Resected Melanoma Research Articles

Italian nivolumab Expanded Access Programme in melanoma adjuvant setting: patient outcomes and safety profile

IntroductionThe CheckMate 238 randomised study demonstrated the relevant benefit in terms of recurrence-free survival (RFS) of nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma patients with a tolerable safety profile. Materials and methodsFrom November 2018 to June 2019, 611 patients with stage III and IV resected melanoma were enroled to receive nivolumab as part of an Italian Expanded Access Programme (EAP). According to stages, 77% were stage III while 141 (23%) were stage IV with no evidence of disease (NED). Among stage III, 121 patients had IIIA (19.8%). ResultsAfter a median follow-up of 23 months, the RFS in the Intention-to-Treat (ITT) population was 76.6% at 1 year and 59.6% at 2 years; 1- and 2-year distant metastasis–free survival were 83.7% and 71.2%, respectively. The overall survival rate in the ITT population was 93.8% at 1 year and 85.5% at 2 years. No significant differences in RFS were observed according to BRAF status. Treatment-related adverse events of grades 3–4 occurred in 11.5% of patients. ConclusionThis paper reports the results of the Italian Nivolumab EAP in the adjuvant setting of stage III and IV NED melanoma patients. Our results confirm in a real-life setting the clinical activity and safety of nivolumab reported in the CheckMate238 registrative/pivotal. The enroled cohort of 611 patients highlights the relevant clinical need in this setting, also confirmed by the very short accrual time, representing one of the largest series reported as adjuvant EAP with the longest follow-up.

A real-world study of adjuvant anti-PD -1 immunotherapy on stage III melanoma with BRAF, NRAS, and KIT mutations.

Melanoma frequently harbors BRAF, NRAS, or KIT mutations which influence both tumor development and treatment strategies. For example, it is still controversial whether adjuvant anti-PD-1 monotherapy or BRAF/MEK inhibitors may better improve the survival for resected BRAF-mutant melanoma. Furthermore, outcomes for melanoma with NRAS and KIT mutation receiving adjuvant immunotherapy remain unclear. One hundred seventy-four stage III melanoma patients who underwent radical surgery in Fudan University Shanghai Cancer Center (FUSCC) during January 2017 to December 2021 were included in this real-world study. Patients were followed up until death or May 30th, 2022. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different category groups. Log-rank analysis was used to identify the prognostic factors for disease-free survival (DFS). There were 41 (23.6%) patients with BRAF mutation, 31 (17.8%) with NRAS mutation, 17 (9.8%) with KIT mutation, and 85 (48.9%) wild-type patients without either genomic alteration of those three genes. Most ( n = 118, 67.8%) of them were acral melanoma, while 45 (25.9%) were cutaneous subtype, and 11 were (6.3%) primary unknown. Among them, 115 (66.1%) patients received pembrolizumab or toripalimab monotherapy as adjuvant therapy; 22 (12.6%) patients received high-dose interferon (IFN), and 37 (21.3%) patients were just for observation. There was no statistical difference in clinicopathologic factors between anti-PD-1 group and IFN/OBS group. Of all the enrolled patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.039). In anti-PD-1 group, patients with BRAF or NRAS mutations had poorer DFS than wild-type group. No survival difference was found among patients harboring different gene mutations in IFN/OBS group. In wild-type patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.003), while no survival benefits were found for patients with BRAF, NRAS, or KIT mutations. Although anti-PD-1 adjuvant therapy provides a better DFS in the general population and in wild-type patients, patients with BRAF, KIT or, especially, NRAS mutation may not benefit further from immunotherapy than conventional IFN treatment or observation.

PD-1 Monotherapy Reigns Supreme in Adjuvant Melanoma…But for How Long?

The results of CheckMate-238 led to the original FDA approval of anti-PD-1 therapy in high-risk, resectable melanoma. In this CCR Translations, we discuss the 5-year update of this pivotal trial and contextualize its results in the face of limited survival data, neoadjuvant therapy, next-generation biomarkers, and novel immunotherapy combinations. See related article by Larkin et al., p. 3352.

The Current State of Neoadjuvant Therapy in Resectable Advanced Stage Melanoma.

The advent of effective immunotherapy and targeted therapy has significantly improved outcomes in advanced-stage resectable melanoma. Currently, the mainstay of treatment of malignant melanoma is surgery followed by adjuvant systemic therapies. However, recent studies have shown a potential role for neoadjuvant therapy in the treatment of advanced-stage resectable melanoma. Mechanistically, neoadjuvant immunotherapy may yield a more robust response than adjuvant immunotherapy, as the primary tumor serves as an antigen in this setting rather than only micrometastatic disease after the index procedure. Additionally, targeted therapy has been shown to yield effective neoadjuvant cytoreduction, and oncolytic viruses may also increase the immunogenicity of primary tumors. Effective neoadjuvant therapy may serve to decrease tumor size and thus reduce the extent of required surgery and thus morbidity. It also allows for assessment of pathologic response, facilitating prognostication as well as tailoring future therapy. The current literature consistently supports that neoadjuvant therapy, even as little as one dose, is associated with improved outcomes and is well-tolerated. Some patients with a complete pathological response may even avoid surgery completely. These results challenge the current paradigm of a surgery-first approach and provide further evidence supporting neoadjuvant therapy in advanced-stage resectable melanoma. Further research into the optimal treatment schedule and dose timing is warranted, as is the continued investigation of novel therapies and combinations of therapies.

