High-risk Melanoma Research Articles

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.

226TiP CLEAR-Me: Interception trial to detect and clear molecular residual disease in patients with high-risk melanoma

226TiP CLEAR-Me: Interception trial to detect and clear molecular residual disease in patients with high-risk melanoma

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.

Clinical and Imaging Follow-Up for High-Risk Cutaneous Melanoma: Current Evidence and Guidelines.

The most recent (eighth) edition of the American Joint Committee on Cancer (AJCC) staging system divides invasive cutaneous melanoma into two broad groups: "low-risk" (stage IA-IIA) and "high-risk" (stage IIB-IV). While surveillance imaging for high-risk melanoma patients makes intuitive sense, supporting data are limited in that they are mostly respective and used varying methods, schedules, and endpoints. As a result, there is a lack of uniformity across different dermatologic and oncologic organizations regarding recommendations for follow-up, especially regarding imaging. That said, the bulk of retrospective and prospective data support imaging follow-up for high-risk patients. Currently, it seems that either positron emission tomography (PET) or whole-body computerized tomography (CT) are reasonable options for follow-up, with brain magnetic resonance imaging (MRI) preferred for the detection of brain metastases in patients who can undergo it. The current era of effective systemic therapies (ESTs), which can improve disease-free survival (DFS) and overall survival (OS) beyond lead-time bias, has emphasized the role of imaging in detecting various patterns of EST response and treatment relapse, as well as the importance of radiologic tumor burden.

Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes.

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

Comparison of Extended Skin Cancer Screening Using a Three-Step Advanced Imaging Programme vs. Standard-of-Care Examination in a High-Risk Melanoma Patient Cohort.

Modern diagnostic procedures, such as three-dimensional total body photography (3D-TBP), digital dermoscopy (DD), and reflectance confocal microscopy (RCM), can improve melanoma diagnosis, particularly in high-risk patients. This study assessed the benefits of combining these advanced imaging techniques in a three-step programme in managing high-risk patients. This study included 410 high-risk melanoma patients who underwent a specialised imaging consultation in addition to their regular skin examinations in outpatient care. At each visit, the patients underwent a 3D-TBP, a DD for suspicious findings, and an RCM for unclear DD findings. The histological findings of excisions initiated based on imaging consultation and outpatient care were compared. Imaging consultation detected sixteen confirmed melanomas (eight invasive and eight in situ) in 39 excised pigmented lesions. Outpatient care examination detected seven confirmed melanomas (one invasive and six in situ) in 163 excised melanocytic lesions. The number needed to excise (NNE) in the imaging consultation was significantly lower than that in the outpatient care (2.4 vs. 23.3). The NNE was 2.6 for DD and 2.3 for RCM. DD, 3D-TBP, or RCM detected melanomas that were not detected by the other imaging methods. The three-step imaging programme improves melanoma detection and reduces the number of unnecessary excisions in high-risk patients.

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 > 50 (OS p = 0.043), acral subtype (PFS p = 0.023), PD-L1 IHC < = 1% (OS p = 0.052, PFS p = 0.002), duration of treatment < 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 > = 1% by IHC was 4/2. TMB mut/mb > 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]

INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (<65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .

Phase II multi-center study of adjuvant nivolumab in combination with ipilimumab in patients with high-risk uveal melanoma (HCRN MEL17-309).

