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PURPOSE Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma. PATIENTS AND METHODS Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis. RESULTS At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined. CONCLUSION Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.

e18758 Background: There are now numerous effective adjuvant immunotherapy options for surgically resected stage III melanoma including novel checkpoint inhibitors and targeted therapies. Current guidelines recommend that the decision to treat stage III melanoma with adjuvant immunotherapy should be individualized and based upon disease burden, patient goals and anticipated therapy tolerance. We sought to assess the contribution of patient, tumor and facility factors on the implementation of immunotherapy in patients with surgically resected stage III melanoma. Methods: Using the National Cancer Database (NCDB), patients from 2012-2017 that underwent excision and were found to have a positive sentinel node were identified. A multivariable mixed effects logistic regression model with a random intercept for site was used to determine the effect of patient, tumor, and facility variables on the probability of immunotherapy. Reference Effect Measures (REM) were used to estimate the variation in immunotherapy use due to unmeasured facility factors (contextual effects) after adjusting for measured patient, tumor, and facility variables. Results: From 2012 to 2017, the percent of patients with stage III melanoma treated with adjuvant immunotherapy increased from 23.7% to 38.5% (p < 0.05). Overall, younger patients and patients with private insurance were more likely to receive immunotherapy. Tumor factors associated with increased use of adjuvant immunotherapy included increasing depth, mitotic rate ³1, ulceration, lymphovascular invasion (LVI), and undergoing a completion lymph node dissection (CLND). Additionally, treatment at a facility with a surgical volume

e21570 Background: Advancements in systemic therapy have reduced recurrence, and the adoption of nodal surveillance in place of dissection has reduced morbidity for patients with Stage III melanoma. The objective of this study was to describe the timing and pattern of recurrence in stage III melanoma patients and evaluate the impact of adjuvant treatment and nodal surveillance. Methods: A multicenter retrospective chart review of patients with pathologically confirmed Stage III cutaneous melanoma seen at either the Juravinski Cancer Centre or Walker Family Cancer Centre in Ontario, Canada from January 1, 2017 to December 31, 2019. Results: There were 137 patients with Stage III melanoma: 18% IIIA, 22% IIIB, 52% IIIC, and 8% Stage IIID as per the 8th American Joint Committee on Cancer (AJCC) 2018 staging system. 103 (75%) patients had sentinel lymph node biopsy (SLNB) only as part of initial surgical therapy, 6 (4%) had SLNB with completion dissection, and 25 (18%) had upfront radical nodal dissection. 67 (49%) patients received adjuvant therapy, of which 50 (74%) had immunotherapy, 17 (25%) received BRAF-targeted therapy, and 1 (1%) had interferon. 54 (39%) patients developed recurrent disease, with a median time to recurrence of 8.5 months (IQR: 4.3-14.9). The recurrence rates were 63% in patients who did not have adjuvant treatment and 37% in those who had adjuvant therapy, with a median time-to-recurrence of 7.5 and 9.0 months respectively. There were 30 (56%) loco-regional recurrences and 24 (44%) distant recurrences. Of the patients with loco-regional recurrence, 26 (87%) had SLNB only compared to 4 (13%) who had upfront or completion dissection. 12 (24%) patients recurred while on adjuvant treatment (7 distant recurrences and 5 loco-regional recurrences), and 8 (13%) patients recurred following completion of adjuvant treatment (5 distant recurrences and 3 loco-regional recurrences). Recurrences were detected by patients, clinicians, CT and nodal US surveillance in 43%, 20%, 28% and 9% of cases, respectively. The majority of loco-regional recurrence was detected clinically (67%) rather than by radiologic surveillance (33%). Of the 30 loco-regional recurrences, 24 underwent surgical resection of the recurrence, 4 had subsequent systemic therapy without surgery, 1 had intra-tumoral injections and 1 had no treatment. Conclusions: Recurrences in Stage III melanoma occur early, often within a year, with higher rates of loco-regional rather than distant disease. Recurrence rates were lower in those who received adjuvant therapy, but the majority of recurrences were detected by patients or clinicians, including loco-regional recurrences in patients who had SLNB only despite surveillance nodal US.