In Situ Implantation of Chitosan Oligosaccharide-Doped Lipoic Acid Hydrogel Breaks the "Vicious Cycle" of Inflammation and Residual Tumor Cell for Postoperative Skin Cancer Therapy.

Surgical excision is the main treatment for skin cancer, but the tumor recurrence caused by the "vicious cycle" between residual tumor cells and postoperative inflammation remains a challenge. Herein, a new material, which can break the "vicious cycle", was developed by incorporating chitosan oligosaccharides into lipoic acid hydrogel (COS@LA-hydrogel). When implanted at the resection site, the COS@LA-hydrogel would have a sustained release of LA and COS, which could not only kill residual tumor cells by synergistically reducing AKT phosphorylation but also decrease inflammation by inhibiting the expression of tumor necrosis factor-α (TNF-α) and inhibiting bacterial infection, respectively. As a proof of concept, in the postoperative melanoma resection model, the COS@LA-hydrogel reduced the expression of pro-inflammatory factors TNF-α and interleukin-6 (IL-6) by up to 78 and 80%, respectively, and they showed almost no tumors and the median survival of the mice was 2.5 times longer than that of the control group. The hydrogel with the function of "vicious cycle" breaking holds clinical potential.

Preferences for Adjuvant Immunotherapy in Adults with Resected Stage III Melanoma-A Discrete Choice Experiment.

This study aimed to quantify adult preferences for adjuvant immunotherapy for resected melanoma and the influence of varying levels of key attributes and baseline characteristics. A D-efficient design generated 12 choice tasks for two alternative treatments, adjuvant immunotherapy or no adjuvant immunotherapy. Recruitment to the online discrete choice experiment (DCE) occurred via survey dissemination by eight Australian melanoma consumer and professional groups, targeting adults with resected stage III melanoma, considering or having received adjuvant immunotherapy. The DCE included six attributes with two to three levels each, including 3-year risk of recurrence, mild, permanent and fatal adverse events (AEs), drug regimen and annual out-of-pocket costs. A mixed multinomial logit model was used to estimate preferences and calculate marginal rates of substitution and marginal willingness to pay (mWTP). The DCE was completed by 116 respondents, who chose adjuvant immunotherapy over no adjuvant immunotherapy in 70% of choice tasks. Respondents preferred adjuvant immunotherapy when associated with reduced: probabilities of recurrence, permanent and fatal AEs, and out-of-pocket costs. mWTP for an absolute reduction of 1% in 3-year risk of recurrence was less for respondents with lower rather than higher incomes, AU$794 (US$527) and AU$2190 (US$1454) per year. Respondents accepted an additional 4% chance of a permanent AE to reduce their absolute risk of 3-year recurrence by 1%. Respondents were willing to accept an extra 2% chance of 3-year recurrence to lower their chance of a fatal AE by 1%. Almost three-quarters of respondents chose adjuvant immunotherapy over no adjuvant immunotherapy, preferring treatment that improved efficacy and safety. Findings may inform decisions about access to adjuvant immunotherapy following surgery for melanoma.

Plasma glycoproteomic biomarkers identify metastatic melanoma patients with reduced clinical benefit from immune checkpoint inhibitor therapy.

The clinical success of immune-checkpoint inhibitors (ICI) in both resected and metastatic melanoma has confirmed the validity of therapeutic strategies that boost the immune system to counteract cancer. However, half of patients with metastatic disease treated with even the most aggressive regimen do not derive durable clinical benefit. Thus, there is a critical need for predictive biomarkers that can identify individuals who are unlikely to benefit with high accuracy so that these patients may be spared the toxicity of treatment without the likely benefit of response. Ideally, such an assay would have a fast turnaround time and minimal invasiveness. Here, we utilize a novel platform that combines mass spectrometry with an artificial intelligence-based data processing engine to interrogate the blood glycoproteome in melanoma patients before receiving ICI therapy. We identify 143 biomarkers that demonstrate a difference in expression between the patients who died within six months of starting ICI treatment and those who remained progression-free for three years. We then develop a glycoproteomic classifier that predicts benefit of immunotherapy (HR=2.7; p=0.026) and achieves a significant separation of patients in an independent cohort (HR=5.6; p=0.027). To understand how circulating glycoproteins may affect efficacy of treatment, we analyze the differences in glycosylation structure and discover a fucosylation signature in patients with shorter overall survival (OS). We then develop a fucosylation-based model that effectively stratifies patients (HR=3.5; p=0.0066). Together, our data demonstrate the utility of plasma glycoproteomics for biomarker discovery and prediction of ICI benefit in patients with metastatic melanoma and suggest that protein fucosylation may be a determinant of anti-tumor immunity.

Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study.

