Hyngstrom, John

Importance Contemporary guidelines recommend sentinel lymph node biopsy (SLNB) for patients with melanoma with predicted risk of SLN metastasis greater than 10% and consideration of SLNB when the risk is 5% to 10%. A gene expression profile (GEP)–based test that can accurately identify patients with a low risk of SLN metastasis would refine selection for SLNB. Objective To establish the predictive capability of the combined clinicopathological factors and GEP (CP-GEP) test to identify patients with primary cutaneous melanoma who can safely forgo SLNB and to investigate the prognostic value of CP-GEP regarding the outcome in patients with cutaneous melanoma after a negative SLNB (not reported herein). Design, Setting, and Participants This prognostic study was conducted from September 2021 to June 2024 at 9 academic medical centers with experienced melanoma surgeons. Included were patients with biopsy-proven invasive cutaneous melanoma with T1 to T3 tumors and clinically negative regional LNs. All patients were deemed candidates for SLNB using standard clinical criteria. GEP was performed on formalin-fixed, paraffin-embedded tissue from the primary melanoma biopsy. Analyses were performed from December 2024 to August 2025. Intervention CP-GEP testing to determine risk of having a positive SLNB in patients with T1 to T3 cutaneous melanoma who were considered appropriate candidates for the procedure based on standard clinical parameters. Main Outcomes and Measures CP-GEP results were reported as low risk or high risk; the primary outcome measure was negative predictive value (NPV) in low-risk cases. Analyses included NPV assessment by tumor (T) subcategory, primary site, and age. Results A total of 1761 patients (median [IQR] age, 64 [53-72] years; 997 male [56.6%]) underwent SLNB (310 [17.6%] SLN positive) and had a successful CP-GEP test; GEP was successful in 97.7% of samples. A total of 651 patients (37.0%) were considered low risk by CP-GEP. Among low-risk cases, 46 (7.1%) were SLN positive, and NPV was 92.9% (95% CI, 90.7%-94.8%). High-risk cases had a 23.8% (264 of 1110) SLN-positive rate. The percentage of cases with low-risk CP-GEP declined with increasing T category (T1 = 346 of 507 [68.2%]; T2 = 295 of 897 [32.9%]; T3 = 10 of 357 [2.8%]). CP-GEP results were consistent in discriminating SLN-positive rates across primary sites, histologic subtypes, and mitotic count categories. In 2 large subsets, clinical stage IB (n = 1187) and patients 65 years and older (n = 832), 6.5% (95% CI, 4.6%-8.8%) of low-risk clinical stage IB cases and 6.6% (95% CI, 4.2%-9.7%) of all low-risk cases in patients 65 years and older were SLN positive vs 18.3% (95% CI, 15.3%-21.6%) and 20.3% (95% CI, 16.8%-24.2%) for high-risk cases, respectively. Conclusions and Relevance In this multicenter, prospective, blinded, prognostic study, the CP-GEP test reliably identified patients with melanoma with less than 10% SLN metastasis risk. SLN metastasis rates were approximately 3-fold greater for high-risk vs low-risk CP-GEP cases. In appropriately selected patients, the CP-GEP test may add value for shared patient-surgeon decision-making.

The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous ) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.

Abstract Background: The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine. Methods: Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis. Results: Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0%, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7%, p = 0.714) and OS (94.6% vs. 93.8%, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw. Conclusions: In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial. Trial Registration This is a clinical trial registered under NCT02301611.

Background The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. Methods Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). Results After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). Conclusions The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. Trial registration number NCT02301611 .

AbstractAnorectal melanoma is an aggressive mucosal melanoma subtype with a poor prognosis. Although recent advancements have been seen for cutaneous melanoma, the optimal treatment paradigm for management of anorectal melanoma is evolving. In this review, we highlight differences in the pathogenesis of mucosal versus cutaneous melanoma, new concepts of staging for mucosal melanoma, updates to surgical management of anorectal melanoma, and current data for adjuvant radiation and systemic therapy in this unique patient population.