9579 Background: Recently, trials have shown the benefit of adjuvant aPD-1 therapy in macroscopic stage III melanoma patients. This treatment has been incorporated in daily clinical practice, however, a substantial part of patients still does not benefit from this therapy, as they develop recurrences. The aim of this study is to evaluate the results of adjuvant aPD-1 therapy and the potency of the IFNγ signature as a prognostic or predictive marker, as it has proven to be predictive of response in neoadjuvant trials. Methods: Patients participating in an ongoing biobank study and naïve for systemic therapy were included, between 10-2017 and 06-2020, after complete resection of macroscopic stage III melanoma. Approval and reimbursement of adjuvant therapy in the Netherlands started in 12-2018, resulting in 2 cohorts of similar high risk patients: prior to availability of adjuvant aPD-1 (cohort A) and thereafter (cohort B). Data cut-off for clinical data was January 1st 2021. Transcriptome sequencing was performed on samples of stage III melanoma by CeGaT GmbH, IFNγ signature was determined on these data with the median as cut-off. Clinical data were compared between cohort A and B as intention-to-treat population, including patients with a recurrence before adjuvant therapy start (n=10). Results: In total, 99 patients were included: 50 in cohort A and 49 in cohort B. Majority of included patients had thick primary melanomas (Breslow >2mm in 59.6%) and stage IIIC/IIID disease (83.3%) according to AJCC 8th edition. At a median follow-up of 20.6 months (95% confidence interval [CI] 16.6-24.7), median recurrence-free survival (RFS) was 6.1 months (95%CI 3.9-8.4) versus 22.8 months (95%CI 8.7-36.9), significantly in favor of cohort B (p=0.011). Median overall survival (OS) was not reached in both patient groups, but was overall significantly different (p=0.040), favoring cohort B. RNA sequencing was performed in 25 patients who received adjuvant therapy and in 24 who did not, excluding patients with an early recurrence (

9577 Background: The management of patients with resected stage III melanoma has changed in recent years, and real-world data on recurrence patterns and adjuvant therapy responses are scarce. This study assessed adjuvant treatment patterns and outcomes in patients with advanced melanoma by BRAF status and relapse location. Methods: Patients diagnosed with stage III advanced melanoma between January 2011 and February 2020 in the nationwide Flatiron Health electronic health record–derived deidentified database were included if they were ≥18 years, received approved first-line (1L) adjuvant therapy after January 2018 with checkpoint inhibitors (CPIs; eg, nivolumab, pembrolizumab) or targeted therapies (TTs; eg, dabrafenib/trametinib), had 6 months’ follow-up and had ≥1 visit after starting adjuvant therapy (Cohort 1). Patients from Cohort 1 were included in Cohort 2 if they had a recurrence following initiation of adjuvant therapy, and those from Cohort 2 were included in Cohort 3 if they had a distant recurrence and available documented BRAF status at any time. Time to next systemic treatment (TTNT), overall survival (OS) and relapse free survival (RFS) were estimated using Kaplan-Meier (KM) methods from adjuvant therapy start (Cohort 1), first recurrence date (Cohort 2) or first distant recurrence date (Cohort 3). Results: Cohort 1 included 447 patients receiving 1L adjuvant therapy; Cohort 2 included patients after first distant (n = 47) or local (n = 35) relapse; Cohort 3 included distant-recurrent patients with tumors that were BRAF wild type (WT) (n = 22) or BRAF mutant (n = 23). The majority of patients were aged < 65 years. Across cohorts, relative use of TTs vs CPIs was similar: Cohort 1 (4.5% vs 96%), Cohort 2 (2.4% vs 98%) and Cohort 3 (2.2% vs 98%). Nivolumab was the most frequent treatment used across cohorts (84%-88%). In Cohort 1, 1- and 2-year KM probabilities for OS, RFS and TTNT were 93.5%/83.8%, 83.2%/70.6% and 84.0%/62.4%, respectively. In Cohort 2, for patients with local recurrence, 6- and 12-month OS probabilities were 93.4% and 78.8%, respectively, which were substantially higher than those for patients with distant recurrence (64.5% and 46.9%). In Cohort 3, for patients with documented BRAF mutations, 6- and 12-month OS rates from disease recurrence were 79.1% and 49.4%, respectively, which were greater than for those with BRAF-WT tumors (54.1% and 46.3%). Conclusions: Early RFS and OS outcomes for patients with surgically resected Stage III melanoma appear comparable to those reported in randomized clinical studies. The majority of patients with advanced melanoma, including patients who experienced recurrence, initiated treatment with CPIs. OS rates were numerically greater for Cohort 3 patients with BRAF-mutant tumors. Outcomes for patients with distant recurrence after adjuvant therapy remain unfavorable and represent a continued unmet medical need.

9502 Background: Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen. Methods: We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response (RECIST 1.1) was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses. Results: A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( < 10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (≥50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1 -year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts (p = 0.016). There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment. Conclusions: Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

