Surveillance After a Previous Cutaneous Melanoma Diagnosis: A Scoping Review of Melanoma Follow-Up Guidelines.

INTRODUCTION: Cutaneous melanoma accounts for more than 70% of all skin cancer deaths. Follow-up surveillance is an integral part of melanoma patient care, to facilitate early detection of recurrences and subsequent primary melanomas. The purpose of this scoping review is to provide an overview of recently published melanoma surveillance guidelines from regional and national melanoma working groups. METHODS: A systematic search for relevant studies in MEDLINE and Embase was conducted in September 2022 and was limited to publications from 2010 or later. RESULTS: A total of 1047 articles were retrieved, and after abstract and full text review, 26 articles from 19 different organizations met inclusion criteria. Life-long annual skin surveillance with a physician was recommended by 53% (9/17) of guidelines. Routine laboratory investigations were recommended by 7/19 guidelines. Regional lymph node ultrasound was recommended by 9/16 guidelines, most often in stage IB or higher, and was optional in 7/16 for patients who met specific criteria. Surveillance with PET-CT or CT and MRI was recommended by 15 and 11 guidelines, respectively, most commonly in stage IIC or higher, with a variable frequency and total duration. Five out of 9 guidelines indicated a preference for skin surveillance to be completed with a dermatologist. CONCLUSION: Guidelines were highly variable for many aspects of melanoma surveillance, which may be partly attributed to regional differences in healthcare workforce distribution and availability of imaging technologies. Further high-level studies are recommended to provide more evidence on the most effective clinical and imaging follow-up surveillance protocols.

Real-world, population-based cohort study of toxicity and resource utilization of second-line ipilimumab for metastatic melanoma in Ontario, Canada.

Second-line ipilimumab has been publicly funded in Ontario for metastatic melanoma (MM) since September 2012. We examined real-world toxicity of second-line ipilimumab compared to standard second-line treatments prior to funding. MM patients who received systemic treatment from April 2005 to March 2015 were included. Patients receiving second-line ipilimumab after September 2012 were considered as cases, and those who received second-line treatment prior to the funding date were included as historical controls. Outcomes assessed include treatment-related mortality, any-cause hospital visits, ipilimumab-related hospital visits and specialist visits (eg, endocrinologists, ophthalmologists, gastroenterologists, rheumatologists and respirologists), which were captured from up to 30 and/or 90 days after end of second-line treatment. Inverse probability of treatment weighting was used to adjust for baseline differences between groups. Odds ratios (ORs) from logistic regressions and rate ratios (RRs) from rate regressions were used to assess differences between groups. We identified 329 MM patients who received second-line treatments (ipilimumab: 189; controls: 140). Ipilimumab was associated greater any-cause (60.1% vs 45.7%; OR = 1.81; P value = .019) and ipilimumab-related (47.2% vs 31.9%; OR = 1.91; P value = .011) hospital visits. Adjusting for different follow-up days, ipilimumab was associated with higher rates of all-cause (RR = 1.56 [95%CI: 1.12-2.16]), and ipilimumab-related (RR = 2.18 [95% CI: 1.45-3.27]) hospital visits. Patients receiving ipilimumab were more likely to visit specialist involved in immunotherapy toxicity management (23.5% vs 13.7%; P value = .04). Compared to historical second-line treatments, second-line ipilimumab was associated with more health service utilization (specifically hospital visits and specialist visits), suggestive of potentially increased toxicity in the real world.

To ban or not to ban tanning bed use for minors: A cost-effectiveness analysis from multiple US perspectives for invasive melanoma.

