Resected Melanoma Research Articles

Estimating Long-Term Survivorship Rates Among Patients With Resected Stage III/IV Melanoma: Analyses From CheckMate 238 and European Organization for Research and Treatment of Cancer 18071 Trials.

Standard-of-care treatments for patients with resected stage III/IV melanoma include the immuno-oncology (IO) agents nivolumab (NIVO) and ipilimumab (IPI). This study used mixture cure models (MCMs) to estimate cure rates among patients treated with NIVO or IPI in the phase III CheckMate 238 (ClinicalTrials.gov identifier: NCT02388906) and European Organization for Research and Treatment of Cancer (EORTC) 18071 (ClinicalTrials.gov identifier: NCT00636168) trials, and to assess the impact of use of adjuvant immunotherapy on cure rates versus watchful waiting. MCMs were applied to patient-level recurrence-free survival data from CheckMate 238 and EORTC 18071. Cured patients were assumed to experience no disease recurrence and mortality risks similar to the general population. Uncured patients were at risk of disease recurrence and all-cause death. The survival trend of the cured patients was estimated using life expectancy data for a general population with the same baseline demographic characteristics. A regression model assessed the odds ratios (ORs) of cure across key subgroups on the basis of baseline characteristics of the study populations. In CheckMate 238, estimated cure rates were 48.3% (95% CI, 41.8 to 54.9) with NIVO and 38.2% (95% CI, 32.7 to 44.1) with IPI. In EORTC 18071, estimated cure rates were 38.0% (95% CI, 32.1 to 44.2) with IPI and 29.2% (95% CI, 24.4 to 34.6) with placebo. In the indirect comparison of the two trials, the odds of cure were significantly higher with NIVO than with placebo (OR, 2.33 [95% CI, 1.49 to 3.65]). Analyses involving two large phase III trials investigating adjuvant IO treatment for resected melanoma demonstrate higher cure rates for both NIVO and IPI than placebo, with NIVO providing the highest cure rate. Similar cure rates were estimated for patients treated with IPI in both trials, despite staging and dosing differences.

Predictive Significance of Combined Plasmatic Detection of BRAF Mutations and S100B Tumor Marker in Early-Stage Malignant Melanoma.

Melanoma is the most aggressive skin cancer with ability to recur also after early-stage tumor surgery. The aim was to identify early-stage melanoma patients at high risk of recurrence using liquid biopsy, estimating of mutated BRAF ctDNA and the level of tumor marker S100B in plasma. Eighty patients were enrolled in the study. BRAF V600E mutation was determined in FFPE tissue and plasma samples using ultrasensitive ddPCR with pre-amplification. The level of S100B was determined in plasma by immunoassay chemiluminescent method. The best prediction of melanoma recurrence after surgery was observed in patients with combined high level of S100B (S100Bhigh) and ctDNA BRAFV600E (BRAFmut) in preoperative (57.1% vs. 12.5%, p = 0.025) as well as postoperative blood samples (83.3% vs. 14.3%, resp., p = 0.001) in comparison with low S100B and BRAF wild-type. Similarly, patients with preoperative and postoperative S100Bhigh and BRAFmut experienced worse prognosis (DFI p = 0.05, OS p = 0.131 and DFI p = 0.001, OS = 0.001, resp.). We observed the benefit of the estimation of combination of S100B and ctDNA BRAFmut in peripheral blood for identification of patients at high risk of recurrence and unfavorable prognosis. There is still no general consensus on molecular markers for deciding the appropriateness of adjuvant treatment of early-stage melanoma. We have shown for the first time that the combined determination of the ctDNA BRAFmut oncogene (liquid biopsy) and the high level of tumor marker S100B in pre- and postoperative plasma samples can identify patients with the worst prognosis and the highest risk of tumor recurrence. Therefore, modern adjuvant therapy would be appropriate for these patients with resectable melanoma, regardless of disease stage.