e21569 Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1mg/kg for two cycles(N3+I1) or anti-PD1 for 3-8 weeks for clinical stage III melanoma have shown rates of pCR/near-pCR about 60% or 30%, respectively. The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-response have a worse outcome and early identification of this group may allow us to tailor treatment before surgery. Methods: We conducted a retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant immune checkpoint blockade who did baseline and pre-operative FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2021, nine patients with clinical stage III melanoma were identified. Six patients received Nivolumab 3m/kg and Ipilimumab 1mg/kg for two cycles and 3 received anti-PD1 for 60 days. Baseline FDG-PET/CT showed just one avid lesion in 7 patients, 2 avid lesions in one patient and 3 avid lesions in one patient. All known lesions identified by CT scan were also captured by FGD-PET/CT. After the neoadjuvant treatment, 4 patients achieved pCR/near-pCR. All of them were treated with N3+I1. Two of them had metabolic complete response (including the one with 3 PET- avid lesions) and 2 had reduction on FDG concentration (-31% and – 76%). Three patients had absence of response: 100% of viable tumor cells (VTC), all of them with increase in FDG concentration (+12% to + 307%) and appearance of a new lesion in one case. Two out of them were treated with anti-PD1. One patient had partial response (40% of VTC). Interestingly, this patient developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of mediastinal lymph-nodes. One patient, who had two lesions, presented a mixed response: complete response in one and 90% of VTC in the other. FDG-PET/CT was able to detect both responses (metabolic complete response and increase of FGD concentration of 17%, respectively). Conclusions: Reduction in FGD-PET/CT concentration with no appearance of new lesion(s) is associated with significant pathological response. An increase of SUV or appearance of new lesion(s) should be carefully interpreted.

9551 Background: Recent data suggest that patients with stage III melanoma are at high enough risk for developing CNS metastases to consider routine surveillance neuroimaging (Journal of Clinical Oncology; PMID: 31990608). Given that a subset of stage II patients have a worse prognosis than stage III patients, we investigated the risk of developing brain metastases in stage II disease and compared it to the risk in stage III disease. Methods: We studied a cohort of prospectively enrolled melanoma patients who had protocol driven follow-up at New York University (NYU) Langone Health. We investigated both the incidence and time to development of CNS metastases, and explored whether the frequency of CNS metastases as a first isolated site of distant disease varies among the different stages. Results: The study cohort included a total of 1,102 patients (stage II: n = 619 with median follow-up 56.5 months; stage III: n = 483 with median follow-up 40.9 months). 85/619 (14%) stage II and 91/483 (19%) stage III patients developed CNS metastases (p = 0.03). The estimated 5-year cumulative incidence was 9% in stage IIA, 14% in stage IIB, and 29% in stage IIC patients (p = 0.0001). It was 10% in stage IIIA, 32% in stage IIIB, 23% in stage IIIC, and 49% in stage IIID (p = 0.0001). The CNS was the site of first metastasis for 32/154 (21%) stage II patients who developed distant disease compared to 28/214 (13%) stage III patients (p = 0.06). Conclusions: A subset of stage II patients are at an elevated risk for developing CNS metastases within 5 years of their initial diagnosis, which is comparable to that seen in stage III patients. The frequency of the CNS as a first site of metastasis in stage II melanoma suggests a propensity for brain tropism that cannot only be explained by a generalized pro-metastatic phenotype. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals.

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

TPS10088 Background: Recent clinical trials of neoadjuvant (neo-adj) ipilimumab combined with nivolumab (OpACIN & OpACIN-neo) in resectable stage III melanoma show that a pathological response ( < 50% viable tumour at the tumour bed as determined by histopathological analysis) is associated with a prolonged relapse-free survival compared to no pathological response. Furthermore, recurrences seldom occur in those who have a pathological response following neo-adj immunotherapy with only 1/71 pts (1.4%) having recurred. In contrast, 15/23 (65.2%) pts with no pathological response have relapsed to date. The NeoPeLe trial will test the hypothesis that the synergistic combination of PD-1 blockade (pembrolizumab) with anti-angiogenic/multiple RTK inhibitor (lenvatinib) will result in a high rate of pathological response in the resected surgical specimen with a low rate of toxicity. Tissue and blood biomarkers are drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response and resistance. We will compare pathological response rate, and other clinical outcomes in this study, with previously published neo-adj clinical trials to select the best schedules for larger-scale clinical testing. Across neo-adj studies, we will also analyse the tissue collected to explore determinants of the optimal therapy for individual pts, whilst minimising toxicity. Methods: Eligible pts with stage IIIB/C/D, resectable and measurable (RECIST 1.1) nodal metastatic melanoma will be enrolled to this phase II single-centre trial (n = 20). All pts undergo complete nodal resection (RES) at wk 6 following neo-adj therapy with pembrolizumab (200mg, IV, 3 wkly) and lenvatinib (20mg, oral, daily). Adjuvant therapy with pembrolizumab is given for 46 wks after RES. After 52 wks of the study treatment, pts will be followed for relapse and survival for 5 years. CT and FDG PET/CT are used to measure response and exclude progression in the neo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, day 8, RES and at relapse if feasible. Faecal samples are collected at baseline and before RES. The primary endpoint is the complete pathological response rate at RES following 6 wks of neo-adj therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analyses. Clinical trial information: NCTNCT04207086.