BACKGROUND: Tanning bed use is common among US adolescents, but is associated with increased melanoma risk. The decision to ban tanning bed use by adolescents should be made in consideration of the potential health benefits and costs. METHODS: The US population aged 14 to 17 years was modeled by microsimulation, which compared ban versus no ban strategies. Lifetime quality-adjusted life years (QALYs) and costs were estimated from a health care sector perspective and two societal perspectives: with and without the costs of policy enforcement and the economic losses of the indoor-tanning bed industry. RESULTS: Full adherence to the ban prevented 15,102 melanoma cases and 3299 recurrences among 17.1 million minors, saving $61in formal and informal health care costs per minor and providing an increase of 0.0002 QALYs. Despite the intervention costs of the ban and the economic losses to the indoor-tanning industry, banning was still the dominant strategy, with a savings of $12 per minor and $205.4 million among 17.1 million minors. Findings were robust against varying inspection costs and ban compliance, but were sensitive to lower excess risk of melanoma with early exposure to tanning beds. CONCLUSIONS: A ban on tanning beds for minors potentially lowers costs and increases cost effectiveness. Even after accounting for the costs of implementing a ban, it may be considered cost effective. Even after accounting for the costs of implementing a ban and economic losses in the indoor-tanning industry, a tanning bed ban for US minors may be considered cost effective. A ban has the potential to reduce the number of melanoma cases while decreasing health care costs. LAY SUMMARY: Previous meta-analyses have linked tanning bed use with an increased risk of melanoma, particularly with initial use at a young age. Yet, it remains unclear whether a ban of adolescents would be cost effective. Overall, a ban has the potential to reduce the number of melanoma cases while promoting a decrease in health care costs. Even after accounting for the costs of implementing a ban and the economic losses incurred by the indoor-tanning industry, a ban would be cost effective.

Real-world comparative effectiveness of second-line ipilimumab for metastatic melanoma: a population-based cohort study in Ontario, Canada.

BACKGROUND: For novel cancer treatments, effectiveness in clinical practice is not always aligned with clinical efficacy results. As such it is important to understand a treatment's real-world effectiveness. We examined real-world population-based comparative effectiveness of second-line ipilimumab versus non-ipilimumab treatments (chemotherapy or targeted treatments). METHODS: We used a cohort of melanoma patients receiving systemic treatment for advanced disease since April 2005 from Ontario, Canada. Patients were identified from provincial drug databases and the Ontario Cancer Registry who received second-line ipilimumab from 2012 to 2015 (treated) or second-line non-ipilimumab treatment prior to 2012 (historical controls). Historical controls were chosen, to permit the most direct comparison to pivotal trial findings. The cohort was linked to administrative databases to identify baseline characteristics and outcomes. Kaplan-Meier curves and multivariable Cox regression models were used to assess overall survival (OS). Observed potential confounders were adjusted for using inverse probability of treatment weighting (IPTW). RESULTS: We identified 329 patients with metastatic melanoma (MM) who had received second-line treatments (189 treated; 140 controls). Patients receiving second-line ipilimumab were older (61.7 years vs 55.2 years) compared to historical controls. Median OS were 6.9 (95% CI: 5.4-8.3) and 4.95 (4.3-6.0) months for ipilimumab and controls, respectively. The crude 1-year, 2-year, and 3-year OS probabilities were 34.3% (27-41%), 20.6% (15-27%), and 15.2% (9.6-21%) for ipilimumab and 17.1% (11-23%), 7.1% (2.9-11%), and 4.7% (1.2-8.2%) for controls. Ipilimumab was associated with improved OS (IPTW HR = 0.62; 95% CI: 0.49-0.78; p < 0.0001). CONCLUSIONS: This real-world analysis suggests second-line ipilimumab is associated with an improvement in OS for MM patients in routine practice.

Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.

BACKGROUND: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. METHODS: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the combined pembrolizumab groups and 15·9 months (13·3-22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the combined pembrolizumab groups versus 3·4 months (2·9-4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48-0·67, p<0·0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis. INTERPRETATION: Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma. FUNDING: Merck Sharp & Dohme.

Melanoma of the Vulva and Vagina: Surgical Management and Outcomes Based on a Clinicopathologic Reviewof 68 Cases.

OBJECTIVE: This study sought to evaluate the clinicopathologic features, surgical management, and survival of patients over 12 years at two academic centres. METHODS: Patients diagnosed with vulvar or vaginal melanoma between 2002 and 2014 were identified through pathology databases. Clinical and pathologic data were extracted from the medical records. The Kaplan-Meier method was used to calculate recurrence-free survival and overall survival (OS), and univariate analyses using a Cox proportional hazard model were used to detect covariates related to survival. RESULTS: Patients with vulvar melanoma were more likely to undergo surgical excision (84.0% vs. 55.6%, P = 0.0243) and were more likely to achieve negative margins (70.0% vs. 16.7%, P < 0.0001). Forty-eight percent of patients with vulvar melanoma had a lymph node evaluation; sentinel node biopsies were performed in 32%. Actuarial median OS for vulvar melanoma was 45 months compared with 10.48 months for vaginal melanoma. A subset of 10 patients with vulvar melanoma who survived longer than 60 months was identified. Eight significant predictors of OS were demonstrated for vulvar melanomas: clinical stage, maximum tumour size, tumour thickness, lymphovascular space invasion status, clinically enlarged lymph nodes, sentinel lymph nodes, lymph node status, and radiation treatment. Patients with positive or indeterminate margin status demonstrated a higher risk of recurrence than did patients with negative margins (hazard ratio 2.60; 95% CI 1.14-5.90). CONCLUSION: Surgical excision with adequate margins is the mainstay of primary management when feasible. Lymph node evaluation, including sentinel nodes, may be considered in selected patients. Vulvar and vaginal sites differ markedly with respect to pathology, initial management, and survival, and they should be evaluated separately.

