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e22086 Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.

e22088 Background: In recent years, adjuvant therapy trials in stage III melanoma have been successful and trials have started with the inclusion of stage IIB/C patients. However, stage IIA melanoma patients are currently not eligible for adjuvant therapy, even though a large part of all melanoma related deaths occur in this patient group. Therefore, a strong clinical need has emerged for diagnostic tools that can identify high-risk patients who currently have no access to adjuvant therapy. Here, we sought to assess the ability of a recently introduced clinicopathologic gene expression model (CP-GEP) (Bellomo et al., JCO Precis Oncol. 2020: in press) to select stage IIA patients at high risk for disease relapse, upon design of a stage-specific operating point. Methods: We assessed the prognostic performance of the CP-GEP model in all 141 stage IIA patients from a Mayo Clinic cohort of 837 consecutive melanoma patients who had a sentinel lymph node biopsy (SLNb) performed within 90 days of their diagnosis. The CP-GEP model combines Breslow thickness and patient age, with the expression of 8 genes in the primary tumor. Moreover, it stratifies patients according to their risk of relapse: CP-GEP High Risk or CP-GEP Low Risk, based on an operating point that was specifically developed for stage IIA. This stage-specific operating point was selected to fulfill the following criteria: hazard ratio RFS > 2 with a p-value < 0.05, and risk groups of similar size. The main clinical endpoint was five-year relapse free survival (RFS). Results: The CP-GEP High Risk group corresponds to 45% (63/141) of all stage IIA patients and captures 62% (18/29) of the total relapses in this substage. Moreover, CP-GEP High Risk patients relapse more frequently than CP-GEP Low Risk patients (RFS of 56% versus 78%; HR, 2.23; P < 0.05). The prognosis for stage IIA CP-GEP High Risk patients in our cohort is worse than for stage IIC/IIIA patients with reported RFS ranging from 63% to 77%. Conclusions: The CP-GEP model can be optimized by designing a stage-specific operating point, to identify a subset of stage IIA patients with an increased risk for disease relapse, not very different from IIC/IIIA patients. Therefore, stage IIA CP-GEP High Risk patients may be considered for inclusion in adjuvant trials. Independent validation studies are ongoing for the newly developed operating point. [Table: see text]

e22039 Background: To date, international consensus concerning the use of PET/CT as a surveillance tool in the follow-up of high-risk melanoma patients after complete resection of disease is lacking. Moreover, with the rise of adjuvant therapy it seems appropriate to investigate the role of this imaging modality to exclude newly developed metastases after resection and prior to starting treatment. The aim of this study was to investigate the use of PET/CT as surveillance tool in the follow-up and prior to adjuvant therapy in asymptomatic patients with complete resection of stage IIIB and IIIC melanoma. Methods: Prospectively two cohorts were set up with stage III melanoma patients with complete resection of disease. In the first cohort (stage IIIB/C AJCC 7th) surveillance PET/CT was performed 6-monthly for two years if patients stayed asymptomatic with normal serum S100B, with a final scan at three years. In the second cohort (stage IIIB/C/D AJCC 8th) patients underwent one screening PET/CT after resection and prior to starting adjuvant treatment. Results: Eighty patients entered follow-up in cohort 1. Of these, the majority did not undergo surveillance scans, because they required treatment for newly detected clinical metastases. Thirty-five patients remained asymptomatic and were included in surveillance cohort one (105 scans) with a median follow-up of 33 months. Twelve patients (34%) developed a recurrence, seven (20%) of which were detected on the first scan at six months. Seven recurrences involved stage IIIC patients, five stage IIIB patients. Sensitivity and specificity were 92% and 100% respectively. Forty-two patients were included in cohort 2. Recurrence was suspected on nine scans, four (10%) of which were true positive. One patient proceeded to undergo a node dissection and then started adjuvant therapy. The other three patients had progressed to stage IV and therefore started radiotherapy and/or systemic immunotherapy. Five (12%) scans were false positive, the suspected lesions were not related to the preceded surgery. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort one and two, respectively. Conclusions: This study shows that PET/CT is a useful surveillance tool for detecting recurrence in asymptomatic high-risk resected stage III melanoma patients, especially within the first six months after surgery and therefore should be considered when monitoring these patients during follow-up as well as prior to starting adjuvant therapy.

International audience; Improved knowledge of sentinel node procedures coupled with the results of adjuvant clinical trials in stage III melanoma have prompted the French Cutaneous Oncology Group to propose new guidelines for the management of stage III melanoma. These guidelines comply with the principles of the evidence-based medicine.

Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma.