10015 Background: Early results of the OpACIN-neo study testing 3 different dosing schedules of neoadjuvant IPI + NIVO demonstrated that 2 cycles IPI 1mg/kg + NIVO 3mg/kg (IPI1NIVO3, arm B) was the most favorable schedule with 20% grade 3-4 immunotherapy-related adverse events (irAEs) and a pathologic response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months, none of the 64 patients (pts) with a pathologic (path) response ( < 50% viable tumor cells) versus 9/21 (43%) without a path response had relapsed. Here, we present the updated 2-year RFS, EFS and long-term toxicity data. Methods: In the phase 2 multi-center OpACIN-neo trial, 86 stage III melanoma pts with resectable and RECIST 1.1 measurable lymph node metastasis were randomized between 3 different dosing schedules of neoadjuvant IPI + NIVO: arm A: 2x IPI3+NIVO1 Q3W (n = 30), arm B: 2x IPI1+NIVO3 Q3W (n = 30), and arm C: 2x IPI3 Q3W followed by 2x NIVO3 Q2W (n = 26). Lymph node dissection was scheduled at week 6. Primary endpoints were toxicity, radiologic RR and pRR; RFS and EFS were secondary endpoints. Results: After a median FU of 24.6 months, the median RFS and EFS was not reached in any of the 3 arms. In total, 2 pts progressed before surgery, 12 pts relapsed (11 pts without path response and 1 pt with pCR) and 5 pts died (4 due to melanoma and one pt due to toxicity). Estimated 24-months RFS was 84% (95% CI 76-92%) for the total population, 97% (95% CI 93-100%) for pts with a path response and 36% (95% CI 17-74%) for pts without a path response. Estimated 24-months EFS for the total population was 82% (95% CI 74-91%). RFS and EFS did not differ between the arms. Of the 81 pts alive, 55 (68%) have ongoing irAEs; only 2 (3%) pts have ≥ grade 3 irAEs. Most frequent ongoing irAEs were vitiligo (35%), fatigue (14%), sicca syndrome (11%), rash (10%), arthralgia (7%) and endocrine toxicities (20%). 17 pts need hormone replacement therapy: 11 (14%) thyroid hormone and 7 (9%) hydrocortisone. No difference between treatment arms was observed. Ongoing surgery-related AEs were observed in 31 (38%) pts of which lymphedema was seen most frequently (17 pts; 21%). Conclusions: Extended follow-up data shows that 2 cycles of neoadjuvant IPI + NIVO without adjuvant therapy induces durable RFS. While almost no ongoing high-grade irAEs were observed, the majority of pts have low-grade ongoing toxicities. These outcomes strongly support the need to test 2 cycles of neoadjuvant IPI1+NIVO3 versus adjuvant anti-PD-1 in a randomized phase 3 trial. Clinical trial information: NCT02977052.

e22096 Background: Large randomized trials have proved that targeted therapy (TT) and immunotherapy (IT) can improve RFS for resectable Stage III melanoma. However, there is still a risk around 15%~25% of relapse within 1 year, especially worse for Stage IIID disease. Several neoadjuvant trials have shown a potentiality of long-term relapse-free after a pathologic complete response, especially for immunotherapy. We conducted a prospective study to investigate the impact of preoperative treatment on the anti-tumor efficacy and disease-free survival for Chinese melanoma. Methods: Stage IIID patients with matted nodes were recruited. For BRAF V600E-muted patients, Vemurafenib (V) was given for one months ahead of the surgery. For BRAF-wide-type patients, anti-PD1 antibody, Pembrolizumab(P) or Toripalimab (T) was given one dose per 3 weeks until response or intention-to-progression was observed. Pathologic assessment followed the principles for neoadjuvant therapy established by INMC. Results: Totally seven patients have been recruited. Detail information was listed in Table. Clinical ORR was 71%, however with no pCR observed. One patient in Vemurafenib group occurred brain mets within 1 month after surgery. All four patients in anti-PD1 group were relapse-free so far after median follow-up of 11 months. Conclusions: Preoperative BRAF targeted and anti-PD1 immunotherapy might guarantee a positive impact on anti-tumor response and local disease control for marginally resectable melanoma. However, the pathological criteria for neoadjuvant treatment might not be suitable to evaluate the matted or bulky specimen after preoperative treatment. [Table: see text]

TPS10087 Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23th, 2020. Clinical trial information: NCT04133948.

