Carlino, Matteo S.

9567 Background: Resected stage IIB/C and microscopic stage IIIA/B/C/D melanoma presents a significant risk of recurrence risk of 37 to 62% at 5 years (yrs). While 1 year of adjuvant PD1 therapy reduces this risk by approximately half, the individual patient’s baseline risk without treatment and their specific benefit from adjuvant PD1 remain unknown. We aimed to generate two separate predictive models for recurrence – one for untreated and one for treated pts - to calculate the individualised benefit of adjuvant PD1. Methods: Pts with resected stage IIB/C or microscopic stage IIIA/B/C/D melanoma, either treated with adjuvant PD1 or untreated at 13 major melanoma centres, and with at least 2 years of follow-up from surgery were included. We analysed pts demographics, disease characteristics, blood parameters, pathological and imaging data at baseline, and clinical outcomes. Propensity scores were estimated using logistic regression with covariates associated with treatment in univariate screening (p<0.05). Separate penalised multivariable logistic regression models were built to predict recurrence for treated and untreated pts. A tool based on these models was created to calculate the individual patient benefit from adjuvant PD1. Results: A total of 3560 pts was included, divided into untreated (discovery n=2384 and validation n=597) and treated (discovery n=404 and validation n=175) cohorts. The model for untreated pts included age, gender, primary site, histological subtype, Breslow thickness, ulceration, mitosis, number and site of regional lymph nodes (LN), mutation status and LDH (AUC 0.70 in discovery, 0.69 in validation). The model for treated pts included age, gender, Breslow thickness, site of regional LN, and mutation status (AUC 0.69 in discovery, 0.61 in validation). ADAPT-M (ADjuvant Anti-PD-1 Tool for Melanoma) calculates the individualized benefit of adjuvant PD1. For example, patient A, a woman ≤45 years old with a primary head & neck melanoma (superficial spreading, thickness >1-2 mm, no ulceration, 1 mitosis/mm 2 ), 2 clinically occult LN metastases in the neck, NRAS mutant, and normal LDH, has a 12-month recurrence risk of 21.9% untreated vs 2.3% treated (benefit 19.6%), and a 24-month risk of 41.1% untreated vs 6.4% treated (benefit 34.7%). While, patient B, a man ≤45 years old with a primary melanoma in the lower limb (nodular, thickness >1-2 mm, no ulceration, 1 mitosis/mm 2 ), 2 clinically occult LN metastases in the groin, BRAF V600 mutant, and normal LDH, has a 12-month recurrence risk of 14.2% untreated vs 11.8% treated (benefit 2.5%), and a 24-month risk of 28.0% untreated vs 30.1% treated (no benefit). Conclusions: ADAPT-M, a clinical tool that estimate individualized recurrence risks with and without adjuvant anti-PD1 therapy, quantifies the absolute benefit of treatment for pts with high-risk resected melanoma, facilitating personalized adjuvant therapy decisions.

9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.

Importance Immune checkpoint inhibitors (ICIs) are efficacious in many cancer types but can produce immune-related adverse events (irAEs). As such, patients with preexisting autoimmune disorders are often excluded from clinical trials, although subsequent studies have shown that many of these patients have acceptable ICI tolerance. The safety and efficacy of ICIs among patients with preexisting neurologic autoimmune disorders (NAIDs) is not well characterized. Objective To evaluate the safety and clinical outcomes associated with ICI therapy among patients with NAIDs. Design, Setting, and Participants This multicenter retrospective cohort study included patients with cancer who were treated with ICIs between October 2013 and May 2023 and had preexisting multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), and other NAIDs as well as a control cohort of patients with Parkinson disease (PD). Exposure ICI therapy. Main Outcomes and Measures Demographic and clinical characteristics (neurologic disability, active or recent immunosuppression), ICI outcomes (response, progression-free survival [PFS], and overall survival [OS]), and safety outcomes (NAID exacerbation, irAEs) were collected. Results A total of 135 patients were included; the median (range) age was 72 (40-88) years, 84 (62%) were men, and 51 (38%) were women. A total of 45 patients had MS; 18, MG; 10, GBS; 5, another NAID; and 57, PD. Exacerbations occurred most frequently in MG (12 of 18 patients [67%]), often resulting in hospitalization (6 [50%]) or death (2 [17%]), with much lower rates in the MS cohort (8 of 45 patients [18%]). Ten patients with a history of GBS tolerated ICI without exacerbations, although 1 developed a fatal case of Lambert Eaton myasthenic syndrome following ICI treatment. No differences in response rate, PFS, or OS were observed between NAID groups. Conclusions and Relevance In this cohort study of ICI use in NAIDs, patients with MG had frequent and more severe exacerbations, while those with MS had few exacerbations. No obvious differences in survival between groups were observed. ICI may be an option for many patients with appropriate oncologic indications and preexisting NAIDs.