LBA9505 Background: Adjuvant pembrolizumab significantly improved distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) in patients with resected stage IIB or IIC melanoma versus placebo. We present the protocol-specified final DMFS analysis from KEYNOTE-716 (NCT03553836). Methods: Eligible patients were ≥12 years old with resected stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer, 8th edition, guidelines and a negative sentinel lymph node biopsy. In part 1 of the study, patients were randomly assigned (1:1) to pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for up to 17 cycles (~1 year) or until disease recurrence, unacceptable toxicity, or withdrawal. Randomization was stratified by T category for adults (T3b vs T4a vs T4b), with a separate stratum for pediatric patients. The primary end point was RFS per investigator review. DMFS per investigator review was a secondary end point. The protocol-specified final DMFS analysis was based on a target of 195 DMFS events. No formal hypothesis testing was performed because DMFS and RFS end points were met at previous interim analyses. The data cutoff date for this analysis was January 4, 2023. Results: Overall, 976 patients were randomly assigned to receive pembrolizumab (n = 487) or placebo (n = 489). Median duration of follow-up (time from randomization to the data cutoff date) was 39.4 months (range, 26.0-51.4). Compared with placebo, adjuvant pembrolizumab improved DMFS (medians: not reached; hazard ratio [HR], 0.59 [95% CI, 0.44-0.79]) and RFS (medians: not reached; HR, 0.62 [95% CI, 0.49-0.79]). The 36-month DMFS rate was 84.4% with adjuvant pembrolizumab versus 74.7% with placebo; the 36-month RFS rate was 76.2% with adjuvant pembrolizumab versus 63.4% with placebo. DMFS benefit with adjuvant pembrolizumab over placebo was observed regardless of cancer stage at baseline (stage IIB HR, 0.62 [95% CI, 0.42-0.92]; stage IIC HR, 0.57 [0.36-0.88]). Similar results were observed with RFS (stage IIB HR, 0.58 [95% CI, 0.43-0.79]; stage IIC HR, 0.65 [95% CI, 0.45-0.94]). No new safety signals were observed. Conclusions: With a median follow-up of 39.4 months, adjuvant pembrolizumab for resected stage IIB and IIC melanoma continued to show DMFS and RFS benefit over placebo, with no new safety signals. Clinical trial information: NCT03553836 .

Minimal residual disease by circulating tumor DNA as a biomarker of recurrence free survival in resected high-risk melanoma patients treated with mRNA-4157/V940, a personalized cancer vaccine, and pembrolizumab.

LBA9515 Background: The combination of mRNA-4157/V940 and pembrolizumab improved recurrence free survival (RFS) compared to pembrolizumab monotherapy in patients with resected high-risk stage III/IV cutaneous melanoma in the randomized Phase 2 mRNA-4157-P201/KEYNOTE-942 trial (RFS event rate of 22.4% (24/107) versus 40% (20/50); HR = 0.561; 95% CI: 0.309, 1.017). Across multiple cancer types and disease settings, detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) assays in plasma identifies patients at higher risk of relapse and progression, and can monitor presence of disease throughout treatment. Herein, we report ctDNA analyses to explore the association between minimal residual disease and the probability of recurrence. Methods: In mRNA-4157-201, baseline tumor core biopsies and matched whole blood were subjected to whole exome sequencing (WES). The personalized amplicon-based NGS assay by Inivata (RaDaR) was used to identify and prioritize up to 48 patient-specific somatic variants to analyze ctDNA in longitudinal plasma samples for MRD detection. This method for ctDNA analysis is distinct from most prior studies in melanoma that report use of ddPCR for single mutations or fixed-gene panels. The association of MRD with RFS was evaluated with Kaplan Meier analyses and assessed with hazard ratio (95% CI) in ctDNApos and ctDNAneg subgroups and across study arms. Results: Of patients enrolled in this study with evaluable ctDNA, 88% (110/125) were ctDNAneg at start of treatment. Significantly longer RFS was observed in patients who were ctDNAneg compared to those with ctDNApos at baseline across study arms (RFS event rate of 20.9% (23/110) versus 80.0% (12/15); HR = 0.150; 95% CI: 0.073, 0.306). Within the mRNA-4157/V940 and pembrolizumab combination arm, significantly longer RFS was observed in patients with ctDNAneg compared to ctDNApos samples (RFS event rate of 10.4% (8/77) versus 76.9% (10/13); HR = 0.087; 95% CI: 0.034, 0.222). This trend was also observed in the pembrolizumab arm (RFS event rate of 45.5% (15/33) versus 100% (2/2); HR = 0.008; 95% CI: 0.001, 0.088) study arm, although the small sample size in pembrolizumab arm (n = 2) limits interpretation. Conclusions: MRD detection by plasma ctDNA assay at the start of adjuvant melanoma treatment is uncommon in mRNA4157-p201 but is associated with shorter RFS. Treatment with the combination of mRNA-4157/V940 and pembrolizumab was associated with prolonged RFS compared to pembrolizumab monotherapy in patients with high-risk resectable melanoma, irrespective of MRD status Additional analyses including assessment of longitudinal ctDNA patterns are ongoing. The association between MRD and mRNA-4157/V940 treatment effect will be further explored in upcoming planned studies. Clinical trial information: NCT03897881 .

Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial.

LBA9503 Background: mRNA-4157 is a novel mRNA-based personalized cancer vaccine which encodes up to 34 patient-specific tumor neoantigens. The open-label randomized Phase 2 mRNA-4157-P201/Keynote-942 trial met its primary endpoint of recurrence free survival (RFS) in patients with resected high-risk stage IIIB/C/D and IV melanoma. The study has shown a statistically significant and clinically meaningful improvement in RFS in the combination therapy compared to pembrolizumab monotherapy, with a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017); 1-sided p-value of 0.0266). This report provides the first analysis of the secondary efficacy endpoint of distant metastasis-free survival (DMFS). Methods: mRNA-4157-p201 is an ongoing multicenter, open-label, randomized Phase II trial in patients with completely resected, high-risk Stage IIIB/C/D and IV cutaneous melanoma. Patients were randomized 2:1 (stratified by stage) to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. mRNA-4157 (1mg) was administered intramuscularly every 3 weeks for a total of 9 doses and pembrolizumab (200mg) intravenously was given every 3 weeks for up to 18cycles. The primary endpoint was investigator-assessed RFS, defined as local, locoregional, distant recurrence, or new primary melanoma. The secondary endpoint of DMFS was pre-specified and hierarchically tested following positive RFS. All tests were performed at 1-sided alpha = 0.99. Results: 157 patients were randomized to the combination of mRNA-4157 with pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). The primary analysis for the primary endpoint occurred after all patients completed a minimum of 12 months on study and 44 RFS events were observed. At a median follow-up of 23 (combination) and 24 (pembrolizumab) months in the primary analysis, RFS events were reported in 22.4% (24/107) of patients in the combination arm and in 40% (20/50) of patients in the monotherapy arm. The 18-month RFS rates (95% CI) were 78.6% (69.0%, 85.6%) vs 62.2% (46.9%,74.3%) in the combination and monotherapy arms respectively. There was also a statistically and clinically significant improvement in DMFS for the combination versus pembrolizumab monotherapy (HR = 0.347; 95% CI: (0.145, 0.828); 1-sided p-value 0.0063). Distant recurrence or death was reported in 8.4% (9/107) and 24% (12/50) of patients, with 18-month DMFS rates (95% CI) were 91.8% (84.2%, 95.8%) vs 76.8% (61.0%, 86.8%) in the combination and monotherapy arm, respectively. Conclusions: mRNA-4157 in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma significantly prolonged DMFS compared to pembrolizumab. These results provide further evidence that a personalized neoantigen approach is potentially beneficial for cancer patients. A phase 3 randomized study will be initiated in patients with melanoma. Clinical trial information: NCT03897881 .

The Microbiome in Advanced Melanoma: Where Are We Now?

This review summarizes recent data linking gut microbiota composition to ICI outcomes and gut microbiota-specific interventional clinical trials in melanoma. Preclinical and clinical studies have demonstrated the effects of the gut microbiome modulation upon ICI response in advanced melanoma, with growing evidence supporting the ability of the gut microbiome to restore or improve ICI response in advanced melanoma through dietary fiber, probiotics, and FMT. Immune checkpoint inhibitors (ICI) targeting the PD-1, CTLA-4, and LAG-3 negative regulatory checkpoints have transformed the management of melanoma. ICIs are FDA-approved in advanced metastatic disease, stage III resected melanoma, and high-risk stage II melanoma and are being investigated more recently in the management of high-risk resectable melanoma in the peri-operative setting. The gut microbiome has emerged as an important tumor-extrinsic modulator of both response and immune-related adverse event (irAE) development in ICI-treated cancer in general, and melanoma in particular.

Long-term outcomes of chronic immune-related adverse events from adjuvant anti-PD-1 therapy for high-risk resected melanoma.

9591 Background: Adjuvant anti-PD1 improves relapse-free survival in high-risk, resected melanoma, but can lead to irAEs, which become chronic in up to 41% of patients (Patrinely et al, JAMA Onc 2021). Given the expanding use of anti-PD-1 in earlier settings in many tumors, it is imperative to assess their long-term effects. We aimed to determine the incidence, characteristics, and long-term outcomes, including resolution vs persistence, of chronic irAEs from adjuvant anti-PD1. Methods: We retrospectively analyzed patients (pts) treated with adjuvant anti-PD1 for resected stage III-IV melanoma from 2015-2022 from 6 institutions; all pts had at least 18 month follow up post-anti-PD1 discontinuation. Demographics, disease characteristics, treatment and recurrence details, and outcomes were collected. Type, grade, duration, treatment, and resolution of acute (onset during treatment) and chronic irAEs (defined as those extending 6+ months after treatment cessation) were characterized. Results: Among 318 pts, 226 (64%) developed acute irAEs arising during treatment, including 44 (20%) with grade 3-5 irAEs. Chronic irAEs developed in 147 (46%) pts, of which 74 (50%) were grade 2+, 6 (4%) were grade 3-5, and 100 (68%) were symptomatic. With long-term follow-up (median 35 months), 52 (35%) pts experienced resolution of chronic irAEs while 95 (30% of the full cohort) had persistent chronic irAEs at last follow-up. Among these 95 pts with persistent chronic irAEs, 43 (45%) were grade 2+, 42 (44%) were symptomatic, 24 (16%) were on steroids, and 42 (29%) were on other management. The most common persistent chronic irAEs were hypothyroid (n = 38), arthritis (n = 18), dermatitis (n = 9), and adrenal insufficiency (n = 8). Of 37 pts with chronic irAEs who received additional immunotherapy, 12 (32%) had a flare, 10 (27%) had no effect, and 20 (54%) had a distinct irAE. Conclusions: In this large cohort of anti-PD1 treated pts, chronic irAEs were common (46%) and frequently were persistent with long-term follow up (30%, most often hypothyroid and arthritis). Prolonged monitoring and management are needed for these long-term survivors. [Table: see text]