Aim: Neoadjuvant treatment of locally advanced disease with BRAF inhibitors is expected to increase the likelihood of a R0 resection. We present six patients with stage III unresectable melanoma, neoadjuvantly treated with BRAF inhibitors.Methods: Patients with unresectable, BRAF-mutated, stage III melanoma, were treated with BRAF inhibitors between 2012 and 2015. Unresectability was determined based on clinical and/or radiological findings. At maximal response, resection was performed. The specimen was reviewed to determine the degree of response.Results: In five of six patients a radical resection was achieved. Postoperative complications were unremarkable. In five of six resected specimens, vital tumor tissue was found.Conclusion: Neoadjuvant BRAF inhibitor treatment of locally advanced melanoma is feasible and has the potential to facilitate an R0 resection.

Vulvar melanoma is a rare and deadly cancer in women, and the prognosis is often poor. There are limited studies on the dermoscopic features of vulvar melanoma. Described criteria include the presence of blue, gray, or white colors. Herein we present the clinical and dermoscopic characteristics of a hypopigmented and heavily pigmented nodule in a 92-year-old and an 80-year-old woman. Dermoscopy in the former revealed structureless milky-red to white areas, remnants of brown pigmentation at the base and polymorphic vessels, while the latter displayed structureless blue-gray areas with black dots and peripheral lines at the base. In both cases, histopathology revealed a stage III melanoma. Our two cases along with a review of the literature suggest that the dermoscopic features described for diagnosing cutaneous nodular melanoma, apply also for vulvar melanoma. Clinicians should always raise the suspicion if observing plaques or nodules with a dermoscopic polymorphic vascular pattern and blue-black color on the genitals of postmenopausal women.

Background D+T has been approved for several indications, including BRAF V600–mutant unresectable or metastatic melanoma and as adjuvant therapy following resected BRAF V600–mutant stage III melanoma. Pyrexia is a common adverse event but is generally low-grade and manageable; further characterization may optimize management and reduce permanent treatment (tx) discontinuation due to pyrexia. Methods Trial databases were queried for reports of pyrexia in pts treated with D and/or T, including adjuvant therapy. Indications included unresectable, metastatic, or resected stage III melanoma; non-small cell lung cancer (NSCLC); colorectal cancer, and other BRAF–mutation positive solid tumors. Data for D+T was compiled from the following trials: COMBI-AD (NCT01682083), COMBI-d (NCT01584648), COMBI-v (NCT01597908), and BRF113928 (NCT01336634). Pyrexia was graded according to the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 1991 pts were included from clinical trials (D+T, n=1076; D, n=586; T, n=329). Pyrexia was observed in 904 pts: D+T, 61% (660/1076); D, 33% (196/586); T, 15% (48/329). Of pts treated with D+T, 6% (62/1076) experienced grade 3 events and 1 of 1076 pts experienced a grade 4 event. The median time to onset was 27 d (range, 1-716 d). Recurrent any-grade pyrexia occurred in 41% (442/1076) of pts; 29% had ≥ 3 episodes. Of the 442 pts with recurrent pyrexia, 377 (85%) experienced a subsequent event within 3mo of the first pyrexia episode. No pyrexia-related deaths were reported. Outcomes were reported for 2252 of 2253 events in pts treated with D+T across trials. Pyrexia management strategies included: tx interruption (939/2253 events [42%]), dose reduction (225/2253 [10%]), and tx discontinuation (62/2253 [3%]); ≥ 98% of events were reported to be resolved following each of the aforementioned interventions. Conclusions Pyrexia in pts treated with D+T is typically low-grade, occurs early during tx exposure, and most pts experience ≤ 1 episode. Tx interruption was the most frequent intervention strategy used in clinical trials. Pyrexia can be effectively managed with nearly all events reported to have been resolved at the time of the analysis. Clinical trial identification Pooled analysis of data from the following trials: NCT01227889, NCT01153763, NCT01266967, NCT01072175, NCT00880321, NCT01336634, NCT01584648, NCT01597908, NCT01682083, NCT01245062, NCT01037127, NCT00687622. Editorial acknowledgement Allison Lytle, PhD, from ArticulateScience LLC, funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure C. Robert: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Array; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Merck. D. Schadendorf: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Immunocore; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Honoraria (self), Advisory / Consultancy: 4SC; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Mologen; Advisory / Consultancy: Sanofi/Regeneron; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: Merck; Honoraria (self): Sysmex; Honoraria (self): Grunenthal Group; Honoraria (self): Agenus; Honoraria (self): Array BioPharma; Honoraria (self): AstraZeneca; Honoraria (self): LEO Pharma; Honoraria (self): Pfizer; Honoraria (self): Philogen; Honoraria (self): Regeneron. R. Dummer: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Novartis; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Merck Sharp & Dhome; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Bristol-Myers Squibb; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Roche; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Amgen; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Takeda; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Pierre Fabre; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Sun Pharma; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Sanofi; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Catalym. K.T. Flaherty: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncoceutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Aeglea Biotherapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Loxo; Advisory / Consultancy: Roche; Advisory / Consultancy: Asana Biosciences; Advisory / Consultancy: Incyte; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy: Tolero Pharmaceuticals; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options: FOGPharma; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tvardi; Advisory / Consultancy: Takeda; Advisory / Consultancy: Varestem; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy: Cell Medica; Advisory / Consultancy, Travel / Accommodation / Expenses: Debiopharm Group; Shareholder / Stockholder / Stock options: Clovis Oncology; Shareholder / Stockholder / Stock options: X4 Pharma; Shareholder / Stockholder / Stock options: PIC Therapeutics; Shareholder / Stockholder / Stock options: Fount Therapeutics; Shareholder / Stockholder / Stock options: Apricity Health; Shareholder / Stockholder / Stock options: Vivid Biosciences; Shareholder / Stockholder / Stock options: Checkmate Pharmaceuticals; Shareholder / Stockholder / Stock options: Strata Oncology. H.A. Tawbi: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy: Roche; Advisory / Consultancy: Array; Research grant / Funding (institution): Celgene. A.M. Menzies: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre. A. D'Amelio: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: GlaxoSmithKline. E. de Jong: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. E. Gasal: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. G.V. Long: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Pierre Fabre.