9509 Background: High-risk uveal melanomas (UM) recur distantly in over 50% by 3 years (median distant metastatic-free survival (DMFS) 32 months). No effective treatment currently exists to reduce the risk of metastatic disease and patients (pts) with metastasis have a very poor prognosis with few therapeutic options. The combination of Nivolumab/Ipilimumab (Nivo/Ipi) has shown limited efficacy in pts with metastatic UM. However, preclinical data suggest differential biology between local vs metastatic UM. We performed a prospective multi-center phase II study of adjuvant Nivo/Ipi in pts high-risk UM patients to compare DMFS to a cohort of UM with the same tumor characteristics. Methods: This investigator-initiated study enrolled pts with high-risk UM, defined as a predicted 3-year distant relapse-free survival (DMFS) of approximately 50% (based on gene expression profiling (GEP) (DecisionDx-UM) class 2 with tumor largest basal diameter (LBD) of 12mm or higher). Pts received Nivo 240mg iv every 2 weeks and Ipi 1mg/kg every 6 weeks for up to 48 weeks. The target sample size was 50 evaluable pts. The primary endpoint was 3-year DMFS. Secondary endpoints were median DMFS, overall survival (OS), and toxicity (AE). In addition, a propensity score method (double robust estimate in R adjusted curves) is used to estimate the average DMFS and compare the nonrandomized treatment (tx) and the control patients. 119 pts from the Cooperative Ocular Oncology Group (COOG) database were defined as high risk, matched for tumor characteristics (GEP class 2, LBD≧12mm) and were used as a control cohort. Results: Fifty-two pts were enrolled and 50 were treated from 12/18/2018-9/29/2021. As of 11/6/2023, with a median follow-up of 36 months, the 3-year DMFS rate vs COOG control, was 69.1% vs 45.1% (two-sided p = 0.012) without any adjustment; and 70.4% vs 43.4% (two-sided p = 0.018) with the propensity score method. The median DMFS was not reached (NR) in the tx cohort vs 33.8 months. There was a reduction in the risk of distant recurrence with Nivo/Ipi vs control cohort (RR 0.52, 95%CI, 0.309-0.888). Median OS has not been reached with only 7 deaths from UM in the tx cohort so far. Grade ≥3 any-cause AE occurred in 27 pts (54%). Grade ≥3 treatment-related (TR) AE occurred in 48%. 22 pts (44%) discontinued the treatment due to toxicity. One pt died due to immune-related myocarditis. Conclusions: This phase II study of adjuvant Nivo/Ipi resulted in clinically meaningful and statistically significant improvement in 3-year DMFS of 70.4% vs 43.4% in control for pts with high-risk UM from the COOG database matched for tumor characteristics. Further investigation of this regimen as adjuvant therapy of high-risk UM is warranted. Clinical trial information: NCT03528408 .

Germline pathogenic variants in a large convenience cohort of multiple melanoma subtypes.

9595 Background: A heritable component accounts for approximately 10% of melanomas. These estimates derive from populations deemed high risk for a germline pathogenic variant (gPV). The prevalence and clinical features of a broader melanoma patient population are unknown. Methods: Using the MSKCC IMPACT dataset, we identified a convenience cohort of all pts with melanoma who had undergone targeted tumor-normal sequencing (NCT01775072) for gPV in 76-90 genes. gPV were categorized by association with cancer predisposition and penetrance. Results: 701 pts with melanoma and germline sequencing demonstrated 105 pathogenic variants in 29 genes (Table). 14% of pts (n=99) harbored a gPV in a cancer susceptibility gene (gPV+); 49% high/moderately pathogenic, 32% low/recessive, and 19% uncertain. 6% of gPV+ pts had 2 gPVs. 77% of gPVs were involved in DNA damage repair pathways. The genes known to be associated with melanoma risk accounted for 9% of gPVs, inclusive of CDKN2A (2%), CDK 4 (1%), MITF (4%), and BRCA2 (2%). A further 15% were in genes with suggested, as yet undefined, susceptibility for melanoma; BRCA1 (6%), ATM (5%), BAP1 (2%) and PALB2 (2%). gPV+ frequency varied by melanoma subtype: unknown primary (19%, n=18), cutaneous (15%, n=64), mucosal (13%, n=13), acral (7%, n=2) and uveal (4%, n=2) (p=0.039). No significant difference in age, sex, race, stage at diagnosis, personal history of other cancer, or family history (FHx) of melanoma was seen between gPV+ and gPV-, on univariate analysis. 47% of gPV+ pts had either >1 primary melanoma, age<45 years or a FHx of melanoma (n=47), of which 14 pts had >1 risk factor. The presence of >1 melanoma and FHx of melanoma was associated with gPV+ (p=0.016). There was no significant difference in somatic TMB and MAPK pathway alterations between gPV+ and gPV-. In this cohort selected for high-risk melanomas, melanoma was the first presenting cancer for 83% of patients with gPV+. Assessment of biallelic loss to clarify if gPVs may be driving melanoma carcinogenesis is ongoing. Conclusions: This represents the largest cohort of sequenced matched germline and somatic analysis in melanoma. There is a 14% overall gPV prevalence that varies by melanoma subtype. The association of >1 primary melanoma, young age and a family history of melanoma with gPV+ is consistent with prior studies, however, would not capture 53% of gPV+ in this cohort. Melanoma represents the index cancer for the majority of gPVs, informing the need to expand germline testing in patients with melanoma. [Table: see text]

