body mass index really predict the response to systemic therapies in metastatic melanoma: A multicenter study from the MelBase French National Cohort?

10031 Background: Obesity is an established risk factor for several cancers and higher body mass index (BMI) is associated with poor prognosis. These data are still debated in melanoma. Furthermore, recently the concept of “obesity paradox” has emerged. In a large cohort published by McQuade JL et al, higher BMI was associated with better survival in patients with metastatic melanoma (MM) especially for those treated with targeted therapy (TT) and immune checkpoint inhibitors (ICI). We studied the association between BMI and progression-free survival (PFS) and overall survival (OS) in patients with MM treated with systemic therapies. Methods: This study was conducted from the prospective MelBase cohort (NCT02828202). Patients with MM treated with first-line ICI, TT, or CT were included. BMI was categorized by WHO criteria. Underweight patients were excluded. The co-primary outcomes were the associations between BMI and PFS or OS, stratified by treatment, sex and age. Multivariate analyses were performed. Results: A total of 1214 patients were analyzed. The majority of them were treated with ICI, followed by TT. Obese patients represented 22% of cohort (Table). Median follow-up was 13.5 months. The patients who were overweight or obese did not have different PFS (p = 0.88) or OS (p = 0.25) than patients with normal BMI. Stratifying this cohort by treatment received, age, sex and others parameters (such as LDH, number of metastatic site) did not revealed any difference. Multivariate analysis did not change the results. Conclusions: BMI was not associated with clinical outcomes in our cohort, especially in ICI and TT groups. Thus, we did not confirm the results presented by McQuade Jl et al. with a cohort quite similar in term of size. Because BMI is too simplistic and then an imperfect measure of body composition, the published data are not reproducible. We caution the oncologists, about BMI as valuable predictive marker of survival for melanoma patients. [Table: see text]

When is it OK to Stop Anti-Programmed Death 1 Receptor (PD-1) Therapy in Metastatic Melanoma?

Systemic therapy for metastatic melanoma has been revolutionized over the past decade with the development of highly effective immune checkpoint inhibition, specifically anti-Programmed Death1 receptor (PD-1) therapy. However, even though one-third of patients will have durable response to single-agent or combination therapy, the optimal duration of therapy is unknown. Identifying the optimal duration of therapy is important, as exposure to anti-PD-1 therapy increases the risk of developing immune-mediated toxicities that can have significant morbidity and are, at times, fatal. It has long been understood that patients with complete responses to high-dose interleukin-2 and ipilimumab typically maintain their responses after a brief treatment course; thus, it is important to better understand the data to help understand the optimal management of melanoma patients treated with anti-PD-1 therapy. The clinical data with anti-PD-1-based therapy and published data on the duration of therapy suggest that patients may not require a full 2years of anti-PD-1 therapy and that the risk of toxicity may be mitigated by further understanding the mechanisms and kinetics of response to therapy. Although novel markers to help guide therapeutic decision making are under investigation, there is an ongoing need to improve our tools to monitor response to therapy and disease activity.

Combined ipilimumab and nivolumab first-line and after BRAF-targeted therapy in advanced melanoma.

The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine-protein kinase B-Raf (BRAF)-targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment-naïve and 22% failed first-line BRAF/MEK inhibitors. Treatment-related adverse events occurred in 67% of patients, grade 3-5 in 38%. The overall objective response rate was 41%, 57% in treatment-naïve and 21% in BRAF/MEK failure patients. Median progression-free survival was 4.0months (95% CI, 3.0-6.0) in the whole cohort, 11.0months (95% CI, 6.0-NR) in treatment-naïve and 2.0months (95% CI, 1.4-4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real-world population. While first-line efficacy appears comparable to trial populations, BRAF-mutant patients failing prior BRAF/MEK inhibitors show less response.

Immunotherapy disparities in metastatic melanoma.

9525 Background: Historically, patients with advanced malignant melanoma had a dismal prognosis with an estimated median overall survival of nine months. Therapy response rates and long-term survival have significantly improved with the advent of immunotherapies and targeted chemotherapies. First approved in 2011, there has been subsequent development of more advanced immunotherapeutic agents and targeted chemotherapies, with continued improvement in median overall survival. We examined patterns in the use of immunotherapy and other systemic therapies for metastatic melanoma, as well as the demographic and socioeconomic predictors for the use of these therapies, in order to identify and understand potential barriers to access in the United States. Methods: We used the NCDB for all patients aged 18-years and older who were diagnosed with metastatic melanoma of cutaneous origin from 2004-2014. Patients were included if they had distant metastases or American Joint Committee on Cancer (AJCC) Stage IV. Sociodemographic data, including race, age, insurance status, facility providing care, Charlson/Deyo comorbidity score11, and education by patient’s zip code, were collected. Results: In patients under age 65 with a Charlson-Deyo score of zero, immunotherapy utilization ranged between 8.5–13.4% during 2004 to 2010. In 2011, the usage increased to 16.5% and rose every subsequent year to 29.6% in 2014. Patients were less likely to receive immunotherapy if they had no insurance, were of older age, or received care at a community practice rather than an academic center. Those who received immunotherapy had greater overall survival compared with those who did not. Conclusions: Immunotherapy and targeted agents have become standard of care in those with metastatic melanoma. Adoption of immunotherapy use for metastatic melanoma has been relatively slow despite evidence showing an overall survival benefit; our analysis suggests this is explained in part by socioeconomic barriers.