Approximately half of melanomas are driven by a point mutation in the BRAF kinase gene, targetable with vemurafenib. However, the chief limitation of continuous BRAF inhibition is that the majority of patients develop resistance within 8 months, including those with surgically unresectable stage III melanoma. Researchers retrospectively reviewed medical records of all patients at our institution with surgically incurable BRAF V600E mutated stage III or limited stage IV melanoma treated with induction vemurafenib, stopped electively during ongoing response, followed by consolidative radiation therapy with or without intervening surgery to debulk nodal metastases. In our six-patient cohort, the median duration of vemurafenib was 5.8 months and the median radiation dose was 57 Gy using conventional fractionation. This algorithm produced 100% locoregional control at 29+ months following radiation and a median progression-free survival of 32.5+ months. Three of six patients remained progression free, and three relapsed in a single organ and achieved ongoing complete response to subsequent therapy. Outcomes greatly exceeding those reported with either BRAF inhibition or radiation alone suggest unanticipated synergies with this therapeutic sequence for both in-field and distant melanoma control, which may be mediated by radiosensitization and immune activation, respectively. In patients with surgically incurable melanoma encompassed within a radiation field, induction vemurafenib and consolidative radiation therapy, rather than continuing vemurafenib until progression, also limit the duration of vemurafenib toxicity and preserve sensitivity to future BRAF inhibition.

Background The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma. Methods We have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples. Results Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel. Conclusions We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse.

The article by Jakub and colleagues describes the adoption of a minimally invasive inguinal lymph node dissection (MILND) for stage III melanoma patients in ten large-volume centers across the United States (1).

BACKGROUND Ipilimumab (Yervoy®) therapy improves outcomes in patients with resected stage III melanoma, and ipilimumab alone or combined with nivolumab (Opdivo®) does so in those with unresectable or metastatic melanoma. These immunotherapies are associated with immune-related adverse events (irAEs). With prompt recognition and appropriate management, serious sequelae or unnecessary treatment discontinuation can be prevented. . OBJECTIVES This article presents consensus statements to guide oncology nurses in the recognition and management of irAEs associated with ipilimumab and nivolumab. . METHODS Members of the Melanoma Nursing Initiative reviewed the current literature and clinical experience regarding nursing interventions related to irAEs associated with ipilimumab or ipilimumab and nivolumab therapy. . FINDINGS The care step pathways provided represent a proactive, evidence-based, and comprehensive plan to support optimal patient outcomes.

New treatment options for patients with resected stage III melanoma have been established with the publication of the results of four pivotal randomized clinical trials, resulting in three drug approvals, with a forth expected, all within only 4 years. Herein, we put these advances into context.

not available.