10064 Background: Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates of 74-78% (OpACIN and OpACIN-neo trial), thus the role of Therapeutic Lymph Node Dissections (TLND) in patients with major pathologic responses (MPR: pathological (near) complete response) is now unclear. In the PRADO trial, TLND was omitted in patients with MPR in their index lymph node ((ILN), the largest LN marked prior to neoadjuvant therapy). We sought to determine if less extensive surgery is associated with better Health Related Quality of Life (HRQoL). These are the first results of the comparison of HRQoL between patients undergoing a TLND or less extensive ILN excision. Methods: HRQoL was assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). A generalized estimation equation was used to assess the difference in HRQoL outcomes between patients who underwent TLND (pathological non- and partial-responders, pNR/pPR) versus those who did not (pathological (near)complete responders, pNCR/pCR). Differences were adjusted for age, gender and follow-up (FU, in weeks), but not for pathological responses (pNR, pPR, pNCR & pCR). Differences in QLQ-C30 scores were classified as clinically important according to published guidelines. Results: A total of 49 patients from the PRADO study had reached at least 24 weeks FU, and were included in the first explorative analysis. The median age of this study population was 58 years (range, 22-84). Questionnaire completion rates were high: 94% at baseline, 100%, 90%, 88% at week 6, 12 and 24, respectively. Sixteen (33%) patients underwent TLND versus 33 (67%) who had ILN excision only. Over a FU period of 24 weeks, patients who underwent TLND scored significantly lower on global (68 vs 78, adjusted difference (diff) = -9.53, p = .005), physical (84 vs 94 diff = -11.1, p = < .001), emotional (69 vs 83, diff = -11.7, p = .001), role (70 vs 85, diff = -13, p = .004), and social functioning (81 vs 91, diff = -8.9, p = .016) and had a higher symptom burden of fatigue (35 vs 23, diff = 11.1, p = .004), insomnia (38 vs 18, diff = 16.6, p = .002) and financial impact (12 vs 4, diff = 7.9, p = .027) than patients undergoing ILN excision only. These differences were indicated as clinically relevant. Conclusions: First results from PRADO suggest that reducing the extent of surgery following neoadjuvant immunotherapy might result in better HRQoL of high-risk stage III melanoma patients. Clinical trial information: NCT02977052.

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.

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.

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...

9586 Background: The combination of IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present, indicating that adjuvant immunotherapy may work most efficiently, when initiated prior to surgery. Methods: Two-arm Phase 1b feasibility trial of 20 high risk AJCC stage IIIB and IIIC melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split two courses neo-adjuvant and two courses adjuvant. Results: In this update all 20 patients are evaluable. Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 18/20 patients had to stop early due to grade 3/4 toxicities. Neo-adjuvant IPI+NIVO reduced tumor load in 8/10 patients (3 pCR, 4 near-pCRs [minimal remaining micrometastases], 1 pPR [75% reduction], 1 SD and 1 PD). To date, after a median follow-up of 45 weeks (range 13-74), none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for both non-responders within the neo-adjuvant arm and for 3 patients within the adjuvant arm. TCR sequencing and MHC tetramer-based analysis to compare the induction and expansion of tumor (neo-)antigen-specific T cell responses between both treatment arms are underway and will be presented. Conclusions: The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage III melanoma patients is feasible and induces very frequent responses. At the same time, severe grade 3/4 toxicity is more frequent than expected from stage IV melanoma patient study data. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage III melanoma. Adjusted combination schemes are currently tested in the phase 2 OpACIN-neo trial, with the aim of reducing toxicity while preserving efficacy. Clinical trial information: NCT02437279.

159 Background: High dose Interferon (IFN) was the standard adjuvant treatment used for stage III melanoma between 2004-2010. To our knowledge, this is the largest study using the NCDB to determine the impact of immunotherapy used prior to 2011 in stage III melanoma. Methods: We identified 19,864 patients with stage III melanoma between 2004-2010. Among these, 5,406 of them received immunotherapy. Chi-square analysis was used to determine demographic differences between those with versus without immunotherapy. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < 0.05 indicated statistical significance. Results: Patients who received immunotherapy had a mean survival of 89.8 months while those who did not had a mean survival of 71 months. The percentage of patients alive at 5 and 10 years was 62% and 52% (among those who received immunotherapy) compared to 46% and 32% (among those who did not receive immunotherapy) respectively. A much higher percentage of these patients were privately insured (73% vs. 47.1%, p

visits for patients treated for localized primary cutaneous melanoma. J Clin Oncol 29:4641-4646, 2011 4. Siegel R, Ward E, Brawley O, et al: Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212-236, 2011 5. Romano E, Scordo M, Dusza SW, et al: Site and timing of first relapse in stage III melanoma patients: Implications for follow-up guidelines. J Clin Oncol 28:3042-3047, 2010

Inthisissue,Mianetal 1 usehigh-resolutionmassspectrometry (MS) to define the serum peptidome of patients with melanoma. They trained machine learning algorithms to recognize serum peptidomic patterns that clustered with specific disease states. This strategy enabled them to discriminatestageImelanomapatientsfromstageIVpatients. Furthermore,thepeptidomicpatternswereabletodiscriminate stage III melanoma patients who developed tumor recurrences within the first year after diagnosis from stage III patients who remained disease free. An artificial neural network analysis of the peptide patterns was able to correctly identify 80% of patients who eventually experienced recurrence,comparedwitha21%predictionratewhentheseinves

3084Background: Cancer-testis antigen NY-ESO-1 is a highly immunogenic melanoma antigen which has been adopted for adjuvant vaccine trials. Three such trials (NCT00124124, NCT00821652, NCT01079741)...