Nature and management of melanoma recurrences following adjuvant anti-PD-1 based therapy

IntroductionApproximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. MethodsThis was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. Results711 patients from 17 sites were included. Median age was 60 [range 16–92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0–68.5) and median follow up time from recurrence was 19.8 months (range 0.2–73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with “second adjuvant” anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. ConclusionMost recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

1103P Real-world efficacy of relatlimab and nivolumab in advanced or resectable melanoma

1103P Real-world efficacy of relatlimab and nivolumab in advanced or resectable melanoma

Immune-related adverse events in a nationwide cohort of real-world melanoma patients treated with adjuvant anti-PD1 – Seasonal variation and association with outcome

IntroductionImmune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making. MethodsThis nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018-2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1-2) to severe (grade 3-4) and fatal (grade 5). ResultsAmong 792 included patients, (55% male, median age 62 years (range 16-88)), 697 patients (88%) experienced an irAE. Severe irAEs occurred in 116 patients (15%) and five (0.6%) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p=0.032) and overall survival (OS) (p=0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer. ConclusionThe prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs.

Adjuvant Therapy in Acral Melanoma: A Systematic Review.

Acral melanoma presents distinct biological characteristics compared to cutaneous melanoma. While adjuvant therapeutic strategies for high-risk resected acral melanoma closely resemble those for cutaneous melanoma, the evidence supporting the clinical application of adjuvant therapy for acral melanoma remains inadequate. Our aim was to systematically analyze the efficacy and safety profile of adjuvant therapy in acral melanoma. This systematic review adhered to a pre-registered protocol. We comprehensively searched four electronic databases and reference lists of included articles to identify eligible studies. The primary outcome was therapeutic efficacy, and the secondary outcome was adverse events (AEs). This systematic review included 11 studies with 758 acral melanoma patients undergoing adjuvant therapy. High-dose interferon α-2b (IFN) regimens showed no significant difference in recurrence-free survival (RFS), though the longer regimen was linked to increased hepatotoxicity. Adjuvant anti-PD-1 therapy demonstrated varying efficacy, with improved RFS in patients who experienced immune-related AEs. Targeted therapy with dabrafenib plus trametinib achieved high 12-month RFS in patients with BRAF-mutated acral melanoma. Comparative studies suggested that adjuvant anti-PD-1 therapy is similarly effective to IFN in prolonging survival for high-risk acral melanoma patients. Additionally, prior treatment with pegylated IFN enhanced RFS in patients receiving adjuvant pembrolizumab. High-dose IFN was widely used as adjuvant therapy for acral melanoma, but serious AEs prompted the search for alternatives. Adjuvant anti-PD-1 therapy shows promise, though it may be less effective than in non-acral melanoma. Further prospective studies are needed to determine the optimal adjuvant treatment for acral melanoma.

1089P Longitudinal biomarker analysis and outcomes for patients (pts) treated with neoadjuvant nivolumab (nivo) and relatlimab (rela) in surgically resectable melanoma

1089P Longitudinal biomarker analysis and outcomes for patients (pts) treated with neoadjuvant nivolumab (nivo) and relatlimab (rela) in surgically resectable melanoma

1100P Anti-PD1 + low-dose anti-CTLA4 immunotherapy pathological response rate in patients with stage III resectable melanoma: Phase III NEOMIMAJOR trial interim analysis

1100P Anti-PD1 + low-dose anti-CTLA4 immunotherapy pathological response rate in patients with stage III resectable melanoma: Phase III NEOMIMAJOR trial interim analysis

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): long-term, health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial

In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results. This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant. Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting. Merck Sharp & Dohme.

Outcomes With Postrecurrence Systemic Therapy Following Adjuvant Checkpoint Inhibitor Treatment for Resected Melanoma in CheckMate 238.

In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy. Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy). Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS. Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

Adjuvant immunotherapy in high-risk resectable melanoma: A real-world experience

Adjuvant immunotherapy with nivolumab or pembrolizumab represents the current standard of care for resected high-risk Stage III and IV malignant melanoma. However, data on its real-world outcomes and efficacy beyond clinical trials are limited. We evaluated the data of high-risk Stage III and IV melanoma patients treated with adjuvant immunotherapy in two hospitals in Western Australia, Australia. The study involved the retrospective collection and analysis of data from 95 eligible patients treated with nivolumab or pembrolizumab. These patients were planned to receive 1 year of immunotherapy, with treatment continuing until disease recurrence, unacceptable toxicity, or voluntary withdrawal. Our evaluation focused on overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS), along with safety outcomes. The findings of our study indicated a 2-year RFS of 73%, a DMFS of 73%, and an OS of 94%. Treatment-related adverse events were observed in 63.1% of patients, with cutaneous manifestations being the most common treatment-related toxicity and gastrointestinal tract issues being the most common higher-grade immune-related adverse event. Importantly, these findings do not significantly differ from the landmark clinical trials, CheckMate-238 and KEYNOTE-054. In conclusion, adjuvant immune checkpoint inhibitor therapy administered for up to 1 year in high-risk Stage III and IV melanoma demonstrates a comparable efficacy and toxicity profile in real-world settings to that observed in the pivotal trials.

