Faculty Bibliography

This review outlines the most up-to-date metastatic melanoma treatment recommendations and relevant risks for patients with solid organ transplants, patients with renal dysfunction, and patients with preexisting autoimmune conditions. These specific treatment populations were excluded from the original clinical trials, which studied immune checkpoint inhibitors and BRAF/MEK inhibitors in the advanced melanoma setting. We have synthesized the current body of literature, mainly case series and retrospective analyses, to reflect the evidence for the treatment of these special patient populations at present.

IMPORTANCE/OBJECTIVE:Acral (AM) and mucosal melanomas (MM) are rare subtypes with a poor prognosis. In those with advanced disease, anti-PD-1 (PD1) therapy has reduced activity compared to that seen in non-acral cutaneous melanoma. OBJECTIVE:To determine the efficacy of adjuvant PD1 in resected AM or MM. DESIGN/METHODS:An international, retrospective cohort study SETTING: Data up to November 2021 collected from 20 centres across 10 countries. PARTICIPANTS/METHODS:AM or MM who received adjuvant PD1 were included and compared to matched patients from the Melanoma Institute Australia (MIA) database using a propensity score matching analysis. MAIN OUTCOMES AND MEASURES/METHODS:Recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) were investigated. RESULTS:Forty five of 139 (32%) AM and 9 of 55 (16%) MM patients completed adjuvant therapy. The main reason for early treatment cessation in both groups was disease recurrence: 51 (37%) and 30 (55%) in the AM and MM groups, respectively. In the AM group adjuvant PD1 was associated with a longer RFS [HR-0.69 (0.52-0.92, p = 0.0127)], DMFS [HR0.58 (0.38-0.89, p = 0.0134)] and OS [HR of 0.59 (0.38-0.92, p-value 0.0196)] when compared to the historical cohort. In the MM group there was no statistical difference in RFS [HR1.36 (0.69-2.68,p-value 0.3799], DMFS or OS. CONCLUSION AND RELEVANCE/CONCLUSIONS:After adjuvant PD1, both AM and MM have a high risk of recurrence. Our data suggests a benefit to using adjuvant PD1 therapy in resected AM but not in resected MM. Additional studies to investigate the efficacy of adjuvant PD1 for MM are needed.

IMPORTANCE:Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. OBJECTIVE:To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTS:This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). MAIN OUTCOMES AND MEASURES:Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. RESULTS:Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. CONCLUSIONS AND RELEVANCE:In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.

BACKGROUND:CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB-IV melanoma. METHODS:Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. RESULTS:T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179). CONCLUSIONS:These findings suggest responses to this combination may be seen even in patients without a typical "immune-active" microenvironment. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT02565992.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10⁶ plaque-forming units (PFU)/mL in week 1, followed by 10⁸ PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297.

The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.

BACKGROUND:Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS:Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS:35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION:Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

There is currently no targeted therapy to treat NF1-mutant melanomas. Herein, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1-WT melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using TCGA data, and immunohistochemistry (IHC). Digital spatial profiling (DSP) with multiplex IHC and immunofluorescence (IF) were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 compared to NF1-WT (P=0.008), which was independently validated both in the TCGA dataset (P=0.01, P=0.03) and with IHC (P=0.013, P=0.036), respectively. DSP analysis showed upregulation of LY6E within the tumor cells [FDR<0.01, lg2FC>1], confirmed with multiplex IF showing co-localization of LY6E in melanoma cells. The combination of MEK and CDC20 co-inhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-MUT cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype.

BACKGROUND:Disparities in cancer outcomes persist for underserved populations; one important aspect of this is limited access to promising early phase clinical trials. To address this, the National Cancer Institute (NCI) funded Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020). We report the tools developed and accrual metrics of the initial year of CATCH-UP.2020 with a focus on racial, ethnic, geographic and socioeconomically underserved populations. METHODS:CATCH-UP.2020 is a P30 supplement awarded to eight NCI designated cancer centers with existing resources to rapidly open and accrue to Experimental Therapeutics Clinical Trials Network (ETCTN) trials with emphasis on engaging patients from underserved populations. Sites utilized patient-based, community-based, investigator-based, and program-based tools to meet specific program goals. RESULTS:From September 2020 to August 2021, CATCH-UP.2020 sites opened 45 ETCTN trials. Weighted average trial activation time for the 7 sites reporting this was 107 days. In the initial year, sites enrolled 145 patients in CATCH-UP.2020 with 68 (46.9%) representing racial, ethnic, rural and socioeconomically underserved populations using the broader definition of underserved encompassed in the grant charge. During the initial year of CATCH-UP.2020, a time impacted by the COVID-19 pandemic, 15.8% (66/417) and 21.4% (31/145) of patients enrolled to ETCTN trials at network and at CATCH-UP sites respectively, were from racial/ethnic minority groups, a more limited definition of underserved for which comparable data are available. CONCLUSION/CONCLUSIONS:Targeted funding accelerated activation and accrual of early phase trials and expanded access to this therapeutic option for underserved populations.

While targeting the MAPK pathway in BRAFV600E mutant melanoma remains an important therapeutic paradigm, the nearly universal development of therapeutic resistance remains a problem in the clinic. In this study, we sought to identify novel strategies to overcome the acquired resistance to Dabrafenib (D)/Trametinib (T) in melanoma cells. Murine and human BRAF V600E mutant melanoma cell lines were chronically exposed D/T to induce stable resistance. By RNA sequencing of the resistant cell lines and analyzing patient-derived RNAseq data, we found that pathways that are involved in transcription and cell cycle progression are commonly enriched in BRAFi/MEKi resistant samples. We selected the CDK4/6 inhibitor Palbociclib and CDK7 inhibitor YKL-5- 124 (YKL) to target key cell cycle regulators to test the hypothesis that these pathways are instrumental in the development of resistance to D/T. YKL showed superior capacity compared with Palbociclib in suppressing the proliferation of multiple D/T-resistant melanoma cell lines. Combination of D/T/Y induced strong cell cycle arrest and higher levels of cell death to the DT-resistant melanoma cells. Mechanistically, D/T/Y combination strongly inhibited phosphorylation of CDK1/CDK2, while inducing elevated markers for genomic instability. Interestingly, the combo also appeared to reduce MITF expression, an important transcription regulator that is overexpressed in melanoma and drives proliferation/survival. In allograft and xenograft experiments, Ythe combo of D/T/Y yielded significantly enhanced suppression to melanoma tumor growth and improved overall survival without causing overt toxicity. In summary, our data suggest that CDK7 inhibitor YKL-5- 124, in collaboration with Dabrafenib/Trametinib, may represent an important therapeutic strategy to control melanoma progression in targeted therapy-resistant patients