A prognostic model based on selected cell state and cellular community scores in patients with advanced melanoma treated with immune checkpoint inhibitors (Ecotype-ICI score) as a predictor of ICI immunotherapeutic benefits.

9568 Background: We conducted an enhanced immune cell state atlas analysis of the data of patients with melanoma treated with ICI to investigate predictors of therapeutic benefits and mechanisms of resistance. Methods: Leveraging RNA-seq from melanoma patients (n=141) treated with ICI within the ORIEN Avatar project (NCT03977402), we constructed a prognostic model based on selected cell state and cellular community scores, also known as ecotype-ICI score ( Li. AACR 2023). We evaluated the model’s predictive value using transcriptomic data from high-risk melanoma patients treated with adjuvant ipilimumab (n=471) or interferon-α (n=248) as part of the E1609 phase 3 trial (1). RNA-seq data were initially deconvoluted for cellular community signatures using EcoTyper. The six prognostic carcinoma ecotype (CE) signatures identified (CE1, CE2, C6, CE7, CD9, CD10) were utilized for calculating a risk score based on a multivariable Cox model, which was trained using Avatar data. For additional external validation, we analyzed data from patients with metastatic melanoma treated with anti-CTLA4 ( Va. n=40), anti-PD1 ( Liu. n=121), and anti-PD1 alone or combined with anti-CTLA4 ( Gide. n=66). A series of ad hoc survival analyses, including Kaplan-Meier analysis, log-rank tests, and Cox regression were further applied. Results: The ecotype-ICI score showed strong prognostic significance in predicting overall survival (OS) in the entire group of E1609 patients (N=719; Cox P < 0.0001, log-rank P < 0.0001), the ipilimumab cohort (Cox P < 0.000143, log-rank P =0.00011), but less so with interferon (Cox P= 0.06). CE9, characterized by its proinflammatory nature and IFN-gamma signaling, and CE10, noted for its canonical T cell state signatures, both demonstrated a leading predictive value according to multivariable Cox regression analysis. Interestingly, CE2, noted for its lymphocyte deficiency signature, also demonstrated complementary predictive value for outcomes following ipilimumab. Within the validation cohorts of public data sets noted above, the ecotype-ICI scores showed similarly strong prognostic significance in predicting OS (Gide. P = 0.045; Liu. P = 0.029; Va. P = 0.011). Ecotype-ICI also demonstrated a distinct distribution in the responder group (complete or partial response) compared to the progressive disease group, underscoring its potential as a discriminative biomarker for ICI response and survival outcomes. Conclusions: Our analysis has successfully established the utility of the immune cell state atlas in predicting therapeutic benefits with ICIs across diverse ICI treatment regimens in melanoma. We will update our results with data related to gene ontology, KEGG pathways and the most complementary pathway signatures at the meeting. 1. Tarhini, 2020.

Radiation and Melanoma: Where Are We Now?