9555Background: Circulating tumor cells have been postulated as indicators of the metastatic spread of cancer via the lymphatic and circulatory systems. We have developed a photoacoustic flow cytom...

e21063Background: Current AJCC staging criteria provide limited prognostic value for stage III melanoma patients, who have a 50% chance of recurrence. Complete loss of PTEN expression is known to b...

9016 Background: There is a need for more sensitive and specific prognostic markers for advanced stage melanoma patients to help improve the risk-benefit ratio of systemic adjuvant therapies. While...

e20097 Background: Significant advances have been made in the treatment of stage IV melanoma through the use of targeted therapies in patients (pts) with BRAF V600 mutations. However, there is a cr...

9064 Background: The extent of regional lymphadenectomy in stage III melanoma is still controversial because most recommendations are not based on statistical analysis of the minimum number of excised nodes necessary to minimize regional recurrence. Methods: We used our center’s melanoma database to identify all patients diagnosed with stage III neck, axillary or inguinal regional metastasis of cutaneous melanoma between 1971 and 2010. We then excluded cases with multiple tumor-involved nodal basins, multiple primaries

9077 Background: High dose Interferon alfa-2b (IFN), an adjuvant immunotherapy for patients (pts) with stage III melanoma, was the only approved treatment option in the US from 1995-2011. There is limited information on how high dose IFN has been disseminated to eligible pts in general clinical practice, and whether variations exist in its adoption according to non-clinical factors. Methods: We obtained data on 34,208 pts diagnosed between 1998-2010 with stage III melanoma from the National Cancer Data Base (NCDB). IFN treatment was abstracted as immunotherapy. We investigated the use of immunotherapy according to pt demographic, socioeconomic, and clinical variables. We conducted multiple logistic regression analysis to examine the effect of these variables on the receipt of immunotherapy. Results: 62% of pts in our study population were male, 88% were Caucasian and 31% were over age 65. Overall, 27% of the pts received immunotherapy. There was no significant trend in its adoption between year 1998 and 2010. After adjustment for clinical variables, age at diagnosis, facility type, and geographic region are predictors strongly associated with use of immunotherapy. Only 16% of pts aged 65-74 and 3% over 75 received immunotherapy compared to 42% of those ages less than 45 (adjusted ORs 0.44 [0.32-0.59], 0.05 [0.04-0.14), respectively). Also 24% of pts treated at a comprehensive community cancer program received immunotherapy compared to 30% of those treated at an academic/research program (OR, 0.71 [0.51-0.99]). The frequency of immunotherapy was 25% in the Atlantic region and 17% in the Western region compared to 33% in Northeast (ORs 0.42 [0.18-0.99], 0.31 [0.13-0.74], respectively). Median household income, insurance type and comorbidity were not associated with adoption of immunotherapy after adjustment for all other variables. Conclusions: Less than one-third of all eligible patients received adjuvant immunotherapy in US general practice over the past decade. There is significant variation in its adoption according to non-clinical factors. Further exploration of the reasons for these variations and whether they are linked to important patient outcomes is needed.

e19000 Background: The 5-year survival of Stage III melanoma ranges from 30-70%. High dose interferon alfa-2b (IFN) is an adjuvant immunotherapy approved in 1995 for stage III melanoma, however, its use has been limited by its significant toxicity and modest benefit. We hypothesized the utilization of adjuvant immunotherapy is less in older age group compared to younger patients. Methods: Using the National Cancer Data Base (NCDB) aggregate data, demographic, socioeconomic, insurance information, and treatment data were analyzed. Proportions were compared using Pearson Chi squared tests. Results: From 2000-2008, 27,365 cases of stage III melanoma were reported to NCDB. Most patients were male (63%) and Caucasian (94.2%). Twenty-nine percent were over the age of 70. Educational and socioeconomic factors across all age groups were not significantly different. The primary insurer for patients younger than 60 was a managed care plan (54.3%) as compared to Medicare with supplemental insurance for patients older than 60 (47.4%). In terms of systemic therapy, 23% received immunotherapy alone, 6% received chemotherapy alone, 2% received both, and 66% received no therapy. When compared to patients under age 39, older age groups were significantly less likely to receive adjuvant immunotherapy as shown in the table below. Conclusions: There is an inverse relationship between age and the use of adjuvant immunotherapy. Further study is planned to adjust for comorbidity, socioeconomic status using patient-level data. [Table: see text]