9578 Background: Anti-PD1 immunotherapy has shown improved clinical outcomes in patients (pts) with advanced cSCC, and recently, in the neoadjuvant setting for resectable disease. Pathological (path) response is predictive of recurrence in melanoma and recent NeoIT trials suggests the same in cSCC; however, an analysis of clinical outcomes in pts with resectable cSCC treated with intended anti-PD1-based NeoIT in larger datasets remains unknown. Methods: Pts with resectable cSCC treated with intended anti-PD1-based NeoIT from 17 cancer centres globally were included. Baseline patient and disease characteristics, treatment regimen, path response and recurrence-free survival (RFS) or progression-free survival (PFS) were collected and examined. Results: 134 pts with resectable cSCC were treated with intended anti-PD1-based NeoIT. Median age was 75 years old (range, 39-97), 72% (n=97) were male. One fifth (22%, n=29) were immunocompromised and 43% (n=58) had ECOG PS of ≥1. Of 125 (93%) pts with known primary cSCC, 82% (n=102) were from the head & neck. Most pts (79%, n=106) were stage III/IV. The majority had anti-PD1 monotherapy (91%, n=122) and 9% (n=12) had anti-PD1+/-investigational agent. Median follow-up from commencement of NeoIT was 10 months (95% CI, 9 - 12). Nearly half of the pts (49%, n=66) underwent surgery; 37 (56%) pts had major pathological response (MPR; ≤10% viable tumour cells at the surgical specimen; 31 [47%] had complete path response [0% of viable tumour cells] and 6 [9%] had near complete path response [1-10% of viable tumour cells]), 6 (9%) had partial path response (pPR; >10% and ≤50% of viable tumour cells), and 23 (35%) had path non-response (pNR; >50% of viable tumour cells). Of the 66 pts who underwent surgery, 11% (n=7) had recurrence (5 loco-regional and 2 distant recurrence), all non-MPR pts (1 pPR and 6 pNR). 12-months RFS was improved with MPR vs non-MPR (100% vs 79%, p=0.004). 52% (n=34) pts had adjuvant treatment (23 anti-PD1 alone, 7 anti-PD1+/-investigational agent, 2 platinum and 2 cetuximab). Within non-MPR pts, 12 had adjuvant treatment (3 recurred; 25%), while 17 did not have adjuvant treatment (4 recurred; 24%). Fifty-one percent (n=68) of pts did not have surgery; 9 (13%) due to progressive disease (PD) and 53 (78%) due to clinical response. Of the 53 pts with a clinical response, 5 (9%) subsequently progressed. Fourteen (10%) pts have died, 6 (4%) related to cSCC; 2 had surgery (non-MPR) and 4 did not have surgery (all due to PD). Conclusions: Anti-PD1-based NeoIT is an active regimen in resectable stage II-IV cSCC and is associated with high clinical response and MPR rates. No pts with MPR from NeoIT has recurred to date, however, 9% of pts who did not have surgery due to clinical response eventually progressed. These findings highlight the importance of further research to investigate the role of surgery in this subgroup of patients.

9569 Background: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The aim of this study was to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international high‐volume melanoma centers. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c and N3c) and without distant disease (M0). Patients were treated with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). We assessed response rates, progression-free survival (PFS), melanoma-specific survival (MSS) and overall survival (OS). Results: A total of 287 patients from 21 institutions in 8 countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. Monotherapy with a PD-1 or CTLA-4 inhibitor was given in 233 (81%) and 23 (8%) patients respectively, while 31 (11%) received both in combination. Overall response rate was 56%, complete response (CR) rate 36% and progressive disease (PD) rate 32%. Median PFS was 10 months (95% CI 7.4-12.6 months) with a 1-, 2- and 5-year PFS rate of 48%, 33% and 18% respectively. Median MSS was not reached, and the 1-, 2- and 5-year MSS rates were 95%, 83% and 71% respectively. Conclusions: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the optimal role for systemic immunotherapy in the context of multimodality therapy including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

9558 Background: Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by a dense fibrous stroma, resistance to chemotherapy and no actionable driver mutation for targeted therapy. We investigated the efficacy of PD-1/L1 inhibitors and correlation with genetic landscape and tumor immune microenvironment in DM. Methods: Retrospective analysis of 1054 pts with melanoma treated with anti-PD-1/L1, resulting in 57 pts with unresectable or metastatic DM. Available baseline biopsies were analysed by digital quantitative immunohistochemistry (IHC) for CD8 and PD-L1 and by whole exome sequencing (WES), compared to available tissue from non-DM pts treated with anti-PD1/L1 at UCLA. Results: At a median follow up of 20 mo, 40 pts (70%, 95% CI 57-82) had an objective response by RECIST 1.1 criteria, including 18 (45%) CRs with no relapse observed to date. Responses were similar in DM subsets (23 pure, 29 mixed and 5 indeterminate). Kaplan-Meier estimated 1-year and 2-year overall survival were 85% (95% CI 78-98) and 74% (95% CI 64-89). WES revealed a median of 1282 (interquartile range 517-1692) non-synonymous somatic mutations per tumor in DM tumors (n = 17), significantly higher (p = 0.02) than the median of 462 (interquartile range 230-1150) in non-DM (n = 23). Mutations in NF-1 were the most common (13/17) followed by loss-of-function TP53 and ARID2, and > 82% of single nucleotide mutations were UV damage signatures. IHC analysis from 19 DM and 13 non-DM revealed a strikingly higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with CD8 density and PD-L1 expression in the tumor invasive margins, indicating an active adaptive immune response. No genetic mechanisms known to cause constitutive PD-L1 expression were detected in these samples. Conclusions: Patients with advanced DM derive significant clinical benefit from PD-1/L1 inhibitors, likely related to the high mutational burden and a highly active adaptive immune response as the main mechanism of immune escape prior to therapy. Our results challenge the general conception that dense fibrous stroma around the malignant cells interferes with immune cell infiltration and efficacy of immunotherapy.