This review summarizes the current role of radiotherapy for the treatment of cutaneous melanoma in the definitive, adjuvant, and palliative settings, and combinations with immunotherapy and targeted therapies. Definitive radiotherapy may be considered for lentigo maligna if surgery would be disfiguring. High risk, resected melanoma may be treated with adjuvant radiotherapy, but the role is poorly defined since the advent of effective systemic therapies. For patients with metastatic disease, immunotherapy and targeted therapies can be delivered safely in tandem with radiotherapy to improve outcomes. Radiotherapy and modern systemic therapies act in concert to improve outcomes, especially in the metastatic setting. Further prospective data is needed to guide the use of definitive radiotherapy for lentigo maligna and adjuvant radiotherapy for high-risk melanoma in the immunotherapy era. Current evidence does not support an abscopal response or at least identify the conditions necessary to reliably produce one with combinations of radiation and immunotherapy.

Melanoma tumor microbiome as a predictor of anti-PD-1 and anti-CTLA-4 immunotherapy response.

e14666 Background: In 2023, it is estimated that 97,610 melanoma diagnoses were made in the United States, resulting in 7,990 deaths. For high-risk melanomas, immune checkpoint inhibitors are often administered as an adjuvant to surgery, though they yield variable response rates. The gut microbiome’s association to these treatments’ success has been demonstrated, largely through fecal transplant and probiotic trials. In this study, we seek to determine whether tissue-resident microbes in melanoma tumors could be used to predict immunotherapy response. Methods: Sequencing data of 289 melanoma tumor tissue samples was downloaded across three distinct studies. Intratumor microbial species abundances were derived from RNA or DNA sequencing data through direct alignment to microbial reference databases. Gene expression profiling was also performed. Microbial abundance values were used to construct models predicting patients’ responses to check-point blockade immunotherapies, which were then validated on an external dataset. Results: 12 and 14 microbial species were differentially abundant in anti-PD-1 responders and anti-CTLA-4 responders, respectively. We identified significant correlations of these species to genes of the PD-1 and CTLA-4 signaling pathways. Among others, greater abundance of Corynebacterium kroppenstedtii and Streptococcus gordonii correlated to decreased expression of PD1 and CTLA-4. With the abundances of these taxa and the expressions of 37 genes known to be implicated in immunotherapy response, we developed two classifiers to predict a patient’s response to anti-PD-1 and anti-CTLA-4 therapies. When tested externally, these models successfully predicted a majority of responders and non-responders with sensitivities of 80.0% and 60.0% and specificities of 95.2% and 95.8%, respectively. Conclusions: Our study revealed that checkpoint blockade response for melanomas could be predicted with microbe abundances. Our analysis demonstrates the potentially promising clinical utility of intratumor microbiota in cancer treatment. Given their location in the tumor microenvironment and their ability to influence immune processes, intratumor microbes could play a critical role in modulating the therapeutic effects of immune checkpoint blockades. We hope that our results could also be applied to other solid tissue cancers, where a significantly smaller fraction of patients respond to immunotherapy. [Table: see text]

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors’ perspective

IntroductionAdjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT.MethodsIn the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients’ ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years.ResultsThe preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60–65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18–22% for ICI and + 15% for TT.ConclusionOur study highlights the importance of understanding the patient’s perspective and a potential difference to the doctor’s view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.

Positron emission tomography-computed tomography vs. brain magnetic resonance imaging for the detection ofcerebral metastases of melanoma: a 5-year retrospective study.