HSR19-095: Healthcare Resource Utilization and Costs in Patients Treated with Systemic Therapies in Metastatic Melanoma

Background: The treatment (tx) landscape for patients (pts) with metastatic melanoma (MM) has changed dramatically from systemic chemotherapy (chemo) to novel therapies, including targeted therapies (TT) and immunotherapies (IO mono- and combination therapy) in recent years. Healthcare resource utilization (HCRU) and cost data are needed to further evaluate tx in a value-based healthcare system. The study aimed to describe HCRU and total cost of care among first line (1L) US MM pts treated with IO, TT, or chemo. Methods: A retrospective observational study was conducted using a U.S. claims database. Adults with ≥2 claims for melanoma and ≥1 claim for metastasis between January 1, 2012 and June 30, 2017 were identified. Pts had pharmacy and medical enrollment ≥6 months pre and ≥3 months post 1L tx start. Per pt per month (PPPM) HCRU and costs were calculated by 1L tx drug class: PD-1, CTLA-4, CTLA-4+PD-1, mono-TT, combo-TT, and chemo. Adjusted odds ratios (OR) for HCRU were estimated by logistic regressions, and adjusted costs were estimated by generalized linear models to control for differences in pt characteristics across groups. Results: Among 1,599 MM pts (255 PD-1, 555 CTLA-4, 88 CTLA-4+PD-1, 210 mono-TT, 102 combo-TT, 389 chemo), mean age ranged from 59–68 years across tx groups, and the majority was male (62%). Any hospitalization during 1L was less frequent among PD-1 (26%) compared to 35%–46% of all other groups (all P&lt;.05). CTLA-4, CTLA-4+PD-1, and combo-TT had increased odds of hospitalization compared to PD-1 (adjusted ORs: 2.10, 2.35, 2.15, respectively; all P&lt;.05). Total adjusted PPPM costs were significantly lower for PD-1 compared to CTLA-4, CTLA-4+PD-1 and combo-TT and higher compared to mono-TT and chemo (Table 1). Conclusions: Hospitalizations represent an important healthcare resource for MM pts and were lowest among PD-1. Total monthly costs varied substantially across 1L regimens and were significantly lower in PD-1 compared to CTLA-4, CTLA-4+PD-1, and combo-TT. HCRU and costs differentiate 1L MM regimens.

NIVOLUMAB EXPERIENCE IN THE TREATMENT OF PRE-TREATED PATIENTS WITH METASTATIC SKIN MELANOMA

The appearance of anti-PD-1 drugs significantly improved prognosis of patients with metastatic skin melanoma. However, little data on the effectiveness of these drugs in the second and subsequent lines of therapy has been accumulated in the international literature. We have analyzed our experience in the use of nivolumab in the treatment of metastatic melanoma. This non-randomized, uncontrolled, continuous study included 53 patients with metastatic or unresectable melanoma, of whom 86.8 % (46) received two or more lines of systemic therapy for metastatic melanoma. The rate of objective response was 22.6 % (95 % Confidence Interval (CI) 53.3–64.4 %). The median progression-free survival was 4.37 months (95 % CI 2.27–6.47). The median overall survival was 17.9 months (95 % CI 8.89–26.99). One-, two-, three-year overall survival contained 66, 35 and 35 %, respectively. The efficacy of nivolumab in the second and subsequent treatment lines is significantly lower than showed in the results of randomized trials of the use of anti-PD-1 drugs in the first line of therapy.

Costs associated with adverse events for systemic therapies in metastatic melanoma.

To determine the costs of adverse events (AEs) associated with current metastatic melanoma (MM) therapies. Two retrospective cohort studies were independently conducted using the PharMetrics and MarketScan databases. Included patients were aged≥18years, and had ≥1MM diagnosis and ≥1 claim for systemic therapy from 2004 to 2015. A total of 1654 and 1329 patients were identified in PharMetrics and MarketScan, respectively. The corresponding adjusted 30-day incremental costs of AEs by category were highest for CNS/psychiatric (US$21,277 and $18,739), gastrointestinal ($18,534 and $15,648), respiratory ($17,338 and $17,064), cardiovascular ($16,083 and $15,430), hematological/lymphatic ($14,997 and $15,538) and metabolic/nutritional AEs ($12,340 and $17,251). The costs of AEs associated with systemic therapies for MM are substantial.