The current state and future of neoadjuvants in resectable melanoma: Review of phase II/III studies conducted between 2018-2022.

e21568 Background: Adjuvant therapy with single agent anti-PD1 and BRAF/MEK-inhibitors (BRAF/MEKi) is approved for patients diagnosed with high-risk stage III melanoma. The goal of adjuvant therapy is to prevent the growth of the occult metastasis to distant organs. The premise of neoadjuvant therapy in clinical stage III melanoma is to allow for a better antigen exposure when checkpoint inhibitors are administered. We aimed to get an overview of the current state of neoadjuvant therapy in resectable melanoma. Methods: A systematic literature search was conducted in November 2022, using PubMed, American Society of Clinical Oncology (ASCO) Journal of Clinical Oncology and European Society for Medical Oncology (ESMO) abstract databases. Eligible studies included Phase 2 and 3 randomized controlled trials (RCT), single-arm trials, pooled analyses, and planned future trials published between 2018-2022 looking at the efficacy of neoadjuvants in resectable melanoma. Two individuals (CL and MM) screened all the studies, and 3 individuals (CM, MM, MW) went over the list of Abstracts. Primary outcomes and secondary outcomes, as well as median duration of follow up and Grade 3 or above adverse effects (AEs) were recorded. Abstracts with more recent findings or final publications were excluded in the final analysis. Results: A total of 14 published studies (4 RTCs, 5 single-arm, 2 OpACIN-neo and 3 related sub-analysis studies) and 16 abstracts (5 ESMO, 11 ASCO) were identified, representing 34 unique Neoadjuvant arms and a total of 1,496 patients. Thirteen of 27 trials making 71% of patients (n = 1061) tested immune checkpoint inhibitors (ICIs). Four of 27 trials of total n = 112 tested BRAF/MEKi. All ongoing or future studies (7 trials) tested combination of ICI with BRAF/MEKi or other molecules such as MDM2 inhibitors, interferon-α, or oncolytic viruses. Most of studies (54% of ICI studies, 50% of BRAF/MEK inhibitor trials, and 80% of other studies) used pathological response as their primary outcome. Other primary end points included event-free survival (EFS) and relapse-free survival (RFS), and 13/14 published studies and 13/16 abstracts met the primary end point. A pooled analysis of complete pathologic response (pCR) revealed an estimate of 38.3% ± 19.7 (mean ± SD) from 16 unique ICI neoadjuvant arms, 51.9% ± 5.3 for BRAF/MEKi (from 3 data points), and 21.0% ± 7.2 for other agents/combinations (from 3 data points). Rate of ≥ Grade 3 AEs was 28.7% ± 31.0 (from 11 data points) for studies testing ICI, 32.5% ± 14.1 (from 6 data points) for BRAF/MEKi, and 23.6% ± 20.2 (from 3 data points) from studies testing other agents/combinations. Conclusions: Recent studies have shown that neoadjuvant in resectable melanoma can offer increased therapeutic efficacy. While past studies have focused on PD-1 and CTLA-4 inhibitors, ongoing and future studies are beginning to test newer agents and novel molecular targets.

Temozolomide plus cisplatin versus toripalimab (anti-PD-1) as adjuvant therapy in resected mucosal melanoma.