Abstract Background: Sentinel lymph node biopsy (SLNB) provides important staging and prognostic information that guides surveillance and adjuvant systemic therapy decisions for patients with cutaneous melanoma. At most centers, SLNB is indicated for patients with cutaneous melanoma with at least a 5% risk of having nodal metastases, typically melanomas ≥0.8 mm in thickness or selected thinner lesions with high-risk features such as elevated mitotic rate and/or ulceration. However, up to 85% of patients who undergo SLNB have a negative result. Currently, there is an unmet clinical need to better identify patients with a low risk of nodal metastasis who may safely forgo SLNB, but otherwise meet established criteria for undergoing SLNB. Previously, a model using primary tumor gene expression profile (GEP) data combined with clinicopathological features (CP) was developed to identify melanoma patients with a low risk of having a positive SLN. The model has been externally validated in multiple retrospective studies. The aim of the MERLIN_001 observational registry study is to prospectively validate the CP-GEP model in an independent multicenter cohort of primary cutaneous melanoma patients, who undergo lymphatic mapping and SLNB per current clinical guidelines. Methods: A total of 9 centers across the US are included in the study with planned enrollment of 2,340 patients, allowing for a loss of up to 30% due to screen failure, tissue loss, low RNA yield, no gene expression profile or failure to perform the planned SLNB. Patients with clinically node-negative cutaneous melanoma and planned SLNB using current guideline indications are eligible for the study and will be followed for five years. Both patients and investigators are blinded to the results (NCT04759781). FFPE material from the initial melanoma biopsy is collected and the GEP of the primary melanoma is assessed. Subsequently, CP-GEP probability scores are calculated and expressed as a binary classification (Low Risk or High Risk for nodal metastasis), which will be compared to SLNB pathology results. Performance metrics for CP-GEP will be evaluated and will include: SLNB Reduction Rate based on Negative Predictive Value, Positive Predictive Value, Sensitivity and Specificity, and the corresponding 95% confidence intervals. Finally, the performance of CP-GEP to stratify patients according to risk of recurrence (recurrence-free survival, distant metastasis-free survival, overall survival) will also be assessed, based on five-year outcomes data. Additional analyses will be performed using the data collected throughout the study. Enrollment of patients started in September 2021 and is ongoing. As of January 2023, 890 patients have been enrolled, representing 46% of the targeted number of patients with a successful SLNB and CP-GEP test result. Citation Format: Tina J. Hieken, Michael E. Egger, Christina V. Angeles, Erin E. Burke, Michael C. Lowe, John R. Hyngstrom, Georgia M. Beasley, Edmund K. Bartlett, Vernon K. Sondak. Merlin_001: a prospective registry study of a primary melanoma gene-signature to predict sentinel node (SN) status and determine its prognostic value for more accurate staging of SN-negative melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT053.

TPS9606 Background: For patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) provides important staging and prognostic information that guides surveillance and adjuvant systemic therapy decisions. At most centers, SLNB is indicated for patients with cutaneous melanoma with at least a 5% risk of having nodal metastases, typically melanomas ≥ 0.8 mm in thickness or thinner lesions with high-risk features such as elevated mitotic rate and/or ulceration. SLNB, generally involving a separate incision, does carry a small but measurable risk of complications including seroma, infection and rarely lymphedema, and most patients have negative sentinel lymph nodes. Currently, there is an unmet clinical need to identify patients who may safely forgo SLNB due to a low (<5%) risk of nodal metastasis, who otherwise meet established criteria for SLNB. Previously, a model consisting of gene expression profile (GEP) of the primary tumor combined with clinicopathological features (CP) has been developed to identify melanoma patients with a low risk of having a positive SLNB. The model has also been validated in multiple retrospective studies. The aim of the MERLIN_001 registry study is to prospectively validate the CP-GEP model in an independent multicenter cohort of primary cutaneous melanoma patients who undergo SLNB for standard indications. Methods: In the next two years, a total of 10 centers across the US will enroll 2,340 patients with clinically node-negative cutaneous melanoma undergoing SLNB using current guideline indications and will follow these patients for 5 years (ClinicalTrials.gov identifier: NCT04759781). Enrollment of patients started in September 2021 and 242 patients have been enrolled as of February 1, 2022. FFPE material from the initial melanoma biopsy will be used to assess the GEP of the primary melanoma. The CP-GEP probability scores will be expressed as a binary classification (Low Risk or High Risk for nodal metastasis) and will be compared to SLN pathology. Performance metrics for CP-GEP will be evaluated and will include: Negative Predictive Value, Positive Predictive Value, Sensitivity and Specificity, and the corresponding 95% confidence intervals. Risk for nodal metastasis will be calculated for Low Risk and High Risk CP-GEP patients. Finally, the performance of CP-GEP to stratify patients according to risk of recurrence (local, regional, distant, death) will also be studied, since data will be collected for up to 5 yrs. Clinical trial information: NCT04759781.

Background Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. Methods Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. Results For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). Conclusions Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. Trial registration number NCT01546571.

Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.