Mucosal Melanoma Research Articles

Overall survival and efficacy subgroup analysis of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9545 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we report the updated efficacy results. Methods: This is a multicenter, single-arm, phase II, pivotal registrational study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors, version 1.1 assessed by independent radiology review committee (IRRC). Results: A total of 100 pts were enrolled and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (October 31, 2023), median follow-up was 24.4 months (95% CI: 21.9, 27.9). The confirmed ORR was 35.8% (95%CI: 26.3%, 46.3%). Median progression-free survival (mPFS) was 4.2 months (95%CI: 3.5, 5.6). The median overall survival (mOS) was immature during last year's ASCO annual meeting, and the present mOS was 13.7 months (95% CI of 10.3–18.0). The IRRC-assessed ORRs by melanoma subtype were 42.9% (95% CI of 29.7–56.8) in acral melanoma, 25.0% (95% CI of 7.3–52.4) in mucosal melanoma. ORRs by NRASmutation site were 41.3% (95% CI of 30.1–53.3), 13.3% (95% CI of 1.7–40.5) and 20.0% (95% CI of 0.5–71.6) for Q61, G12, and G13, respectively. ORR in patients who had been treated with immunotherapy was 40.6% (95% CI of 28.5–53.6), while in those without immunotherapy, ORR was 25.8% (95% CI of 11.9–44.6). The difference in PFS was not statistically significant across subgroups, regardless of melanoma type, NRAS mutation site, line of previous treatment, type of previous treatment and previous treatment with immunotherapy. The safety profile is similar with last year's ASCO annual meeting. The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, facial oedema, peripheral oedema, and increased aspartate aminotransferase. No treatment-related death was reported. Conclusions: Tunlametinib demonstrated an encouraging treatment response rate in patients with advanced NRAS-mutant melanoma with a manageable safety profile. These results suggest that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those who had previously received immunotherapy. Clinical trial information: NCT05217303 .

Enhanced dacarbazine efficacy in advanced melanoma patients previously treated with immune checkpoint inhibitors in Korea.

e21528 Background: Immune checkpoint inhibitors (ICI) have revolutionized advanced malignant melanoma treatment. But the lack of effective options post-ICI failure presents a significant challenge. Despite its modest efficacy, chemotherapy with dacarbazine remains practical choice in metastatic melanoma patients after ICI failure. Researchers suggested an increased efficacy of chemotherapy in melanoma patients previously treated with ICI. In this study, we aimed to assess the efficacy of dacarbazine of patients with or without prior ICI treatment. Methods: 71 patients with histologically confirmed malignant melanoma, who diagnosed and underwent chemotherapy between 2011 and 2023 at the Kyungpook National University Chilgok Hospital (Daegu, Korea) were included in this retrospective study. We included patients who had received either dacarbazine single or CVD(Cisplatin, Vinblastine, Dacarbazine) regimen for an unresectable stage IIIC, IIID or IV acral, cutaneous, mucosal melanoma according to American Joint Committee on Cancer(AJCC) 8th edition. Results: Among a total of 71 individuals, there were 16 patients who had not previously received pembrolizumab treatment (DTI-only group). There were 55 patients in the pembrolizumab (pem-DTI group) experienced group. The median PFS was 2.3 months in the DTI-only group and 3.9 months in the pem-DTI group, reflecting a significant PFS difference of 1.6 months. And the median OS was 6.8 months in the DTI-only group and 19.0 months in the pem-DTI group, demonstrating a statistically significant difference. In the univariate and multivariate analysis for PFS, the use of pembrolizumab was advantageous compared to non-use (HR 0.246, 95% CI 0.106-0.576, p= 0.001). The only favorable condition in the univariate analysis for OS was the use of pembrolizumab compared to non-use (HR 0.198, 95% CI 0.068-0.574, p= 0.003). The mean duration of response for the DTI-only group was 4.64 months, while for the pem-DTI group, it was 8.11 months, indicating that the pem-DTI group exhibited a longer duration. Conclusions: We have demonstrated superior PFS and OS in the group of metastatic melanoma patients who received dacarbazine after prior treatment with pembrolizumab compared to those treated with dacarbazine alone. Dacarbazine may still be a valid option after failure of ICI +/- targeted treatment. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially enhance sensitivity to immune checkpoint-based therapy.

Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: Lenvamel, a multicenter retrospective study of the French Group of Skin Cancers.

9546 Background: Treatment options for patients (pts) with advanced melanoma who experience resistance to immunotherapy (ICI) +- targeted therapy are lacking. Studies suggest the anti-tumour activity of combined pembrolizumab and lenvatinib in pts progressing on ICI. We report the clinical outcomes of combined lenvatinib and anti-PD-1 in this population. Methods: This French multicenter real-world study was conducted from 09/2020 to 07/2023. The primary endpoint was objective response rate (ORR) according to the RECIST criteria (v.1.1). Secondary endpoints were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS) and duration of response (DOR). Results: Of the 67 pts included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV M1c or M1d disease. Baseline characteristics are presented (Table). Overall ORR was 28.4% (95%CI, 18–41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. ORR was 71.4% (95%CI, 29–96%) for mucosal melanoma, 32,8% (95%CI, 21–46%) for pts pre-treated with anti-PD-1 + anti-CTLA-4, and 31,5% (95%CI, 20–46%) for BRAF wild-type melanoma. Median DOR was 3.1 (IQR, 1.3–4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5–3.7) and 9.8 (95% CI, 5.6–13.9) months respectively. Grade 3–4 TRAEs occurred in 16 pts (24%, no grade 5); common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). Conclusions: Our study demonstrates an interesting response rate and acceptable safety profile of this combination, with manageable toxicities, in an immuno-refractory population with poor prognostic factors. Pts pre-treated with anti-PD-1+ anti-CTLA-4, and those with BRAF wild-type melanoma seemed to benefit more from this strategy. Our study also provides promising data (considering the small sample) for pts with mucosal melanoma. Our data support this treatment option for refractory melanoma, though not yet approved by the health authorities, and highlight the need for new strategies. [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 .

Intracranial outcomes with ipilimumab and nivolumab in melanoma brain metastases following progression on anti-PD-1 therapy.

9555 Background: Ipilimumab + nivolumab (ipi/nivo) is effective for melanoma brain metastases (MBM), but the efficacy of ipi/nivo in MBM in patients (pts) whose melanoma has progressed on anti-PD-1 is unknown. Methods: We conducted a retrospective analysis of pts with progressive MBM who received ipi/nivo at Memorial Sloan Kettering Cancer Center following prior anti-PD-1. Cohort A included pts with ≥1 untreated MBM (≥5mm) without local interventions (such as neurosurgery, radiotherapy). Cohort B included pts who had received local interventions for all MBMs before starting ipi/nivo. The primary endpoint was intracranial (IC) progression free survival (PFS). IC response was assessed based on clinical radiological interpretation for Cohort A. Kaplan-Meier methods were used to estimate time-to-event outcomes. Results: Fifty-seven pts were identified: 28 and 29 in Cohort A and B, respectively. All pts had received prior anti-PD-1, 42% prior ipi, a median of 2 (IQR: 1, 3) prior lines, and 21% (12/57) of pts prior treatment was in the adjuvant setting only. 79% (45/57) of pts had cutaneous, 14% (8/57) acral, 5% (3/57) unknown primary and 2% (1/57) mucosal melanoma. Median age was 64 (IQR: 58, 71) and 55 (IQR: 47, 70) years in Cohort A and B, respectively. Cohort A had median lesion size (largest measurable MBM) of 1.0cm (IQR: 0.60, 2.12), and 64% (18/28) of pts had >5 lesions; Cohort B had a median lesion size 1.5cm (IQR: 1.10, 2.00) and 28% (8/29) of pts had >5 lesions. 14% (8/57) of pts received concurrent steroid (equivalent of ≥dexamethasone 4mg daily) upon starting ipi/nivo, and leptomeningeal disease was present in 14% (4/28) and 7% (2/29) of Cohort A and B, respectively. The IC response rate was 11% (3/28, 2 were complete (CR)) in Cohort A.Both patients with CR were asymptomatic with ≤ 2 lesions and no prior CTLA-4 exposure. Most (20/28, 71%) in Cohort A had best response of progressive disease (PD); all that had a best response of stable disease (SD; 5/28, 18%) sustained that response for less than 6 months. Median IC-PFS was 1.7 (95% CI: 1.3,4.4) and 7.6 (95% CI: 3.6, -) months, and median overall survival (OS) was 6.7 (95% CI: 3.6,10) and 24 (95% CI: 11, -) months in Cohort A and B. 24-month OS was 19% (95% CI: 8.1,45) and 51% (95% CI: 35,75) in Cohort A and B. 30% (8/27) and 66% (19/29) of pts had subsequent systemic therapy, and 48% (13/27) and 52% (15/29) subsequent local therapy in Cohorts A and B. Conclusions: Ipi/nivo has limited efficacy in patients with progressive MBM post-PD-1 therapy in the absence of local therapy. These results highlight the unmet clinical need for more effective therapies to address progressive MBM post-PD-1 therapy, an increasingly relevant clinical scenario particularly in light of the growing use of adjuvant and neoadjuvant anti-PD-1.