9508 Background: Chemotherapy (temozolomide plus cisplatin) has been demonstrated to be a better adjuvant regimen compared to high-dose interferon alpha-2b in resected Mucosal Melanoma (MuM) in the pre-immunotherapy era. Yet in the present immunotherapy era, PD-1 inhibitor was recommended as a standard adjuvant therapy for resected Melanoma. No adjuvant trial comparing chemotherapy with PD-1 inhibitor in resected MuM had been reported. we conducted this study to determine the efficacies of adjuvant chemotherapy versus PD-1 inhibitor in resected MuM. Methods: All patients (pts) with resected MuM received chemotherapy (temozolomide 200 mg/m2/day orally on days 1 to 5 plus cisplatin 75 mg/m2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or Toripalimab (anti-PD-1, 3 mg/kg every 2 weeks via intravenous infusion) as adjuvant therapy from 2013 to 2019 were included retrospectively. Demographic and clinical characteristics between the two groups were matched with 1:1 by propensity score matching (PSM) to reduce the bias. After PSM, the efficacies of the two groups were compared, and subgroup analysis was performed according to the baseline characteristics. The endpoints were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Kaplan-Meier methods and Cox regressions were used to estimate median RFS, DMFS, OS and HR. Results: A total of 247 pts were included, of which 78 were in the Toripalimab group and 169 were in the Chemo group. PSM matched 65 pts from each of the two groups. The baseline characteristics were similar. At a median follow-up of 52.6 months (95%CI, 44.6-60.6 months), patients receiving chemo had a longer median RFS (28.2 vs. 12.0 months; HR=0.64, 95% CI, 0.42 to 0.98; P=0.04), DMFS (42.0 vs. 19.0 months; HR=0.58, 95% CI, 0.36 to 0.92; P=0.02) and OS (93.4 vs. 39.3 months; HR=0.56, 95% CI, 0.33 to 0.94; P=0.03) versus the toripalimab group (Table). Conclusions: Adjuvant chemotherapy (temozolomide plus cisplatin) shows remarkable longer RFS, DMFS, and OS than Toripalimab (anti-PD-1). It suggested that adjuvant chemotherapy may be a better option for patients with resected mucosal melanoma even in the present immunotherapy era. [Table: see text]

Impact of adjuvant immunotherapy in resected stage II/III/IV melanoma: A single center experience.

e21565 Background: The incidence of malignant melanoma (MM) in Mediterranean countries is estimated at 3- 5/100.000 inhabitants/year with a predicted rising trend. MM is responsible for over 90% skin cancer deaths due to its tendency to metastasize early. Surgical excision is the treatment of choice for early-stage melanoma, however, 40-60% of patients with high recurrence risk melanoma, thick ulcerated primary melanomas (Stage IIC) and those with lymph node involvement (Stage III), experience a tumor relapse. Adjuvant therapy in resected high-risk melanomas has shown improved Relapse-Free-Survival (RFS), although no Overall Survival (OS) benefit has been observed to date. This retrospective observational study, conducted in one center, aims to evaluate effectiveness and safety of adjuvant therapies for resected high-risk melanoma. Methods: Single center cross-sectional study that included patients with a resected high-risk melanoma candidate for adjuvant treatment, at 2015-2022 period. Convenience sampling 48 patients recruited. Median follow up 55,4 months. Results: Median age was 54y, 52% were male and 93’6 is cutaneous melanoma. 53% were BRAF WT. Median Breslow (mm) was 3’85, median num/mm2 mitosis are 4 and 62’5% had ulceration. 15% presented satelosis or intransit metastasis and 55% had a lymphadenectomy. Melanoma stage: 9%IIB, 11%IIC, 11%IIIA, 25%IIIB, 38%IIIC, 2% IIID and 2% IV. Adjuvant treatment: 22% nivolumab, 20% ipilimumab+nivolumab, 12% ipilimumab, 16% interferon.75% of patients completed adjuvant treatment, 14% stopped for toxicity and 9% presented disease relapse (21% loca, 64% systemic). Best treatment response in relapse was 12% partial response, 37% progression. Toxicity: 18% presented grad ¾ toxicity. Efficacy: median RFS was 78’8m and median OS was NR. Conclusions: Adjuvant treatment is associated with an increased DFI in resected high risk melanoma patients. Adjuvant therapy was generally well tolerated, with manageable adverse events, consistent in type and incidence to those seen in clinical trials that allowed the approval for these compounds in adjuvant and metastatic scenarios. Prospective studies are needed to determine new biomarkers for the selection of those patients who could benefit to a greater extent from adjuvant therapies in resected high-risk melanoma.

Multicenter analysis of melanoma recurrence pattern and management after adjuvant immunotherapy.

e21573 Background: PD-1 inhibitors improve outcomes in resected stage II-IV melanoma. However, recurrence patterns and prognostic factors are less known. Methods: We conducted a retrospective study in resected stage II-IV melanoma patients (p) treated with adjuvant PD-1 inhibitors (clinical practice or clinical trials) from 5 centers. Demographic, disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcome were recorded. Descriptive assessment for recurrence patterns and analysis for prognostic factors were performed. Results: From June 2017 to June 2022, 181 p were included. Median age was 59 years [22-81], 57% were male, 85% had cutaneous melanoma, 28% had BRAFV600E mutation. 9 p (5%) presented stage II, 147 (81%) stage III and 25 (14%) stage IV. Ulceration was present in 59% p, mitotic rate >1/mm2 in 84%, Breslow index >3 mm in 65% and elevated LDH in 51%. 81% p received PD-1 inhibitors alone and 19% in combination with other immunotherapies. 52% of p completed treatment, 12% discontinued due to toxicity and 26% due to relapse. 13% of p presented grade 3-4 adverse events and there was a grade 5 myocarditis. With a median follow-up of 18,1 months, 68 (37%) p recurred (Table). Median relapse free survival (RFS) was 48,8 months (95% CI 31,1-66,4). Recurrence was significantly associated with a higher stage, mitotic rate, LDH level and Breslow index, BRAFV600E mutation, non-cutaneous melanoma and delayed initiation of adjuvant immunotherapy in univariate analysis (p<0,05). Stage, non-cutaneous melanoma and initiation of immunotherapy >3 months (16% p) were associated with higher recurrence in multivariate analysis (<0,05). Locoregional recurrence was treated in 23 p with surgery (14p), surgery + RT (7p) or RT alone (2). Systemic recurrence was treated in 50 p: all BRAF mutant p received targeted therapy (24p, 43%) with a disease control rate (DCR) of 91% and a median progression free survival (PFS) of 56 months (95% CI 24,1-NR); BRAF wild type p (26p, 47%) were treated with anti-PD-1 alone (9p) or in combination (7p), anti-CTLA-4 (2p), chemotherapy (1p) or best supportive care (7p), with DCR of 33% and a median PFS of 8 months (95% CI 6,9-10,8). Conclusions: We observed a 37% relapse rate and systemic recurrence were more frequent than locoregional recurrence. Treatment at relapse with targeted therapy in BRAF mutant p achieved higher DCR and PFS than immunotherapy in BRAF wild type p; with better outcomes than previously reported.[Table: see text]