8595 Background: Use of adjuvant systemic therapy in patients with stage III melanoma is widely known to be variable based upon multiple factors such as patient age and comorbidities as well as the preference and even geographic location of the oncologist and patient. The purpose of this study was to compare the use of adjuvant therapy among patients treated in teaching hospitals and community hospitals. Methods: The study population consisted of patients with stage III melanoma enrolled into the National Cancer Database (NCDB) between 2000-2008. Patients were selected based upon surgery as the first course of therapy which resulted in a total of 27,353 eligible for analysis. The study population was then categorized into those who were treated at Teaching Hospitals (TH) including National Cancer Institute-designated cancer centers or Community Hospitals (CH). Multiple variables including age, median household income, insurance status, race and overall survival were compared between patients in the two hospital groups. Results: The overall proportion of stage III patients who received adjuvant systemic therapy was approximately 30%. There was no difference in the proportion of patients receiving adjuvant systemic therapy between patients treated in TH as compared to CH, and there was no obvious trend towards increased use over time. Of interest was that the cohort of patients designated as being treated at TH had a higher proportion of patients less than 70 years old as compared to CH. Median household income was found to be higher in patients treated at TH. Finally, despite the observation that the proportion of patients who received adjuvant therapy was not different, there a significantly higher 5-year overall survival in patients treated at TH as compared to CH. Conclusions: Although the proportion of patients who received adjuvant systemic therapy was comparable in TH and CH, there was a significant increase in 5-year overall survival within TH. Additional factors such as age, lesser comorbidities, more favorable socioeconomic factors or other unmeasured factors such as type of adjuvant therapy or whether adjuvant therapy was completed may have contributed to the improved survival in patients treated at TH.

8551 Background: Patients with regionally disseminated malignant cutaneous melanoma, stage III, have a variable prognosis with reported 5-year survival of 24-67%, depending on subcategory. There is...

8506 Background: High dose IFNalfa2b, according to the ECOG 1684 schedule, is the only approved adjuvant treatment for stage III melanoma. The risk/benefit profile has limited its use, while effica...

8556 Background: Patients with advanced (AJCC Stage III & IV) malignant melanoma (MM) have variable outcomes despite similar stage. Defining prognostic factors is important to identify patients mos...

8506b Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long-term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6µg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3µg/Kg/wk, sc) for a total treatment duration of up to 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1-2M0 without in-transit metastases). Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant metastasis-free survival (DMFS) was the primary endpoint. Relapse-free survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed Results: Median follow-up was 7.6 yrs is shown in the table. Conclusions: Long-term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. P...

9039 Background: This is a pilot study evaluating of high-risk melanoma patients (pts) treated with peptide-DC vaccine after lymphadenectomy (LND). DC vaccination was designed to induce the immune response against melanoma antigens in melanoma pts who remain at high risk of dissemination after LND. Methods: DCs were generated from the bone marrow with the use GM-CSF, SCF, FLT3-L and TNFa or from peripheral blood adherent monocytes with GM-CSF and IL-4. DCs pulsed with HLA-A2-binding TYR, MART-1 and gp100 peptides and/or HLA-A1-binding MAGE-1, MAGE-3 peptides, tumor lysate if available, or with tracer antigen keyhole limpet hemocyanin (KLH), were injected sc 9 times within 8 months (mos). Boost injections were performed after 12 and 24 mos. Vaccinated pts were matched to unvaccinated controls (22 of 587) by sex, number of metastatic lymph nodes, extracapsular involvement, completion or therapeutic LND, Breslow stage (T), and ulceration. Results: HLA-A2+, -A1+ or -A3+ melanoma pts (n=22), stage III, N1b-N3, enrolled between Sept. 2002 and Apr. 2004, received 5–16 vaccinations (median: 11) within 2 yrs. Cutaneous delayed type hypersensitivity (DTH) to melanoma peptides was induced in 12 of 22 pts. Peptide-specific IFNg producing CD8+ cells were detected in peripheral blood of 13 of 19 pts after vaccination. At least one of these responses to melanoma antigens was elicited in 17 of 22 pts. DTH to KLH was positive in 15 of 22 pts. Nine vaccinated pts are free of disease, and 1 is stable by Dec. 2008 (follow up is 58–76 mos after LND). Survival analysis for vaccinated pts and matched controls is presented in the Table . Conclusions: The DC/peptide vaccine elicited immune responses to melanoma antigens. Vaccinated pts had clinically substantially longer overall survival (OS) and disease free survival (DFS) than matched control. OS was associated with the immune responsiveness to melanoma antigens and to KLH. [Table: see text] No significant financial relationships to disclose.