Confocal Laser Endomicroscopy in Resection of Sinonasal Malignant Melanoma-Preliminary Report on Real-Time Margin Assessment and Support in Surgical Decision-Making.

Background/Objectives: Building upon the rising value of Confocal Laser Endomicroscopy (CLE) in squamous cell carcinoma of the head and neck, we present the first application of CLE during the resection of sinonasal malignant melanomas. This study aims to evaluate the potential of CLE to assist surgeons in intraoperative decision-making, with a particular focus on resection margin assessment within the constrained nasal cavity. Methods: Two cases of sinonasal malignant melanoma were included in this study. CLE was employed to examine visible tumors and their margins, both pre- and post-endoscopic resection. The findings were compared to histopathological results as well as data on squamous cell carcinoma, for which malignancy criteria had already been established in prior projects. Results: CLE provided the real-time visualization of sinonasal malignant melanomas and their margins, successfully differentiating between healthy and neoplastic tissue compared to histopathological findings. Conclusion: CLE offers the potential for real-time assessment, aiding surgeons in more precise tumor resection and potentially improving patient outcomes. This study demonstrates the feasibility of using CLE in the resection of sinonasal malignant melanoma, highlighting its ability to differentiate between healthy and neoplastic tissue intraoperatively.

Letter to the Editor Regarding “Mutational Status and Clinical Outcomes Following Systemic Therapy with or without Focal Radiation for Resected Melanoma Brain Metastases”

Letter to the Editor Regarding “Mutational Status and Clinical Outcomes Following Systemic Therapy with or without Focal Radiation for Resected Melanoma Brain Metastases”

PET-CT Incidental Finding of Duodenum Late Melanoma Metastasis: A Case Report

Three years post-primary resection of a skin melanoma with right inguinal lymphadenectomy, a 62-year old Caucasian female patient presented with high grade fever episodes and was admitted to Helios Hospital Pforzheim for further medical evaluation. A suspicious mass was unexpectedly discovered in the descending duodenum and head of pancreas during PET-CT scan. Upper endoscopic examination with ultrasonography revealed a 30 mm tumor mass originating from the descending part of the duodenum, which had infiltrated the head of pancreas and caused/resulted in loop obstruction. Endoscopic biopsy confirmed the presence of neoplastic cells with melanin granules and positive for Melan-A/SOX10 staining, indicating the presence of a metastatic malignant melanoma. Importantly, the tumor showed no BRAF-Mutation. These additional staining was evaluated postoperatively, and colonoscopy did not reveal any tumors. After this procedure, the patient was strongly recommended to undergo surgical resection, to which the patient agreed. A pylorus preserving pancreaticoduodenectomy was performed at the Department of General Surgery at Helios Hospital Pforzheim. In the surgically resected Whipple specimen, the mass was 5 x 4 cm large, solid and ulcerated. Histologically the tumor infiltrated all duodenal layers and the tissue around them. Immunocytochemistry and electronic microscopy findings confirmed the diagnosis of malignant melanoma consistent with the skin specimen from the right thigh. Herefore, the duodenal lesion was a metastasizing skin melanoma originating from the skin melanoma in the right thigh. The postoperative course of the patient was favorable, therefore she was discharged from the hospital after 13 days. Subsequently, she underwent immunotherapy with Ipilimumab and Nivoluma, and no recurrence was identified during the close monitoring of the patient in the 5-month follow-up period. The patient’s medical history began three years prior with resection of a skin ...........

Endoscopic resection of primary sinonasal mucosal melanoma with orbital invasion: How I do it

Primary sinonasal mucosal melanoma is a rare aggressive malignancy. In this video, a case of a 68-year-old female who presented with diplopia for 2 weeks is described. The present video reports the endoscopic endonasal surgical excision of a primary sinonasal mucosal melanoma. The video contains patient's medical history, preoperative radiological evaluations and step-by-step description of surgical steps of the procedure with the utilization of computer-assisted navigation system.