NeoPlus: A phase II study of neoadjuvant lenvatinib and pembrolizumab in resectable mucosal melanoma.

9514 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, ongoing 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 Event free survival (EFS), Overall survival (OS) and safety. Results: As of Dec 2022, 19 pts were enrolled with a median follow-up of 49 wks (95%CI, 38 -60). Median age was 57 yrs, 14 were female. Primary sites included: 8 female genital, 6 ano-rectal, 4 head & neck (1 nasal, 3 oral),1 esophageal. 12 pts were localized disease,7(37%) were regional lymphatic disease. KIT or NRAS mutations were presented in 2 and 3 pts, respectively. 15 pts underwent surgery, 2 pts had a pCR (13.3 %), 1 MPR, 3 pPR, with a pathologic response rate of 40%(6/15,95%CI 16-67%). 4 pts did not proceed with planned surgery for pts preference. Median EFS has not been reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R=pCR+ MPR + pPR) than non-responders (NR=pNR) (p = 0.04). In 6 pts(one pPR and 5pNR) with paired pre and post treatment samples, CD3+ and CD8+ T cells were significantly increased following treatment (p =0.03). Most common AEs were proteinuria (6, 32%), hypothyroidism (6, 32%), dysphonia (5, 26%). One pt(5%, 1/19) had grade 3 ALT elevation. No grade 4-5 toxicities were observed. Conclusions: The combination of pembrolizumab plus lenvatinib as neoadjuvant therapy in resectable MM is safe. The preliminary data has shown promising pathologic response with increased CD8+ T cell infiltration, supporting further investigation of neoadjuvant treatment in MM. Acknowledgement: Investigational funding and products are granted from Merck Sharp & Dohme LLC. Clinical trial information: NCT04622566 .

Efficacy of adjuvant therapy in patients (pts) with AJCC v8 stage IIIA cutaneous melanoma.

9518 Background: Pts with resected AJCC v8 stage IIIA melanoma have been under-represented in clinical trials of adjuvant drug therapy. The benefit of adjuvant targeted and immunotherapy in this population is unclear. Methods: In this multicenter, retrospective study, pts with stage IIIA melanoma (AJCC v8) who received adjuvant pembrolizumab or nivolumab (PD1), BRAF/MEK-targeted therapy dabrafenib + trametinib (TT), or no adjuvant treatment (OBS) were included. Recurrence free survival (RFS), distant metastasis free survival (DMFS), and toxicity rates were examined. Results: 613 pts from 34 centers across Australia, Europe and USA were included. The median follow-up was 2.6 yrs (IQR, 1.6-3.4 yrs). Pt characteristics and follow-up were similar across the cohorts (Table). Completion rates of 12-month PD1 and TT therapy were 57.0% and 69.2% respectively. 1-yr RFS was 93.3% (95% CI, 90.3-96.4) in PD1, 100% in TT and 91.3% (95% CI, 88.1-94.7) in OBS cohorts. 2-yr RFS was 79.3% (95% CI, 74.1-84.8) for PD1, 100% for TT and 84.3% (95% CI, 79.9-89.0) in OBS cohorts. 2-yr DMFS was 88.4% (95% CI, 84.3-92.8) in PD1, 100% in TT and 91.1% (95% CI, 87.7-94.7) in OBS cohorts. Risk of recurrence was associated with higher breslow thickness (HR 1.73, 95% CI 1.36-2.20), higher mitotic rate (HR 1.07, 95% CI 1.02-1.12) and neck as the site of nodal metastases (HR 2.71, 95% CI 1.45-5.06) in the overall cohort (p<0.05). Neck nodal metastases were associated with higher risk of recurrence in OBS cohort (HR 3.82, 95% CI 1.91-7.66; p<0.05) but not in the PD1 cohort. Rates of ≥ Grade 3 toxicities were 10.9% with PD1 and 20.0% with TT; discontinuation due to toxicity occurred in 25.0% and 30.0%, respectively. No new safety signals were observed. Rates of unresolved toxicity at last follow-up were 26.9% in PD1 and 7.7% in TT cohorts. Conclusions: In this large international study, adjuvant PD1 or TT did not significantly improve RFS or DMFS compared to OBS in pts with resected stage IIIA melanoma. Prognosis in stage IIIA melanoma is favourable and outcomes after adjuvant therapy in this population needs further study in prospective randomised trials. [Table: see text]

The validity of a machine learning algorithm in predicting response to immune checkpoint inhibitors in melanoma.