Nivolumab combined with high dose multisite radiotherapy in previously untreated advanced melanoma (NIRVANA): A non-randomised, open-label, multicenter, phase 2 trial.

e21505 Background: Outcome of advanced melanoma remains poor for the majority of patients (pts) and new treatment strategies are needed. Preclinical and clinical data suggest a potential increase of the immunotherapy efficacy when combined with hypofractionated multisite radiotherapy (HMR). Objective: To assess the impact of HMR combined with nivolumab in advanced melanoma. Methods: This is a non-randomised, open-label, multicentre phase 2 trial(NCT02799901). Pts must have locally advanced or metastatic melanoma (AJCC7), previously untreated. Pts with mucosal or uveal melanoma, those with brain metastasis and LDH ≥ 1.5 the upper limit were not included. Pts received (until progression or unacceptable toxicity) nivolumab (fixed dose 240 mg/15 days) plus radiotherapy (day 15) delivered 3 x 6 Gy every second day, at every metastatic organ, if feasible.At progression, second irradiation was authorized while pursuing nivolumab (rechallenging strategy).The primary endpoint was 1-year overall survival (OS) (hypothetic improvement of 1-year OS from 71%1). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Subgroups and multivariate analyses were performed. Results: A total of 64 pts were included, from 03/2017 to 07/2019. Median follow-up was 23.5 months [IQR 2.3-43.8]. Median age was 64 years [35-95], majority of pts were male (67%), had an ECOG-PS 0 (75%), a stage IV-M1C disease (47%) and were BRAF-wild-type (67%).] The 1-year OS and PFS rates were 79% and 56% respectively (p = 0.12 and p = 0.0.3 in comparison with the 1-year OS and PFS of 71% and 43% of Robert et al’study1). 39 pts were irradiated at 1 target, 25 at ≥2 targets (total of 92 tumor targets). The 2-years OS rates were 83% and 52% for pts who were irradiated on several sites and one site respectively (p = 0.03). The ORR in the whole cohort was 53% [95% CI, 40.23; 65.72], 33% [95% CI, 14.59; 56 .97] and 62% [95% CI, 45.64; 76.43] in BRAF mutated and BRAF-wild type respectively. Among BRAF status, gender, PS, stage, age, LDH level and number of irradiated sites (1 vs ≥ 1), the independent prognostic factors for OS in multivariate analysis were number of irradiated sites (HR = 0.26, p = 0.03) and ECOG-PS (HR = 6.2, p = 0.001). Rechallenging was performed in 11 pts, among them; 3 were progression-free at last follow-up, 10 were reirradiated once and 1 was reirradiated 3 times. ICI was stopped due to toxicities for 6 pts. Drug-related adverse events of grade 3-4 occurred in 8.3% of the patients (no grade 5). Conclusions: Combined nivolumab and HMR did not improve significantly OS compare to nivolumab alone but improve significantly PFS1. However, this strategy has an acceptable safety and could be a treatment option for some patients. Multisite irradation and rechallenging strategies deserve to be considered. 1 Robert et al, J Clin Oncol 2020. Clinical trial information: NCT02799901 .