Patient Indications for Mohs Micrographic Surgery: A Systematic Review.

The purpose of the present review was to describe evidence-based indications for Mohs micrographic surgery (MMS) in patients with a diagnosis of skin cancer. Relevant studies were identified from a systematic MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews search of studies published from 1970 to 2017. Randomized controlled trials (RCTs), prospective and retrospective comparative studies with greater than 30 patients, and single-arm retrospective studies with multivariate analyses were included. A total of 2 RCTs, 3 prospective studies, and 16 retrospective studies (14 comparative and 2 single-arm) were included. Data on recurrence rate, cure rate, complications, cosmesis, and quality of life were extracted. Surgery (with postoperative or intraoperative marginal assessment) or radiation for those who are ineligible for surgery should remain the standard of care for patients with skin cancer given the lack of high-quality, comparative evidence. MMS is recommended for those with histologically confirmed recurrent basal cell carcinoma (BCC) of the face and is appropriate for primary BCCs of the face that are >1 cm, have aggressive histology, or are located on the H zone of the face. The available evidence is difficult to generalize to all patients with skin cancer because the evidence did not adequately cover non-BCC skin cancers; however, those skin cancers can be considered on a case-by-case basis for MMS. MMS should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada Specialist Certificate or equivalent, and have received advanced training in MMS.

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).

BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.

Prospective Evaluation of the Impact of the 21-Gene Recurrence Score Assay on Adjuvant Treatment Decisions for Women with Node-Positive Breast Cancer in Ontario, Canada.

BACKGROUND: The 21-gene Recurrence Score (RS) assay is only reimbursed in Ontario for node-negative and micrometastatic node-positive (N+) early-stage breast cancer (EBC). We carried out a prospective study to evaluate the impact of the assay on treatment decisions for women with N+ EBC. SUBJECTS, MATERIALS, AND METHODS: Women with estrogen receptor-positive, human epidermal growth receptor 2-negative EBC and one to three positive axillary lymph nodes, who were candidates for adjuvant chemotherapy in addition to hormonal treatment, but in whom the benefit of chemotherapy was uncertain, were eligible. The primary objective was to characterize how the results of the RS assay affected physicians' recommendations for adjuvant chemotherapy. Secondary objectives were to characterize changes in the physicians' and patients' level of confidence in treatment recommendations, to determine whether the results of the RS assay affected patients' treatment preferences, and to determine the final treatment administered. RESULTS: Seventy-two patients were recruited; the mean age was 61. RS was <18 in 55%, between 18 and 30 in 36%, and ≥31 in 9% of patients. Treatment recommendations changed in 36% of all evaluable patients. The most significant change was in the group with a low RS. Physicians' and patients' confidence in treatment recommendations increased in 49% and 54% of cases, respectively. Upfront chemotherapy was recommended to 79% of patients before the assay; 42% ultimately received chemotherapy. CONCLUSION: The RS assay resulted in a substantial decrease in the number of patients who received chemotherapy and in an increase in physicians' and patients' confidence in the adjuvant treatment recommendations. IMPLICATIONS FOR PRACTICE: This is the first decision impact study to include exclusively women with ER-positive, HER2-negative, early-stage breast cancer with 1-3 positive lymph nodes, a population typically treated with adjuvant chemotherapy. This study provides evidence that, in these patients, the Oncotype Dx Recurrence Score assay influences systemic treatment decisions. Most of the changes in treatment recommendation resulted in withdrawal of chemotherapy or change in recommendation from a chemotherapy regimen with anthracyclines to a taxane-only regimen. If prospective studies confirm that these decisions result in good outcomes, a reduction in the use of chemotherapy might result in pharmacoeconomic savings.

Motivation and preferences of exercise programmes in patients with inoperable metastatic lung cancer: a need assessment.