9523 Background: We previously reported the development of a machine learning algorithm to predict immunotherapy response in patients with advanced melanoma using retrospectively collected pretreatment histologic slides (Johannet et al, CCR 2021). In this study, we tested the validity of the same algorithm in two independent cohorts of melanoma patients enrolled in phase III clinical trials of immune checkpoint inhibitors (ICI), one metastatic, and one adjuvant. Methods: We examined 336 patients enrolled in CheckMate 067(NCT01844505) and CheckMate 238 (NCT02388906). We used deep convolutional neural networks (DCNN) to automatically segment images into three regions of interest: tumor, lymphocytes, and stroma. The algorithm was previously trained and tested to predict the complete and partial response (CR/PR) versus progression of disease (POD) and to predict the probability of progression-free survival (PFS) while on ICI. We tested the performance in the two cohorts; the first (CheckMate 067) included 164 patients with stage III/IV unresectable melanoma who received ipilimumab (n= 49), nivolumab (n = 59), or combination (n= 56) therapy as a first line, then tested whether the algorithm could perform as well in the second cohort (CheckMate 238) which included 172 patients with stage III/IV resectable melanoma who received adjuvant ipilimumab (n = 87) or nivolumab (n = 85) therapy as first line. Results: The segmentation classifier identified tumor within slides with an area under the curve (AUC) of 0.99. A combined model of DCCN and treatment predicted POD with an AUC of 0.72 in metastatic melanoma patients enrolled in Checkmate 067. The DCCN classified patients into high and low risk based on their likelihood of PFS (P <0.0001). However, the same algorithm is not effective in predicting recurrence in patients treated in the adjuvant setting in Checkmate 238 (AUC 0.52). Retraining and testing using only patients treated in the adjuvant setting improved the AUC average to 0.65-0.70. Conclusions: Our results show the reproducibility of our previously developed algorithm in predicting response in patients with advanced metastatic melanoma. The inability of the model to predict recurrence in patients treated in the adjuvant setting might reflect the difference in the endpoint tested (response versus recurrence), which requires further training on larger datasets for this particular endpoint prediction, and/or the limited tumor volume in resected disease below a threshold that machine learning can predict a difference.

Tumor-informed circulating tumor DNA (TI-ctDNA) based molecular residual disease (MRD) detection and relapse risk for patients with stage II-IV melanoma in surgical remission: A single center experience.

9572 Background: Melanoma is associated with significant risk of relapse after surgery. While the odds of relapse increase with advancing stage, long term relapse free survival (RFS) is possible without adjuvant therapy in a significant subset of patients as shown by AJCC v8 staging long term survival data. TI-ctDNA (Signatera™) is a non-invasive biomarker for MRD detection and functions by sequencing the patient’s own tumor for the creation of a customized panel of PCR probes based upon a tumor’s unique mutational profile. Positive TI-ctDNA testing is significantly associated with relapse after surgical resection in colorectal cancer and may help inform treatment decision-making, allowing for intensification or de-intensification of patient management. This study describes the operating characteristics of TI-ctDNA in monitoring for relapse in patients with resected melanoma. Methods: This is a single center retrospective analysis of patients with stage IIb-IV melanoma in surgical remission. Between January 2021 and January 2023, male and female patients presenting in surgical remission were monitored with TI-ctDNA at 6- or 12-week intervals. Surveillance imaging for relapse was performed according to standard of care guidelines appropriate for tumor stage. Patients were treated with immunotherapy, targeted therapy, or melanoma specific anti-tumor vaccine. Duration of RFS from surgery to detectable TI-ctDNA was recorded, along with duration of RFS from surgery to confirmed melanoma relapse. Results: 45 eligible patients were included in the analysis. 10 patients had detectable TI-ctDNA during the study period. 7 patients had confirmed relapse, 6 of whom were TI-ctDNA positive and 1 who was TI-ctDNA negative. The total relapse rate in TI-ctDNA positive patients (6/10) was significantly higher than the relapse rate in TI-ctDNA negative patients (1/35) [p = 0.0002]. Time to detection of positive TI-ctDNA was variable and ranged from 0 to 664 days (median 73 days). Conclusions: TI-ctDNA testing demonstrated preliminary ability to differentiate melanoma patients at the highest risk of relapse. Prospective evaluation of TI-ctDNA monitoring for determination of patients at high versus low risk of relapse is warranted and may help to inform future clinical trial designs by allowing for patient stratification to low risk (undetectable TI-ctDNA) and high risk (detectable TI-ctDNA) disease states.