Background A goal of adjuvant therapy is to prolong disease-free survival, with the risk of mortality approaching that of the general population. From the literature, recurrences in stage III melanoma are most likely to occur within 3 years after surgery. Mixture-cure models (MCMs) capture survival heterogeneity of cancer patients by assuming they are either “cured” or “uncured”, where cured patients are defined as having a low risk of relapse. Methods We applied MCMs to 3-year recurrence-free survival (RFS) outcomes in patients with resected melanoma treated with adjuvant nivolumab (NIVO) or ipilimumab (IPI) in the double-blind, phase III CheckMate 238 trial (NCT02388906) and assumed that the cured fraction has mortality risks similar to that of the general population. Patient age, sex, and geographic region information from CheckMate 238 and mortality rates from the World Health Organization were used to derive a cohort-level background survival distribution representative of “cured” or “disease-free” patients. Parametric functions were used to model uncured population outcomes. Parameters of the MCM were estimated by means of maximum likelihood methods. Statistical goodness-of-fit metrics and visual inspection showed that generalized gamma and log-logistic distributions were best suited for survival analyses of cured and uncured patients, respectively. Results The 3-year RFS rates were explained by the fraction of patients with a low risk of relapse in the NIVO arm at 55.1% (95% CI, 49.2–60.1) and IPI arm at 39.9% (95% CI, 33.6–46.1). Sensitivity analyses indicated that the estimated fraction of patients with a low risk of relapse was > 50% in the NIVO arm. Estimated RFS distributions of the uncured patients exhibited similar patterns for both arms, implying the differences in RFS rates between treatment arms can be explained with the elicited differences in proportions of patients at high vs low risk of relapse. Conclusions MCM analyses from CheckMate 238 suggested that adjuvant treatment with NIVO leads to a higher proportion of patients with low risk of relapse compared with IPI. Validation of the results from MCMs will include analyses of longitudinal RFS and overall survival data from the EORTC 18071 trial. Clinical trial identification NCT02388906. Editorial acknowledgement Kakoli Parai, PhD, and Andrea Lockett at StemScientific, an Ashfield Company, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure J.S. Weber: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: AltorBioScience; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Licensing / Royalties, Named on a patent for a PD-1 antibody biomarker: Biodesix; Shareholder / Stockholder / Stock options: Biond; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: cCam Biotherapeutics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celldex; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Ichor Medical Systems; Research grant / Funding (institution): Incyte; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lion Biotechnologies; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Licensing / Royalties, Named on patent for an ipilimumab biomarker: Moffitt Cancer Center; Honoraria (self), Advisory / Consultancy: Nektar; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pieris Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Sellas Life Sciences; Honoraria (self), Advisory / Consultancy: WindMIL; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: CytomX Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. M. Kurt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. M. Edmondson-Jones: Advisory / Consultancy: Bristol-Myers Squibb. A. Amadi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. M. Lobo: Full / Part-time employment: Bristol-Myers Squibb. A. Moshyk: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. S. Kotapati: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. P. Mohr: Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Merck, Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Merck Germany; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Sanofi.

Background Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of Methods Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg + NIVO 1 mg/kg, either adj 4 courses or split 2 courses neoadj and 2 adj. Path response, as reviewed by a blinded pathologist, was defined as Results After a median FU of 36.7 months (minimum 28.3 months FU of pts alive) none of the 7 pts with a path response in the neoadj arm have relapsed. Both non-responding pts in the neoadj have relapsed versus 4 pts in the adj arm. One pt has died in the neoadj arm and 3 in the adj arm. The estimated 3-year RFS rate was 80% for the neoadj arm and 60% for the adj arm. The 3-year OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed 1 or more grade 3-4 adverse events all have recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal supplementation therapy that are ongoing in 8 (50%) of 16 pts alive. Conclusions OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. At 3 years FU, no new safety events occurred and none of the pts with a path response have relapsed, suggesting that path response could be considered as surrogate marker for RFS and OS in neoadjuvant checkpoint inhibitor trials. Clinical trial identification NCT02437279. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Pierre Fabre. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius Therapautics; Advisory / Consultancy: Gadet; Advisory / Consultancy: GSK. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options, Venture partner: Third Rock Venture. E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. All other authors have declared no conflicts of interest.

Background In the multi-center investigator-initiated OpACIN-neo trial, patients (pts) with macroscopic stage III melanoma were randomized (stratified by center) to 3 different dosing schemes of neoadjuvant (neoadj) IPI+NIVO. Two cycles IPI 1mg/kg + NIVO3mg/kg was identified as the most favorable regimen with 20% grade 3-4 adverse events and a pathological response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months (mo) none (0/86) of the pts with a pathologic (path) response had relapsed, while 9/21 (43%) without a path response relapsed. Post-hoc analyses were conducted to investigate potential differences between pts treated in Europe (EU) and in Australia (AUS). Methods Baseline patient characteristics, safety and efficacy in terms of path response were evaluated in pts treated in EU (n=48) and AUS (n=38). Multivariate analyses were performed using logistic regression method. Median FU was 9.3mo for EU pts and 6.9mo for AUS pts. Results Baseline characteristics (AUS vs EU) differed in age (median 60 vs 53 year [yr], p=0.017) and AUS pts were more likely to be male (65.8 vs 50.0%, p=0.142) and have an unknown primary melanoma (36.8 vs 20.8%, p=0.100); no difference in PD-L1 expression was observed. There was a trend to a higher pRR for AUS pts than for EU pts (84.2% vs 68.1%, OR 2.50, p=0.092). pRR was also higher for pts >60yr compared to £60yr (91.2% vs 64.7%, OR 5.64, p=0.010) and males vs females (83.7% vs 63.9%, OR 2.90, p=0.041). Multivariate analysis including continent, age and gender showed an adjusted OR for path response of 1.85 (p=0.289) for AUS vs EU pts, an OR of 4.89 (p=0.021) for pts >60yrs vs £60yrs and an OR of 2.50 (p=0.095) for males vs females. The frequency of high grade toxicity was the same in pts 60yr (42.3% vs 32.4%, p=0.353). Conclusions The continental difference in path response appears mostly driven by differences in age and gender. It remains to be elucidated whether the higher pRRs in elderly pts and pts from AUS can be explained by differences in mutational burden (analysis in progress and will be presented). Our data also indicate that neoadj IPI+NIVO is safe and highly effective in the elderly. Clinical trial identification NCT02977052. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. R.A. Scolyer: Advisory / Consultancy: MSD; Advisory / Consultancy: Neracare; Advisory / Consultancy: Novartis. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. J. Hansson: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: GenMab; Research grant / Funding (institution): NanoString. All other authors have declared no conflicts of interest.