OBJECTIVES: The aim of this study is to investigate the motivation, ability, preferences, and perceived potential facilitating factors/barriers of patients with inoperable metastatic lung cancer towards exercise programmes. METHODS: This is a cross-sectional study using survey adopting the Theory of Planned Behaviour (TPB) to obtain patients' experience recruited through Odette Cancer Centre, Sunnybrook Health Sciences Complex. Results were expressed in percentages, P value, and Spearman's rho. RESULTS: Sixty patients were recruited from January 2014 to April 2014. Patients generally had a high level across TPB measures, with 63% of them indicating that they have the motivation to exercise. Significant association in relation to motivation was established on attitudes (importance, P = 0.005, rho = 0.326; helpfulness, P = 0.015, rho = 0.348; and easiness, P = 0.001, rho = 0.375) and subjective norm of close members (P = 0.0069, rho = 0.348) and healthcare professionals (P = 0.012, rho = 0.328). Being a non-smoker (P = 0.042, rho = 0.311), having a past exercise history prior to diagnosis (P = 0.000, rho = 0.563), and absence of COPD (P = 0.016, rho = -0.312) were also shown to have a significant association with motivation to exercise. DISCUSSIONS AND CONCLUSIONS: Patients were motivated to participate in an exercise programme despite contrary belief; however, they might have limited ability and preferred light intensity type of exercise such as walking. Their motivation to exercise was driven by different factors when compared to other cancer patient populations. Thus, it is important for healthcare professionals to understand the factors influencing their motivation and increase their awareness (only 26% of patients indicated receiving advice regarding exercise) to better the care towards patients with metastatic lung cancer.

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease.

PURPOSE: Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies. The aim of this study was to validate the role of intralesional interleukin (IL)-2, to understand its mechanism of action, and to better understand factors that may influence its response. METHODS: We retrospectively collected the clinicopathological data of 31 consecutive patients who presented to a tertiary care cancer center for treatment of in-transit melanoma with intralesional IL-2. Kaplan-Meier survival curves and multivariable Cox regression analysis were performed. Immunohistochemistry (IHC) was used to better understand the immune response to localized IL-2 therapy. Targeted next-generation sequencing was performed to genomically characterize the tumors. RESULTS: Ten patients (10/31, 32 %) achieved a pathologic complete response (pCR), 17/21 (55 %) had a partial response, and 4/21 (19 %) had progressive disease on treatment. pCR to IL-2 therapy was associated with overall survival (log-rank p = 0.004) and improved progression-free survival (PFS) [adjusted hazard ratio (HR) 0.11; 95 % CI 0.02-0.47; p = 0.003). A higher CD8+ T cell infiltrate was identified in in-transit lesions with a pCR compared with the other lesions (mean IHC score 3.78 vs. 2.61; p = 0.01). Patients with an elevated CD8+ infiltrate demonstrated an improved PFS (unadjusted HR 0.08; 95 % CI 0.01-0.52; p = 0.008). CONCLUSIONS: Thirty-two percent of patients achieved pCR with intralesional IL-2 therapy and had a significantly improved PFS compared with the rest of the cohort, which may be explained by a systemic CD8+ T-cell response.

Cost-effectiveness analysis of staging strategies in patients with regionally metastatic melanoma.

PURPOSE: Variability exists regarding optimal staging for node-positive melanoma. Options include combinations of physical examination (PE), radiography, computed tomography (CT), and positron emission tomography (PET). Cost-effectiveness of regimens has never been investigated. METHODS: A modeled cost-effectiveness analysis was performed to examine the cost per surgery performed and per accurate diagnosis achieved with three staging regimens (PE/chest radiography, CT, PET/CT) for node-positive melanoma. Incremental cost-effectiveness ratios were used to compare regimens. Deterministic and probabilistic sensitivity analyses were undertaken to address variation in parameters. Costs are direct from the perspective of the Canadian single-payer system and 2012 valuations. RESULTS: Staging with PE/radiography is the least cost-effective option, resulting in greater costs than CT alone, and fewer accurate diagnoses. Compared to CT alone, PET/CT incurs greater incremental cost ($902.81CAD), but results in 4% fewer lymphadenectomies and 4% more accurate diagnoses. PET/CT costs $22,570.25CAD for each additional accurate diagnosis achieved compared to CT alone. Sensitivity analyses demonstrate that the optimal staging strategy is influenced by diagnostic test characteristics and the willingness-to-pay threshold, but robust to other varied parameters. CONCLUSIONS: PE/radiography appears to be the least cost-effective staging regimen. The benefit of PET/CT over CT alone depends on a health system's priorities and willingness-to-pay.