Circulating Tumor DNA Analysis and Functional Imaging Provide Complementary Approaches for Comprehensive Disease Monitoring in Metastatic Melanoma.

Circulating tumor DNA (ctDNA) allows noninvasive disease monitoring across a range of malignancies. In metastatic melanoma, the extent to which ctDNA reflects changes in metabolic disease burden assessed by 18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is unknown. We assessed the role of ctDNA analysis in combination with FDG-PET to monitor tumor burden and genomic heterogeneity throughout treatment. We performed a comprehensive analysis of serial ctDNA and FDG-PET in 52 patients who received systemic therapy for metastatic melanoma. Next-generation sequencing and digital polymerase chain reaction were used to analyze plasma samples from the cohort. ctDNA levels were monitored across patients with mutant BRAF, NRAS, and BRAF/NRAS wild type disease. Mutant BRAF and NRAS ctDNA levels correlated closely with changes in metabolic disease burden throughout treatment. TERT promoter mutant ctDNA levels also paralleled changes in tumor burden, which provide an alternative marker for disease monitoring. Of note, subcutaneous and cerebral disease sites were not well represented in plasma. Early changes in ctDNA and metabolic disease burden were important indicators of treatment response. Patients with an early decrease in ctDNA post-treatment had improved progression-free survival compared with patients in whom ctDNA levels remained unchanged or increased over time (hazard ratio, 2.6; P = .05). ctDNA analysis contributed key molecular information through the identification of putative resistance mechanisms to targeted therapy. A detailed comparison of the genomic architecture of plasma and multiregional tumor biopsy specimens at autopsy revealed the ability of ctDNA to comprehensively capture genomic heterogeneity across multiple disease sites. The findings highlight the powerful role of ctDNA in metastatic melanoma as a complementary modality to functional imaging that allows real-time monitoring of both tumor burden and genomic changes throughout therapy.

Association of Surgical Treatment, Systemic Therapy, and Survival in Patients With Abdominal Visceral Melanoma Metastases, 1965-2014

Systemic therapy for metastatic melanoma has evolved rapidly during the last decade, and patient treatment has become more complex. To evaluate the survival benefit achieved through surgical resection of melanoma metastatic to the abdominal viscera in patients treated in the modern treatment environment. This retrospective review of the institutional melanoma database from the John Wayne Cancer Institute at Providence St Johns Health Center, a tertiary-level melanoma referral center, included 1623 patients with melanoma diagnosed as having potentially resectable abdominal metastases before (1969-2003) and after (2004-2014) advances in systemic therapy. Overall survival (OS). Of the 1623 patients identified in the database with abdominal melanoma metastases, 1097 were men (67.6%), and the mean (SD) age was 54.6 (14.6) years. Of the patients with metastatic melanoma, 1623 (320 [19.7%] in the 2004-2014 period) had abdominal metastases, including 336 (20.7%) with metastases in the gastrointestinal tract, 697 (42.9%) in the liver, 138 (8.5%) in the adrenal glands, 38 (2.3%) in the pancreas, 109 (6.7%) in the spleen, and 305 (18.8%) with multiple sites. Median OS was superior in surgical (n = 392; 18.0 months) vs nonsurgical (n = 1231; 7.0 months) patients (P < .001). The most favorable 1-year and 2-year OS was seen after surgery for gastrointestinal tract (52% and 41%) and liver (51% and 38%) metastases, respectively. Multivariable analysis found increasing age (hazard ratio [HR], 1.01; 95% CI, 1.00-1.01; P = .02) and the presence of ulceration (HR, 1.21; 95% CI, 1.01-1.45; P = .04) were associated with a worse OS. Alternatively, treatment with metastasectomy (HR, 0.59; 95% CI, 0.46-0.74; P < .001) and metastases involving the gastrointestinal tract (HR, 0.65; 95% CI, 0.48-0.87; P = .004) were associated with a better OS. The systemic treatment era did not significantly affect outcomes (HR, 0.82; 95% CI, 0.67-1.02; P = .15). Overall, patients with gastrointestinal tract metastases undergoing complete, curative resection derived the greatest benefit, with a median OS of 64 months. To our knowledge, this series is the largest single-institution experience with abdominal melanoma metastases, demonstrating that surgical resection remains an important treatment consideration even in the systemic treatment era.

Costs associated with adverse events for systemic therapies in metastatic melanoma.

9560Background: Current systemic therapies of metastatic melanoma (MM) include immunotherapy, target therapy (if BRAF mutated), high-dose IL-2, and chemotherapy, all of which are associated with di...