Patients with melanoma present a high risk of developing extracutaneous metastases. Positron emission tomography--computed tomography (PET-CT) is one of the preferred examinations for the staging of oncological patients. It is not the method of choice to detect brain metastases, but this technique has shown significant improvement and allows the detection of some of them. However, it is unclear how it performs compared with magnetic resonance imaging (MRI), the current gold standard for diagnosing brain metastases. To compare the accuracy of PET-CT and cerebral MRI to detect brain metastases in patients with melanoma. We retrospectively included all patients diagnosed with melanoma stage IIC-IV (American Joint Committee on Cancer 8th Edition, 2017) who presented at the skin tumour board of the University Hospital of Bern between January 2018 and December 2022. All radiological reports extracted from the patient management system were analysed to assess discrepancy between the visibility of brain metastases on PET-CT and brain MRI. In this study including 393 patients, brain MRI demonstrated significantly better performance than PET-CT in detecting brain metastases. In 47 patients, cerebral metastases were detected completely, detected partially, or not detected by PET-CT in 2 (4%), 15 (32%) and 30 (64%), respectively. Despite the increasing performance of PET-CT, this study highlights the crucial role of brain MRI, which remains the gold standard to detect cerebral metastases. Brain MRI should be performed in patients with high-risk melanoma from stage IIC to exclude brain metastases.

Abstract LB452: Effects of AKT1, 2, and 3 knock-out by CRISPR-Cas9 in CD133+human melanoma stem cells treated with MEK and AKT inhibitors

Abstract Melanoma-initiating stem cells are involved in tumorigenesis, invasion, and drug resistance in malignant melanoma, and are characterized by increased expression of the stem cell marker CD133. We previously showed that CD133 knockout (KO) by CRISPR-Cas9 enhanced MEK inhibitor trametinib (T) -induced apoptosis in patient-derived BAKP melanoma cells by reducing anti-apoptotic p-AKT and p-BAD and increasing pro-apoptotic BAX. Dox-induced CD133 expression, in contrast, diminished apoptosis in T-treated cells, and exhibited elevated p-AKT, p-BAD, and decreased activation of BAX and caspases-3 and -9. This is the first time that CD133 is shown to activate a survival pathway wherein (1) CD133 increases AKT phosphorylation and activation, which induces (2) BAD phosphorylation and inactivation, and (3) reduces caspases-3 and -9 activity leading to apoptosis suppression, increased cell survival and drug resistance in melanoma. We investigated the effects of MEK inhibition with T in combination with the pan-AKT inhibitor capivasertib (AZD5363; C) in BAKP melanoma cells, with or without Dox-induced CD133 expression. Kinetic XTT cell viability and Annexin-Sytox Blue apoptosis assays revealed significantly reduced survival of BAKP cells exposed to a combination of T+C, compared to T alone. To determine the relative contribution of each of the three AKT genes to increased drug resistance of CD133-inducible melanoma stem cells, AKT 1, 2, and/or 3 were knocked out using sgRNAs specific to each of the three AKTs in a CRISPR-Cas9 lentiviral vector, followed by puromycin selection. Gene knockout was confirmed by immunoblot analysis using antibodies specific to each of the three AKTs, as well as by DNA sequence analysis. BAKP control or AKT KO cells were then exposed to T or T+C, and subjected to apoptosis assays, as well as immunoblot analysis with antibodies to apoptosis markers. Single KO of AKT 2 or 3, but not AKT 1, sensitized BAKP cells exposed to T alone, partially obviating the requirement for C to inhibit AKT. Triple KO of AKT 1, 2, and 3 rendered cells even more sensitive to T alone. Targeting nodes of the AKT and MAPK survival pathways with trametinib and AZD5363 highlights the potential for combination therapies for melanoma stem cells increasing the arsenal of more effective treatments for patients with high-risk melanoma. Targeting AKT 1, 2, and/or 3 might be effective in eliminating recalcitrant CD133-positive stem-like cells that may be responsible for tumor recurrence. Citation Format: Cynthia M. Simbulan-Rosenthal, Nusrat Islam, Ryyan Alobaidi, Alejandro Moreno, Veerupaxagouda Patil, Amal Alzharani, Peter Sykora, Dean S. Rosenthal. Effects of AKT1, 2, and 3 knock-out by CRISPR-Cas9 in CD133+human melanoma stem cells treated with MEK and AKT inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB452.