Magnetic seed localization is feasible for non-palpable melanoma, Merkel cell carcinoma, and soft tissue sarcoma lesions

BackgroundLocalization of non-palpable melanoma, Merkel cell carcinoma (MCC) and soft tissue sarcoma (STS) lesions can be difficult due to size, location, and obesity of patients or fibrosis due to previous treatments. Magnetic seed localization (MSL) is a common method to localize non-palpable breast lesions, but the feasibility of MSL for non-palpable melanoma, MCC and STS lesions has not yet been described. MethodsIn this retrospective single center cohort study, all consecutive patients between January 2021 and October 2023 who had a resection of a non-palpable melanoma, MCC or STS lesion guided by Sirius Pintuition, a MSL technique, were included. The primary endpoint was successful lesion localization during surgery and the secondary endpoints were seed migration, negative resection margins, and complications. ResultsSeventy-nine seeds were placed for 76 lesions, which were resected during 68 surgeries in 61 patients. All lesions (100 %) were localized and resected. Median time of surgery was 44 min. No seed migration was observed. A negative resection margin was achieved for 60 (78.9 %) lesions. Clavien Dindo grade ≥2 complications occurred in 7.4 %. ConclusionMagnetic seed localization with Sirius Pintuition is feasible for both non-palpable melanoma, MCC, and STS lesions.

Combination or sequence of vemurafenib, cobimetinib, and atezolizumab in high-risk, resectable melanoma (NEO-TIM): Primary results.

LBA9513 Background: Adjuvant immune checkpoint blockade (ICB) and target therapy (TT) improve outcomes of patients (pts) with high-risk resectable melanoma. Prospective neoadjuvant (NAT) clinical trials with TT or ICB are now running in a subgroup of high-risk melanoma pts with pooled overall promising preliminary results of high rates of pathologic complete responses (pCRs, 30–50%) and early data of positive correlation between pCR and relapse-free survival (RFS). We aimed to conduct a randomized, non-comparative phase II trial to define the role of NAT plus adjuvant TT and ICB, given in combination or sequence, in pts with high risk surgically resectable melanoma. Methods: 95 pts with resectable, RECIST measurable stage IIIB/IV, BRAF-mutant melanoma were randomized 1:1 in arm A and arm B, respectively, to receive NAT vemurafenib (V) and cobimetinib (C) for 6 weeks or NAT triplet combination (V and C plus atezolizumab (A), followed by complete lymph node dissection (CLND). Patients with BRAF wild-type melanoma were included in Arm C with NAT C and A. All pts had 17 cycles of A 1200 mg IV q3w post-CLND. Primary endpoint is pCR centrally/independently determined defined as residual cancer burden 0. Secondary endpoints are RFS, Overall Survival (OS), Pathological Overall Response Rate (pORR), Safety, Biomarkers analyses. Results: At data cut-off Dec 15, 2023, 29% of pts were female, median age was 59 yrs, 60% had a clinical stage IIIC, and median f/u was 17 months (IQR: 10-22). The Major Pathological Response (defined as pCR/near-pCR) was reached in 13 (45%), 10 (34%) and 13 (36%) pts in arm A, B and C, respectively. Five (17%), 4 (14%) and 6 (16%) pts did not receive surgery, and 1 (3%) patient of arm B is still under evaluation of pathological respose rate (pRR). At 12 months,RFS was 78%, 86% and 82% in arm A, B and C, respectively. Nearly 19% of pts treated in arm C were discontinued before surgery due to PD, AEs or patient’s withdrawn consent, 7% and 14% in arm B and A, respectively, due to comorbidities and AEs. G3-G4 toxicity was observed in 38%, 24% and 22% of pts in arm A, B and C. Conclusions: Pts treated with TT upfront had highest response to NAT but the pts who received IO as NAT had a better RFS. Clinical trial information: NCT04722575 . [Table: see text]

Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma.

Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR)=0.37 (p=.005) for RFS and HR=0.33 (p=.002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR=0.45; p=.022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.

Neoadjuvant pembrolizumab and lenvatinib in resectable mucosal melanoma: NeoPlus study update.