9069 Background: Follow up (F/U) of patients (pts) with AJCC stage III melanoma but with NED is currently empiric with respect to frequency of clinical exams, F/U duration, and diagnostic tests. Data-based F/U guidelines are needed. Methods: Clinical records of 429 pts with stage III NED pts seen at MSKCC between 1998 and 2002 and who ultimately relapsed were reviewed retrospectively to evaluate: site and date of 1st relapse, interval between the stage III NED and 1st relapse; how the 1st relapse was detected, date of death or last F/U. We also determined the overall 5 yr relapse-free survival (RFS) of all stage III pts seen at MSKCC during this period. Results: The overall 5 yr RFS for stage IIIA, B, and C patients at MSKCC was: 52%, 29%, and 15%, respectively. Among the relapsing pts, 280 had adequate F/U to be evaluable for all parameters (35 stage IIIA, 155 stage IIIB, 90 stage IIIC). The site of 1st relapse was local/in-transit (28%), regional nodal (20%), or systemic sites (52%). The most common sites of 1st systemic relapse were lung, liver, brain. There were significant differences among substages. First relapses were detected by the pt or family, MD, or by screening radiological tests in 52%, 19%, and 29% of cases, respectively. Multivariate analysis revealed better overall survival (OS) was not associated with time to relapse but was associated with younger age and if 1st relapse was: a) local/in-transit or nodal, b) asymptomatic, or c) resectable. By noting when the risk for 1st local/intransit, nodal, or systemic (lung, liver, brain) relapse became sufficiently low ( [Table: see text] No significant financial relationships to disclose.

9069 Background: An important part in the treatment planning for metastatic melanoma is an evaluation of the presence or absence of distant melanoma metastases. However, melanoma has the well-known...

8504 Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6μg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3μg/Kg/wk, sc) for a total treatment duration of 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1–2M0 without in-transit metastases). Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant Metastasis-Free Survival (DMFS) was the primary endpoint. Relapse-Free Survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed. Results: Median follow-up was 3.8 yrs: HR = Hazard Ratio; NR = Not Reached In N1-pts (n=543) the benefit of PEG-IFN seemed more pronounced than in N2-pts (n=713): RFS (HR 0.73 p=0.02 and HR 0.86 p=0.12 for N1 and N2, respectively), DMFS (HR 0.75 p=0.03 and HR 0.94 p=0.53) and OS (HR 0.88 p=0.43 and HR 1.01 p=0.91). PEG-IFN therapy relative dose intensity (actual/planned dose while treated) reached median 88% (induction) and 83% (maintenance). 251 pts (40 %) stopped PEG-IFN because of toxicity. Grade 3–4 - mostly grade 3 - toxicities were reported in 45% (PEG-IFN), vs 12% (Obs.), including most frequently fatigue (15%), hepatotoxicity (10%) and depression (6%) with ECOG 0–1 Performance Status maintained in 83% of pts during maintenance. Conclusions: Long term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (Sentinel Node positive) seemed to have greater benefit in terms of both RFS and DMFS. Similar better effects of adjuvant IFN therapy in pts with lower disease burden are observed in 2 consecutive EORTC trials (18952 and 18991) involving 2644 pts. [Table: see text] [Table: see text]

8518 Background: S100B serum levels have been reported to correlate with tumor stage and outcome, especially in metastatic melanoma. In the EORTC 18952 randomized trial assessing the value of intermediate doses (10 MU or 5 MU) of IFNa vs Observation, a side study on S100B has been set-up in order to assess 1) the prognostic importance of initial measurement of S100B; 2) the risk of developing distant metastases in patients with a S100B≥0.2 μg/l; 3) the prognostic importance of the latest measurement of S100B level on the subsequent outcome. Methods: The serial measurements of S100B, made by immunoluminometric assay LIA-mat (Sangtec Medical, Sweden) have been performed at randomization in 18952 study, at end of 4-week IFNa induction/observation, and thereafter, at month 1, 3, 6, 9, 12, 16, 20, 24, 30 and 36. The prognostic impact regarding DMFS of the latest value of S100B was assessed via the Cox time-dependent model. Results: A total of 211 patients, stage IIb (N=51) or stage III (N=160), were randomized in the 18952 study between 1996 and 2000, had their initial serum S100B protein level assessed: in 178 patients (84%) S100B was [Table: see text]

8020 Background: Recent revisions in the AJCC staging system have increased its complexity without comparable improvement in prognostic accuracy for patients with Stage III melanoma. Furthermore, there remains significant prognostic heterogeneity, even within Stages IIIA, IIIB, and IIIC. The current study was undertaken to develop a model for individual patient risk assessment, both to facilitate patient care, and to help define prognostically homogeneous patient populations for entry into clinical trials. Methods: Patients with AJCC Stage III melanoma were identified from a prospective single institution database. Overall survival was calculated from the date of Stage III to last followup. A multivariate Cox model of independent prognostic factors was developed, and a multivariable individualized patient risk assessment nomogram was built from that model. Results: Among 1,064 patients with Stage III melanoma, 535 have died, at a median followup of 44 months. Independent predictors of overall survival are shown in the table. Individual patient three and five year survival was predicted by incorporating all eight variables into a prognostic nomogram. The nomogram was superior to the AJCC Staging system in predicting outcome in Stage III melanoma patients. Conclusions: Individual patient risk assessment is more accurate than traditional AJCC staging in predicting outcome in Stage III melanoma. This approach, which can be easily incorporated into a handheld computing environment, offers potential advantages for both patient care and clinical research, and should be explored in the next iteration of the AJCC staging system. [Table: see text] No significant financial relationships to disclose.