Melanoma: immune checkpoint blockade story gets better

The 10-year survival for patients with metastatic melanoma is less than 10%. 1 Balch CM Gershenwald JE Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27: 6199-6206 Crossref PubMed Scopus (3603) Google Scholar After decades of failed attempts to improve treatment outcomes in patients with this disease, 2 Bhatia S Tykodi SS Thompson JA Treatment of metastatic melanoma: an overview. Oncology. 2009; 23: 488-496 PubMed Google Scholar the recent successes with ipilimumab and the inhibitors of BRAF and MEK (vemurafenib, dabrafenib, and trametinib) have ushered in a new era in systemic therapy. 3 Bhatia S Thompson JA Systemic therapy for metastatic melanoma in 2012: dawn of a new era. J Natl Compr Canc Netw. 2012; 10: 403-412 PubMed Google Scholar , 4 Hodi FS O'Day SJ McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-723 Crossref PubMed Scopus (10966) Google Scholar , 5 Chapman PB Hauschild A Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364: 2507-2516 Crossref PubMed Scopus (6022) Google Scholar , 6 Flaherty KT Infante JR Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367: 1694-1703 Crossref PubMed Scopus (2101) Google Scholar , 7 Flaherty KT Robert C Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367: 107-114 Crossref PubMed Scopus (1681) Google Scholar These breakthroughs have not only provided more treatment options for patients with melanoma, but have also spurred the investigation of a new generation of drugs for cancer therapy. In The Lancet, Caroline Robert and colleagues 8 Robert C Ribas A Wolchok JD et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; (published online July 15.)http://dx.doi.org/10.1016/S0140-6736(14)60958-2 PubMed Google Scholar report the results of programmed-death-receptor-1 (PD-1) blockade with pembrolizumab (MK-3475) in patients with melanoma previously treated with an anti-cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4) antibody ipilimumab; these findings are another important advance in the rapidly evolving landscape of cancer immunotherapy. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trialThe results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. Full-Text PDF

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

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. BRAF inhibitors have demonstrated efficacy in active (i.e. untreated or progressing) brain metastases in BRAF 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. 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.

Surveillance for brain metastases in patients receiving systemic therapy for advanced melanoma.

The objectives of this study were to determine the cumulative incidence and timing of new brain metastases over the course of systemic therapy for metastatic melanoma and to identify prognostic factors for brain metastases. Chemo-naive patients underwent computed tomography or MRI of the brain every 6 weeks. The cumulative incidence of confirmed brain metastases was calculated at 12-week intervals. Univariable and multivariable competing risk regression models were used to assess the association between the development of brain metastases and potential risk factors of interest. Cumulative incidence with competing risk and competing risk regression was used to assess the brain metastasis-free interval from the time of diagnosis of stage IV disease. The clinical characteristics of the 315 patients with brain metastases were compared with those of 370 brain metastasis-free patients. Among patients with brain metastases, a significantly higher proportion had stage M1b and M1c disease at diagnosis compared with stage M1a and a greater proportion had metastatic disease in three or more visceral sites. Significantly shorter brain metastasis-free intervals were found in these patients compared with patients with M1a disease and those with no visceral metastases. More than 80% of the 230 patients who developed brain metastases during systemic therapy had their brain metastases confirmed within 60 weeks from the onset of advanced melanoma. Imaging studies at 12-week intervals for 60 weeks after the diagnosis of advanced melanoma will detect brain metastases in most of the patients who will eventually develop them.

A Single-Arm, Open-Label, Expanded Access Study of Vemurafenib in Patients With Metastatic Melanoma in the United States

This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

Treatment patterns in patients with metastatic melanoma: a retrospective analysis.

Objective. To describe treatment patterns and factors influencing treatment in a real-world setting of US patients with metastatic melanoma (MM). Methods. This was a retrospective claims-based study among patients with MM diagnosed between 2005 and 2010 identified from MarketScan databases. Results. Of 2546 MM patients, 66.8% received surgery, 44.7% received radiation, 38.7% received systemic therapies, and 17.7% received all modalities. Patients with lung, brain, liver, or bone metastases were less likely to undergo surgery (all P < 0.0001); patients with lung (P = 0.04), brain (P < 0.001), or liver metastases (P = 0.03) were more likely to receive systemic therapies; patients with brain (P < 0.0001) or bone metastases (P < 0.0001) were more likely to receive radiation therapy. Oncologists were more likely to recommend systemic therapy (P < 0.0001) or radiation (P < 0.0001), while dermatologists were more likely to recommend surgery (P = 0.002). Monotherapy was the dominant systemic therapy (82.4% patients as first-line). Conclusions. Only 39% of MM patients received systemic therapies, perhaps reflecting efficacy and safety limitations of conventional systemic therapies for MM. Among those receiving systemic therapy, monotherapy was the most common approach. Sites of metastases and physician speciality influenced treatment patterns. This study serves as a baseline against which future treatment pattern studies, following approval of new agents, can be compared.