2512 Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly (P=0.0013) prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS (HR=0.76) and distant metastasis-free survival (DMFS) (HR=0.76), assessed by an IRC, and overall survival (OS) (HR=0.72) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168. [Table: see text]

TPS9596 Background: Adjuvant pembrolizumab showed significantly longer recurrence-free survival than placebo in patients with resected stage III melanoma in the KEYNOTE-054 study. KEYNOTE-716 (NCT03553836) is a randomized, placebo-controlled, double-blind, multicenter phase 3 study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Methods: Key eligibility criteria are age ≥12 y with newly diagnosed, completely resected stage IIB/IIC cutaneous melanoma, defined by the AJCC Cancer Staging Manual, 8th edition (wide excision and negative sentinel lymph node biopsy with no evidence of distant metastasis). Patients with mucosal or uveal melanoma or prior treatment (including radiation) for melanoma beyond resection of primary disease within 12 wk of the start of study treatment were excluded. In this 2-part study, in the double-blind phase (part 1), patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg for patients ≥18 y or 2 mg/kg for patients ≥12 y to < 18 y (maximum dose, 200 mg) or placebo every 3 wk for 17 cycles. Study treatment will begin within 12 wk of complete resection. Tumor imaging will be performed every 24 wk while treatment is ongoing, at the end of treatment, every 6 mo for the first 3 y off treatment, and then yearly for up to 2 y or until recurrence (up to 5 y of total imaging). Adverse events will be recorded until 30 d after treatment end (90 d for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the unblinded phase (part 2), patients with confirmed recurrence may be rechallenged (patients received pembrolizumab in part 1) or crossed over to pembrolizumab (patients received placebo in part 1). Resected local or distant recurrence or unresectable disease will be treated for an additional 17 or 35 cycles, respectively. Tumor imaging in part 2 will occur every 12 wk during treatment. The primary end point is recurrence-free survival; secondary end points are distant metastasis-free survival, overall survival, and safety. Approximately 954 patients will be enrolled. Clinical trial information: NCT03553836.

TPS9605 Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052.

2517 Background: Several studies suggested that patients (pts) with an immune-related adverse event (irAE) during immunotherapy have better outcomes than those without. It remains uncertain whether these observations can be explained by guarantee-time bias or the role of irAE as an indicator of drug activity. Here, we investigated the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 trial that compared pembrolizumab and placebo in high-risk stage III melanoma pts. Methods: Eligible pts included adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (lymph node metastasis > 1 mm), IIIB or IIIC (without in-transit metastasis) and with no active autoimmune disease that required systemic treatment in past 2 years. We used a Cox model adjusted for sex, age, and stage with a time-varying covariate taking a value zero before the irAE onset and a value one afterwards to estimate the association between the occurrence of irAEs and RFS. Results: Consistent with the main analysis in the ITT population (n = 1019, Eggermont et al, NEJM, 2018), RFS was longer in the pembrolizumab than in the placebo arm (HR = 0.56, 98.4% CI: 0.43-074) among pts who started the treatment (n = 1011). The incidence of irAE on study was 37.3% in the pembrolizumab (n = 509) and 9.0% in the placebo arm (n = 502) and, in each treatment group, it was similar in males and females. The occurrence of an irAE was significantly associated with a longer RFS in the pembrolizumab arm (HR = 0.61, 95% CI: 0.39-0.95, P = 0.03). This was true for both males and females. However, in the placebo arm, no association was observed (HR = 1.39, 95% CI: 0.83-2.32, P = 0.21). Compared to the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater (P = 0.028) after an onset of an irAE (HR = 0.37, 95% CI: 0.24-0.57) than without/before an irAE (HR = 0.61, 95% CI: 0.49-0.77). Conclusions: In the EORTC 1325/KEYNOTE-054 study conducted in high-risk stage III melanoma pts, the occurrence of an irAE was strongly associated with a longer RFS in those treated with pembrolizumab, but not with placebo. Clinical trial information: NCT02362594.