Metastatic melanoma: optimizing outcomes by managing dermatologic toxicities associated with novel therapies.

The last couple of years have seen the beginning of a new era in the treatment of metastatic melanoma. This disease is typically characterized by its poor prognosis and limited choice of therapy. Two mechanistically diverse classes of agents - BRAF inhibitors and immune modulators - have demonstrated an overall survival benefit. Along with their significant clinical benefits, there are also unique adverse events (AEs) related to these agents. While most of the AEs are mild and easily managed with supportive treatment, others require more aggressive management strategies. Education of all members of the multidisciplinary care team and awareness of these toxicities are crucial in order to optimize patient outcomes. The landscape of melanoma is continually evolving as ongoing trials are evaluating monotherapy and combination options. While these regimens continue to show promise for the future, understanding and managing toxicities of currently available therapies is required.

Surveillance evaluations in patients with stage I, II, III, or resectable IV melanoma who were treated with curative intent: A systematic review.

PURPOSE: Appropriate surveillance of patients with melanoma treated with curative intent is vital to improve patient outcomes. A systematic review was conducted to capture locoregional recurrence and metastatic disease, and to evaluate the effectiveness of various surveillance strategies. METHODS: MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews, and National Cancer Institute Clinical Trials Database were searched. Randomized controlled trials (RCTs) and comparative studies reporting at least one patient-related outcome were included. Exclusion criteria included: published in non-English or recruited >20 % or an uncertain percentage of non-target patients without conducting a subgroup analysis for the target patients. This review was registered at PROSPERO (CRD42021246482). RESULTS: Among 17,978 publications from the literature search, one RCT and five non-randomized comparative studies were included and comprised 4016 patients. The aggregate evidence certainty was low for the RCT and very low for the comparative studies, as assessed by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. For patients with stage IA-IIC melanoma, a reduced follow-up schedule with clinical follow-up strategies alone may be safe and cost-effective. For stage IIC-IIIC patients, at least two serial PET/CT or whole-body CT and brain MRI imaging within a median follow-up of 31.2 months may detect 50 % of recurrences that lead to additional management, such as surgery. PET/CT may have a higher positive predictive value and lower false positive rate compared with CT alone in detecting recurrence in stage I-III patients. CONCLUSION: Surveillance protocols should be based on individual risk of recurrence and established best practices when formulating follow-up strategies, as suggested by the studies reviewed. Future high-quality studies are needed to clarify the frequency of imaging follow-up strategies, especially in patients with high-risk stage II melanoma.

Cost-effectiveness of second-line ipilimumab for metastatic melanoma: A real-world population-based cohort study of resource utilization.

BACKGROUND: The efficacy-effectiveness gap between randomized trial and real-world evidence regarding the clinical benefit of ipilimumab for metastatic melanoma (MM) has been well characterized by previous literature, consistent with initial concerns raised by health technology assessment agencies (HTAs). As these differences can significantly impact cost-effectiveness, it is critical to assess the real-world cost-effectiveness of second-line ipilimumab versus non-ipilimumab treatments for MM. METHODS: This was a population-based retrospective cohort study of patients who received second-line non-ipilimumab therapies between 2008 and 2012 versus ipilimumab treatment between 2012 and 2015 (after public reimbursement) for MM in Ontario. Using a 5-year time horizon, censor-adjusted and discounted (1.5%) costs (from the public payer's perspective in Canadian dollars) and effectiveness were used to calculate incremental cost-effectiveness ratios (ICERs) in life-years gained (LYGs) and quality-adjusted life years (QALYs), with bootstrapping to capture uncertainty. Varying the discount rate and reducing the price of ipilimumab were done as sensitivity analyses. RESULTS: In total, 329 MM were identified (Treated: 189; Controls: 140). Ipilimumab was associated with an incremental effectiveness of 0.59 LYG, incremental cost of $91,233, and ICER of $153,778/LYG. ICERs were not sensitive to discounting rate. Adjusting for quality of life using utility weights resulted in an ICER of $225,885/QALY, confirming the original HTA estimate prior to public reimbursement. Reducing the price of ipilimumab by 100% resulted in an ICER of $111,728/QALY. CONCLUSION: Despite its clinical benefit, ipilimumab as second-line monotherapy for MM patients is not cost-effective in the real world as projected by HTA under conventional willingness-to-pay thresholds.

Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Immune checkpoint inhibitors have led to unprecedented prolongation of overall survival (OS) for patients with advanced melanoma. Five-year follow-up of KEYNOTE-006 showed pembrolizumab prolonged survival versus ipilimumab. Efficacy results with 7-year follow-up are presented. At data cutoff (April 19, 2021), median follow-up was 85.3 months (range, 0.03-90.8 months). Median OS was 32.7 months for pembrolizumab versus 15.9 months for ipilimumab (hazard ratio [HR], 0.70; 95% CI, 0.58 to 0.83); 7-year OS was 37.8% and 25.3%, respectively. OS HRs favored pembrolizumab regardless of BRAF status or prior BRAF/MEK-inhibitor treatment and prognostic characteristics (elevated lactate dehydrogenase, large tumor size, and brain metastasis). Median modified progression-free survival (mPFS) was 9.4 months for pembrolizumab versus 3.8 months for ipilimumab; 7-year mPFS was 23.8% and 13.3%, respectively. In patients who completed ≥94 weeks of pembrolizumab, the 5-year OS was 92.9% and the 5-year mPFS was 70.1%. The objective response rate with second-course pembrolizumab (n = 16) was 56% (95% CI, 30 to 80) and the 2-year mPFS was 62.5%. These findings confirm that pembrolizumab provides long-term survival benefit in advanced melanoma.

Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination.

PURPOSE: Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136). METHODS: Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review. RESULTS: A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count). CONCLUSION: Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.

A tailored approach to horizon scanning for cancer medicines.

BACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement. METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type. RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation. CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective. POLICY SUMMARY: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities.

Impact of biomarkers on clinical trial risk in breast cancer.

We determined the success rate of new drug approval by the US FDA in two breast cancer indications, one of which used a biomarker. This allowed us to assess if biomarkers improved clinical trial risk in breast cancer. We performed a retrospective screening of industry-sponsored drug development programs registered on clinicaltrials.gov from 1998 to 2012 for HER2-positive patients compared to patients that had either failed or had been exposed to anthracycline or taxane, whose first phase I in this indication occurred no earlier than 1998. Compounds not registered on clinicaltrials.gov and studied exclusively outside the US were excluded. Twenty-nine drugs for HER2-positive patients and 28 drugs for anthracycline/taxane-exposed patients met our screening criteria. The overall success rate of new drug development in anthracycline/taxane patients was only 15 %, while in HER2-positive patients it was 23 %. However, HER2-targeted therapies underperformed compared to broad acting agents. The cost for clinical trial testing alone, when adjusted for the risk of failure, for HER2-positive breast cancer patients was $199 million, significantly lower than the cost of $274 million for anthracycline/taxane-experienced patients. The use of a validated biomarker, such as HER2, reduced clinical trial risk by as much as 50 % resulting in cost savings of 27 % in advanced and metastatic breast cancer. However, these data have to be evaluated in a context in which studies combining a novel drug with a novel biomarker not yet recognized by the FDA may actually increase clinical trial risk.

Current State of Adjuvant Therapy for Melanoma: Less Is More, or More Is Better?

Advances in melanoma treatments over the past decade have changed the course of survival for patients. Several adjuvant therapies have been approved and are now considered standard of care for high-risk patients. These therapies have shown improvements for recurrence-free survival and distant metastases-free survival, but not overall survival, as the data are maturing. The 5-year recurrence-free survival in the COMBI-AD study, which compared dabrafenib and trametinib with placebo, was 65% and 58%, respectively. In the KEYNOTE-054 study, the recurrence-free survival at 3 years was 63.7% versus 41%. Despite these advances, approximately 50% of patients will succumb to their disease. Adjuvant therapy is considered potentially curative and avoids the morbidity of relapsed disease and the poor outcomes seen in metastatic disease. However, the lack of overall survival benefit in clinical trials of patients with high-risk stage II and stage III disease raises the question of whether it is more efficacious to treat when there is residual microscopic disease, or to wait until the disease recurs to avoid treating those who may have been cured by surgery alone. Immunotherapy also has the potential for substantial toxicity that may be lifelong; hence, discussion of risks and benefits of therapy is warranted because there should be less tolerance for substantial toxicity in the adjuvant setting. Adjuvant trials are needed that will integrate biomarkers to allow for better selection of patients who will truly benefit from adjuvant therapy.