Адъювантная таргетная терапия и анти-PD-1-иммунотерапия у пациентов с меланомой кожи III стадии с мутацией в гене BRAF. Данные реальной клинической практики

Targeted therapy and anti-PD1 immunotherapy are standard of adjuvant stage III (or equivalent stage III) melanoma treatment. Both treatments significantly improve relapse-free survival compared with placebo and ipilimumab. The impact of adjuvant immunotherapy on overall survival remains unclear. Targeted therapy improved 3-year overall survival, but data didn’t reach statistical significance. There is still a lack of direct comparison in randomized trials between targeted therapy and immunotherapy. Data limited to a few retrospective studies. We conducted a single-center observational retrospective study comparing two adjuvant treatment options in BRAF-mutated high-risk melanoma patients who were treated or consulted at the N.N. Blokhin National Medical Research Center of Oncology.

Neoadjuvant Dual Checkpoint Inhibitors vs Anti-PD1 Therapy in High-Risk Resectable Melanoma

Despite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known. To compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM. In this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM. Patients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab. The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered. Among 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy. In this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

A new era of risk prediction for patients with high-risk melanoma

A new era of risk prediction for patients with high-risk melanoma

Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis

The introduction of adjuvant systemic treatment for patients with high-risk melanomas necessitates accurate staging of disease. However, inconsistencies in outcomes exist between disease stages as defined by the American Joint Committee on Cancer (8th edition). We aimed to develop a tool to predict patient-specific outcomes in people with melanoma rather than grouping patients according to disease stage. Patients older than 13 years with confirmed primary melanoma who underwent sentinel lymph node biopsy (SLNB) between Oct 29, 1997, and Nov 11, 2013, at four European melanoma centres (based in Berlin, Germany; Amsterdam and Rotterdam, the Netherlands; and Warsaw, Poland) were included in the development cohort. Potential predictors of recurrence-free and melanoma-specific survival assessed were sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. A prognostic model and nomogram were developed to predict 5-year recurrence-free survival on a continuous scale in patients with stage pT1b or higher melanomas. This model was also calibrated to predict melanoma-specific survival. Model performance was assessed by discrimination (area under the time-dependent receiver operating characteristics curve [AUC]) and calibration. External validation was done in a cohort of patients with primary melanomas who underwent SLNB between Jan 30, 1997, and Dec 12, 2013, at the Melanoma Institute Australia (Sydney, NSW, Australia). The development cohort consisted of 4071 patients, of whom 2075 (51%) were female and 1996 (49%) were male. 889 (22%) had sentinel node-positive disease and 3182 (78%) had sentinel node-negative disease. The validation cohort comprised 4822 patients, of whom 1965 (41%) were female and 2857 (59%) were male. 891 (18%) had sentinel node-positive disease and 3931 (82%) had sentinel node-negative disease. Median follow-up was 4·8 years (IQR 2·3-7·8) in the development cohort and 5·0 years (2·2-8·9) in the validation cohort. In the development cohort, 5-year recurrence-free survival was 73·5% (95% CI 72·0-75·1) and 5-year melanoma-specific survival was 86·5% (85·3-87·8). In the validation cohort, the corresponding estimates were 66·1% (64·6-67·7) and 83·3% (82·0-84·6), respectively. The final model contained six prognostic factors: sentinel node status, Breslow thickness, presence of ulceration, age at SLNB, primary tumour location, and maximum diameter of the largest sentinel node metastasis. In the development cohort, for the model's prediction of recurrence-free survival, the AUC was 0·80 (95% CI 0·78-0·81); for prediction of melanoma-specific survival, the AUC was 0·81 (0·79-0·84). External validation showed good calibration for both outcomes, with AUCs of 0·73 (0·71-0·75) and 0·76 (0·74-0·78), respectively. Our prediction model and nomogram accurately predicted patient-specific risk probabilities for 5-year recurrence-free and melanoma-specific survival. These tools could have important implications for clinical decision making when considering adjuvant treatments in patients with high-risk melanomas. Erasmus Medical Centre Cancer Institute.