9593 Background: With the approval of adjuvant therapy for stage III melanoma, accurate staging in melanoma patients is important more than ever to prevent over- or undertreatment. Sentinel node biopsy (SNB) is an accurate staging tool, yet the presence of capsular nevi (CN) can lead to a false positive diagnosis. We compared positive SNB and CN patient outcomes and aimed to evaluate the cause of false positive SNB and discern diagnostic pitfalls in their evaluation. Methods: Retrospective analysis of AJCC 7th Edition stage IIIA melanoma patients (N1-2a, non-ulcerated primary tumor) who were treated at our institute between 2000 and 2015. SNB slides were reviewed for this study by an expert melanoma pathologist. Baseline characteristics were assessed for SN+ and CN+ patients. Concordance rates for SNB evaluation before and after revision were documented and diagnostic pitfalls were discerned. Results: 169 patients were diagnosed, 10 could not be reviewed due to lack of evaluable slides. Of these 159 cases, 14 patients originally diagnosed with metastatic melanoma were shown to have capsular nevi (8.8%). Another 2 patients were shown to have melanophages that were incorrectly interpreted as metastases (1.3%). Thus, 10.1% was considered false positive after revision. In 14 patients the SN tumor burden was originally reported > 1 mm, but turned out to have < 1 mm SN tumor burden. 4 patients originally reported as SN tumor burden < 1 mm before revision turned out to have > 1 mm SN tumor burden. These 32 patients (20%) might have potentially been over- or undertreated in the current era of adjuvant therapy for stage III melanoma. Conclusions: False positive sentinel node results in melanoma are real, they can occur for a number of reasons, but distinguishing metastatic melanoma from benign capsular nevi and melanophages can be a diagnostic challenge. We plead for an expert pathologists’ review in any case, but certainly when using the SNB+ results to determine treatment consequences for SN+ melanoma patients.

TPS145 Background: Adjuvant pembrolizumab showed significantly longer recurrence-free survival compared with placebo in resected stage III melanoma in the KEYNOTE-054 study [1]. KEYNOTE-716 is a randomized, placebo-controlled, multicenter phase 3 study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Methods: Patients must be ≥12 years of age and have newly diagnosed, completely resected stage IIB/IIC cutaneous melanoma, defined by the AJCC Cancer Staging Manual, 8th edition [2] (wide excision and negative sentinel lymph node biopsy, with no evidence of distant metastasis). Patients cannot have mucosal or uveal melanoma or have received prior treatment for melanoma, including radiation, beyond resection of primary disease within 12 weeks of the start of study therapy. The study has a 2-part design. In the double-blind phase (part 1), patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg for patients ≥18 years or 2 mg/kg for patients 12-17 years (maximum dose, 200 mg) or placebo every 3 weeks for 17 cycles. Stratification: 1 stratum for pediatric patients (12-17 years); 3 strata for adult patients per T stage (T3b/T4a/T4b). Study treatment will begin within 12 weeks of complete resection. Tumor imaging will be performed every 24 weeks while treatment is ongoing, at the end of treatment, every 6 months for the first 3 years off treatment, and then yearly for up to 2 years or until recurrence (up to 5 years of total imaging). Adverse events will be graded per NCI Common Terminology Criteria for Adverse Events, version 4.0. In the unblinded phase (part 2), patients with confirmed recurrence may be rechallenged (patients received pembrolizumab in part 1) or crossed over to pembrolizumab (patients received placebo in part 1). Resected local or distant recurrence or unresectable disease will be treated for an additional 17 or 35 cycles, respectively. Tumor imaging in part 2 will occur every 12 weeks while treatment is ongoing. The primary end point is recurrence-free survival; secondary end points are distant metastasis-free survival, overall survival, and safety. Approximately 954 patients will be enrolled. Clinical trial information: NCT03553836.

There are insufficient numbers of prognostic factors available for prediction of clinical outcome in patients with stage III malignant cutaneous melanoma, even when known adverse pathological risk factors, such as macrometastasis, number of lymph node metastases, and ulceration are taken into consideration. The aim of this study was therefore to identify additional prognostic factors to better predict patients with a high risk of relapse, thus enabling us to better determine the need for adjuvant treatment in stage III disease. An RNA oligonucleotide microarray study was performed on first regional lymph node metastases in 42 patients with stage III melanoma: 23 patients with short-term survival (≤ 13 months) and 19 with long-term survival (≥ 60 months), to identify genes associated with clinical outcome. Candidate genes were validated by real-time PCR and immunohistochemical analysis. Several gene ontology (GO) categories were highly significantly differentially expressed including glycolysis (GO: 0006096; P0.001) and the pigment biosynthetic process (GO: 0046148; P0.001), in which overexpression was associated with short-disease-specific survival. Three overexpressed glycolytic genes, GAPDHS, GAPDH, and PKM2, and two pigment-related genes, TYRP1 and OCA2, were selected for validation. A significant difference in GAPDHS protein expression between short- and long-term survivors (P=0.021) and a trend for PKM2 (P=0.093) was observed in univariate analysis. Positive expression of at least two of four proteins (GAPDHS, GAPDH, PKM2, TYRP1) in immunohistochemical analysis was found to be an independent adverse prognostic factor for disease-specific survival (P=0.011). Our results indicate that this prognostic panel in combination with established risk factors may contribute to an improved prediction of patients with a high risk of relapse.