9580 Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Relapse free survival (RFS, time from surgery to any event), Overall survival (OS) and safety. Results: Between Sep 2021 and Apr 2023, 26 pts were enrolled, median age was 57 yrs(range: 49-75), 19 were female. Primary sites included: 11 female genital, 8 ano-rectal, 5 head &amp; neck (1 nasal, 4 oral),2 esophageal. 15 pts (58%) were localized disease,11 (42%) were regional lymphatic disease. BRAF V600, NRAS or KIT mutations were presented in 1, 3 and 2 pts, respectively. 21 pts underwent surgery, 2 pts had a pCR (9.5%), 2 near PCR, 4 pPR, with a pathologic response rate of 38% (8/21,95%CI 18-62%). 5 pts did not proceed with planned surgery for pts preference. As of Dec 2023, 12 of 21 resected pts had relapsed (9/11 in female genital,2/4 in ano-rectal, 1/5 in head &amp; neck). Median follow up time was 19.1 months (95%CI 13.7-24.5). Median RFS was 12.4 months (95%CI 4.0-20.8), no difference was observed among these primary sites (female genital: 6.6 months, ano-rectal: 14.1 months, head &amp; neck: not reached). Median DMFS was not reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R: pCR+near PCR+ pPR) than non-responders (NR: pNR) (p = 0.046). Tertiary lymphoid structures were detected in 9 pts. Most common TRAEs were hypertension (13, 50%), proteinuria (12, 46%), LDH increased (9,35%), hypothyroidism (8, 31%). Three pts experienced a dose reduction and 5 experienced a dose interruption due to an AE. No grade 4-5 toxicities were observed. Conclusions: Updated results confirmed that the combination of pembrolizumab plus lenvatinib as neoadjuvant therapy had moderate anti-tumor efficacy in resectable mucosal melanoma. Increased CD8+ T cell infiltration was observed in tumor with pathologic response, supporting further investigation in mucosal melanoma.

Clinical outcomes after adjuvant anti-PD1 therapy for high-risk resectable melanoma and predictors of response.

e21502 Background: Adjuvant anti-PD1 is the standard of care for high-risk resectable melanoma but many still suffer recurrence. We report a single institution observational study of patients who received adjuvant anti-PD1 with a particular focus on those who recurred. Methods: Through an approved protocol by Huntsman Cancer Institute IRB, patients with resected high-risk melanoma who first received anti-PD1 in the adjuvant setting were consented and followed. Clinical outcomes were assessed per RECIST 1.1, progression free survival (PFS), and overall survival (OS). Results: 186 eligible patients were included, 105 male and 81 females, median age at C1D1 58 (22-93), 12/161/7 at stage II/III/IV and 5 unstageable. Subtypes included 79 (43%) superficial spreading, 50 (27%) nodular, 16 (9%) lentigo/nevoid, 13 (7%) non-acral skin (NOS), 10 (5%) acral, 4 (2%) mucosal, and 14 (7%) others. With median follow up of 708 days (23-9599), 66 (35.5%) had progressive disease (PD), including 33 (50%) early PD and 33 (50%) late PD. Statistically significant predictors of worse outcome included age &gt; 50 (OS p = 0.043), acral subtype (PFS p = 0.023), PD-L1 IHC &lt; = 1% (OS p = 0.052, PFS p = 0.002), duration of treatment &lt; 3 months (OS p = 0.005, PFS p = 1.8E-07), early PD (OS p = 0.003, PFS p = 1.5E-6) and distant recurrence (OS p = 0.002). Trends that were not significant included: male gender (worse OS), BRAF mutation (better PFS), NF1 mutation (better PFS). No correlation between outcomes and TMB, NRAS, TERT mutation, and primary location. In the early/late PD groups, median age was 57/55 (range 28-79 / 25-84), 64/61% male, 1/0, 29/31, 3/2 stage II, III, IV. 17/13 were superficial spreading, 6/10 nodular, 2/5 acral, 2/2 lentigo, 1/0 mucosal and 4/3 other non-acral skin. Primary site was 12/12 head/neck, 9/5 trunk, 4/7 upper limb, 8/9 lower limb. BRAF was 9/11 wildtype, 15/9 mutant and 9/13 unknown. PD-L1 &gt; = 1% by IHC was 4/2. TMB mut/mb &gt; 10 was 6/5. Sites of recurrence included 6/12 local, 7/7 regional LN, 20/14 distal (3/1 in brain) relapses. For unresectable PD (13/13 early/late) response to next line systemic therapy is shown in Table 1. Conclusions: One third of patients developed PD after adjuvant anti-PD1 for high-risk melanoma. PD-L1 negativity and short duration of treatment was associated with worse outcome. Early PD corresponded to more distant metastasis, poorer OS and response to subsequent systemic therapy. Importantly most late PD can still have a favorable response by resuming anti-PD1 therapy. Further molecular study is ongoing to investigate mechanisms of resistance. [Table: see text]