Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.Zeynep Eroglu ... Hidde M Kroon ... et al

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases – A multicenter cohort study

Purpose: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. Results: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4e12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. Conclusion: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.Carl-Jacob Holmberg ... Brendon Coventry ... Hidde Kroon ... et al

Characterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation

Background Patients with BRAF-mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy. Methods In this study, we characterized the treatment-naive immune context in patients with BRAF-mutant and BRAF wild-type (BRAF-wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC). Results In single-cell data, BRAF-mutant melanoma displayed a significantly reduced infiltration of CD8+ T cells and macrophages but also increased B cells, natural killer (NK) cells and NKT cells. We then validated this finding using bulk RNA-seq data from the skin cutaneous melanoma cohort in The Cancer Genome Atlas and deconvoluted the data using seven different algorithms. Interestingly, BRAF-mutant tumors had more CD4+ T cells than BRAF-wt samples in both primary and metastatic cohorts. In the metastatic cohort, BRAF-mutant melanoma demonstrated more B cells but less CD8+ T cell infiltration when compared with BRAF-wt samples. In addition, we further investigated the immune cell infiltrate using flow cytometry and multiplex IHC techniques. We confirmed that BRAF-mutant melanoma metastases were enriched for CD4+ T cells and B cells and had a co-existing decrease in CD8+ T cells. Furthermore, we then identified B cells were associated with a trend for improved survival (p=0.078) in the BRAF-mutant samples and Th2 cells were associated with prolonged survival in the BRAF-wt samples. Conclusions In conclusion, treatment-naive BRAF-mutant melanoma has a distinct immune context compared with BRAF-wt melanoma, with significantly decreased CD8+ T cells and increased B cells and CD4+ T cells in the tumor microenvironment. These findings indicate that further mechanistic studies are warranted to reveal how this difference in immune context leads to improved outcome to combination immune checkpoint blockade in BRAF-mutant melanoma.Minyu Wang, Soroor Zadeh, Angela Pizzolla, Kevin Thia, David E Gyorki, Grant A McArthur, Richard A Scolyer, Georgina Long, James S Wilmott, Miles C Andrews, George Au-Yeung, Ali Weppler, Shahneen Sandhu, Joseph A Trapani, Melissa J Davis, Paul Joseph Neeso

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node Positive Melanoma at Major Referral Centers

First published: 19 December 2022Objective: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. Summary Background Data: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. Methods: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. Results: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. Conclusions: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.Kristy K. Broman ... Hidde M. Kroon ... et al

Surveillance of sentinel node-positive melanoma patients with reasons for exclusion from MLST-II: multi-institutional propensity score matched analysis

Background In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown. Study design SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared. Results Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p ConclusionsSLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.Kristy K Broman, Tasha M Hughes, Lesly A Dossett, James Sun, Michael J Carr, Dennis A Kirichenko ... et al

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases: A multicenter cohort study.

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

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy trial II (MSLT-2)

Published online April 7, 2021Abstract not availableKristy Kummerow Broman ... Hidde M. Kroon ... et al