Measures of prognosis are typically estimated from the time of diagnosis. However, these estimates become less relevant as the time from diagnosis increases for a patient. Conditional survival measures the probability that a cancer patient will survive some additional number of years, given that the patient has already survived for a certain number of years. In the current study, the authors analyzed data regarding patients with stage III melanoma to demonstrate that survival estimates from the time of diagnosis underestimate long-term survival as the patient is followed over time. The probability of surviving to year 5 for patients at the time of presentation compared with patients who had already survived for 4 years increased from 72% to 95%, 48% to 90%, and 29% to 86%, respectively, for patients with substage IIIA, IIIB, and IIIC disease. Considering the major role played by survival estimates during follow-up in patient counseling and the development of survivorship programs, the authors strongly recommend the routine use of conditional survival estimates.

Contains fulltext : 170905.pdf (Publisher’s version ) (Open Access) PURPOSE: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. EXPERIMENTAL DESIGN: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. RESULTS: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154-162, gp100:280-288, and tyrosinase:369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154-162, gp100:280-288, and tyrosinase:369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. CONCLUSIONS: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response.

Lymph node dissection is a standard treatment for Stage III melanoma. Indocyanine green fluorescence lymphography and angiography may help to perform en-bloc dissection, to decide the levels to be excised, and to prevent postoperative wound dehiscence especially in groin dissection.

Stage III melanoma, defined as regionally advanced disease based on the presence of either microscopic or gross lymph node involvement, remains a challenge for clinicians to treat secondary to the limited therapies that have clearly shown any benefit in overall survival compared with observation alone. The US FDA approved peginterferon alfa-2b (pegIFN alfa-2b) in March 2010 for use in the adjuvant setting to treat stage III malignant melanoma. The approval of pegIFN alfa-2b was based on results from the EORTC 18991 trial, which showed pegIFN alfa-2b had superior relapse-free survival compared with observation alone. PegIFN alfa-2b is administered subcutaneously and, aside from the nonpegylated IFN-α, is the only systemic therapy approved by the FDA to treat stage III melanoma. In this review, emphasis will be placed on describing the history of the use of IFN-α in regionally advanced melanoma, with a primary focus on the efficacy and safety profile of pegIFN alfa-2b as an adjuvant therapy in treating mali...

Introduction: High preoperative serum S-100B values and Standardized Uptake Values (SUV) of Fluorodeoxyglucose (FDG) in PET for clinically stage III melanoma patients could be indicators of recurrence after surgical treatment. Aim was to assess the correlation and the prognostic value of these markers.Methods: All melanoma patients with palpable nodal metastases, without distant metastases, were included from February 2004 to December 2007. Preoperative SUV and S-100B was determined. The correlation between SUV and S-100B and their relations with DFS and DSS were calculated by Cox Proportional Hazard Analysis.Results: 62 Patients, median age 56.9 years, were included in the study. An elevated S-100B was found in 31 patients (50%) and elevated SUV in 24 patients (38.7%). No relation was found between S-100B and SUV. DFS was reduced (31.1%) for patients with an elevated S-100B (HR = 3.1; p = 0.02) in comparison to a normal S-100B (44.6%). The DFS was 42.0% for patients with a SUV below the cut-off point and 29.0% for patients with an elevated SUV (HR = 1.1; p = 0.8). DSS was 60.7% in a normal S-100B and 44.7% for patients with an elevated S-100B (HR = 2.2; p = 0.07). DSS was 59.1% for patients with a normal SUV and 43.5% for patients with elevated SUV (HR = 1.1; p = 0.8).Conclusion: S-100B and SUV in stage III melanoma are not correlated and each have different associations with various histopathological factors. S-100B, in contrast with SUV, is associated with nodal tumor load, and when elevated, predicts a shorter DFS. Synopsis: Preoperative serum S-100B and Fluorodeoxyglucose (FDG) Standardized Uptake Value (SUV) in clinically stage III melanoma are not correlated. S-100B is a strong predictor for Disease Free Survival (DFS) in stage Ill melanoma. (C) 2010 Elsevier Ltd. All rights reserved.

9591Background: The COMBI-AD trial demonstrated that adjuvant treatment with D + T in patients (pts) with resected stage III BRAF-mutant melanoma significantly reduced the risk of melanoma recurren...

e21574Background: Adjuvant treatment options for stage III melanoma patients (pts) are increasing with the approval of new agents. Little has been reported about the real world treatment patterns i...

The EORTC 18991 trial assessed the effect of long-term adjuvant pegylated interferon (Peg-IFN) alpha-2b administered weekly in patients with lymph node-positive melanoma. Serum concentrations were analyzed to determine exposure to Peg-IFN alpha-2b.After surgery, patients were randomized to receive Peg-IFN alpha-2b or to observation only. The treatment group received 6 microg/kg/week Peg-IFN alpha-2b subcutaneously for 8 weeks, followed by a maintenance dose of 3 microg/kg/week for up to 5 years. Blood samples were collected between months 3 and 60.A total of 208 Peg-IFN alpha-2b concentrations from 48 patients were available. Serum trough concentrations increased in a dose-related manner. Mean dose-normalized serum concentrations and intersubject variability over the 5-year study period in patients with melanoma were similar to those observed in patients with chronic hepatitis.Data suggest that the exposure to Peg-IFN alpha-2b was sustained during long-term adjuvant treatment with Peg-IFN alpha-2b in patients with melanoma, consistent with the EORTC 18991 trial's conclusion of a significant, sustained, and relapse-free survival benefit.

Purpose: Patients with macroscopic stage III melanoma represent a heterogeneous cohort with average 5-year overall survival rates of Experimental Design: Lymph node sections from 29 patients with stage IIIB and IIIC melanoma, with divergent clinical outcome including 16 “poor-prognosis” and 13 “good-prognosis” patients as defined by time to tumor progression, were subjected to molecular profiling using oligonucleotide arrays as an initial training set. Twenty-one differentially expressed genes were validated using quantitative PCR and the 15 genes with strongest cross-platform correlation were used to develop two predictive scores, which were applied to two independent validation sets of 10 and 14 stage III tumor samples. Results: Supervised analysis using differentially expressed genes was able to differentiate the prognostic groups in the training set. The developed predictive scores correlated directly with clinical outcome. When the predictive scores were applied to the two independent validation sets, clinical outcome was accurately predicted in 90% and 85% of patients, respectively. Conclusion: We describe a gene expression profile that is capable of distinguishing clinical outcomes in a previously homogeneous group of stage III melanoma patients.

There is no consensus regarding the optimal tumor markers for melanoma. We compared 3 tumor markers, TA90-immune complex (TA90IC), melanoma-inhibiting activity (MIA) protein, and S100B protein in Stage III melanoma patients undergoing adjuvant vaccine immunotherapy.The serum of 75 patients representing 3 prognostic cohorts was assayed for the tumor markers prior to initiating immunotherapy and at 6 follow-up time points. Upper limits of normal for TA90IC, MIA and S100B were set at OD 0.41, 8.5 ng/ml, and 2.5 microg/l, respectively.At least 1 marker became elevated prior to 41 (80 percent) of 51 recurrences. TA90IC was the earliest elevated marker in 29 (57 percent), MIA in 11 (22 percent), and S100B in 4 (8 percent). Multivariate regression analysis revealed that TA90IC was an independent predictor of survival when elevation occurred between 2 weeks and 3 months, whereas MIA was an independent predictor at 4-6 months. In the poor prognostic cohort, mean values for MIA and S100B increased progressively, whereas TA90IC exhibited a parabolic curve.In this patient population, TA90IC and MIA were complementary; elevation of the immune complex preceded elevation of the tumor antigen in patients who developed recurrence. Additional studies in populations not receiving vaccine will further clarify the clinical utility of these assays.

International audience; Introduction: When sentinel lymph node is positive for metastasis (exclusion for micro-metastasis) and in cases of palpable adenopathy, a lymphadenectomy should be performed. Many incisional surgical approach have been described in literature. We perform two type of incision (vertical with skin excision and transversal) for inguinal lymphadenectomy. The aim of this study was to compare post-operative morbidity between these two approach in cases of Stage III Melanoma. We analyzed chronic lymphoedeme, skin necrosis, wound dehiscence, wound infection and seroma rates between the two techniques.-three patients underwent to inguinal lymphadenectomy for Stage III melanoma at CHU of Rennes. Patients were stratified in 2 groups according to the surgical approach, group 1 with a vertical incision with skin excision and group 2 with a transverse incision. Results: Chronic lymphedema rate for group 1 was 37.04% and for group 2 rate was 26.92%, this complication was lower un group 2 but no significant difference was observed (p=0.558). Skin necrosis (p=0.235), wound dehiscence (p=1.000), wound infection (p=0.236) and seroma (p=0.757) were not significantly different. Two cases of skin necrosis were observed in group 2 (7.69%) and none in group 1. Conclusion: We do not found significant difference for chronic lymphedema between these two approach. However, we had less lymphedema with the transversal technique which has the advantage to reduce the skin suffering when external iliac lymphadenectomy dissection is necessary in addition to the inguinal lymphadenectomy.