Exploring the correlation between high HRD status and immunotherapy response in melanoma.

e21541 Background: Homologous recombination deficiency (HRD) status demonstrates DNA instability in tumor cells and has been implicated as a response marker for immune checkpoint inhibitors (ICI). Here, we explore the correlation between high HRD status and ICI response biomarkers, homologous recombination repair (HRR) mutations, and the prognostic advantage of high HRD status following ICI in cutaneous melanoma patients. Methods: Melanoma samples (N = 2158) were profiled for genomic loss of heterozygosity (LOH) by NGS at Caris Life Sciences (Phoenix, AZ). As a surrogate for HRD, LOH-high was defined as LOH at ≥ 16% of the segments analyzed (up to 552). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) was tested by IHC/NGS.Tumor mutational burden (TMB)-high was defined as ≥ 10 mutations/Mb. interferon gamma (IFN-g) and T-cell inflamed scores. Real-world overall survival (rw-OS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from the start of immunotherapy until the last date of contact. Mann-Whitney U, Chi-square, and Fisher exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Results: Melanoma patient samples include - cutaneous: 1853; acral: 130; mucosal: 175, with LOH-high observed in 8.3% of cutaneous specimens, 13.1% of acral, and 30.9% of mucosal. Firstly, most biomarkers associated with response to ICI (PD-L1, TMB-high, total neoantigen load, IFN-g score, T-cell inflamed level, and dMMR/MSI-H) were not significantly different between LOH-high and LOH-low cohorts in all melanoma subtypes. However, TMB-high was significantly more prevalent in LOH-low cutaneous melanoma patients (54.9% vs 63.3%, p = 0.039). Prevalence of HRR gene mutations was not significantly different between high and low LOH groups in all cohorts, except for the ATRX gene which exhibited a significantly higher prevalence in the high LOH cutaneous (8.6% vs 1.3%, p < 0.001) and mucosal (28.8% vs 2.5%, p < 0.00001) melanoma specimens. Analysis of rw-OS showed no improvement in the treatment of LOH-high cutaneous melanoma patients with ICI compared to LOH-low (HR: 1.397 [95% CI: 0.759- 2.569], p = 0.281). Conclusions: This study demonstrates that HRDness reflected by the high-LOH status in melanoma did not correlate with mutations in HRR genes. In addition, melanoma specimens with high HRD status did not exhibit an overall higher prevalence of biomarkers associated with ICI response. Our study did not demonstrate improved survival outcomes in patients with high HRD status following anti-PD1 therapies. Future investigation is needed to assess other therapeutic approaches for these patients such as PARP inhibitors.

Median Breslow thickness during, post and pre-COVID-19 lockdown and correlation with socioeconomic factors.

e21574 Background: Access to routine cancer care during COVID-19 pandemic was greatly affected. The impact of this on melanoma care is unknown. Breslow thickness (BT) was seen to decrease and then increase during and post-COVID-19 lockdown in Italy. Here, we aim to study the impact of COVID-19 lockdown on melanoma care in the United States. Methods: Patients diagnosed with cutaneous melanoma (CM) pre (September 15th 2019-March 14th 2020), during (March 15th-June 14th 2020), and post-lockdown (June 15th-December 14th 2020) were retrospectively studied using Metropolitan Detroit Cancer Surveillance System (MDCSS) database. Patients without an identifiable primary lesion, or with ocular, mucosal, or acral melanoma were excluded. Demographic and clinical characteristics were reviewed. The primary endpoint was median BT during and post vs pre-lockdown. Fisher's exact and Kruskal-Wallis tests were performed for categorical and continuous variables, respectively, to compare groups. Interaction in subgroup analyses was assessed using likelihood ratio tests. Linear regression analyses were performed with Box-Cox transformed BT. Cox proportional hazards regression analyses were performed for overall survival. Covariates for multivariable analysis were selected using LASSO-based penalized regression models. Results: 802 patients were included (pre N = 347, during N = 87, post N = 368). Patients diagnosed with CM post-lockdown were younger (age < 50 years pre = 14%, during = 13%, post = 23%). More patients diagnosed pre-lockdown carried government-issued insurance (pre = 48%, during = 39%, post = 38%). No difference (diff) in median BT was seen between periods (median = 0.6mm for pre, during, and pos). Married status was associated with a lower BT vs unmarried (diff = -0.19, 95% CI -0.36 to -0.014, p = 0.034) and higher census tract poverty level was associated with a higher BT (5%-10% diff = 0.17, 95% CI 0.004 to 0.33, p = 0.045; 10%-100% diff = 0.27, 95% CI 0.093 to 0.45, p = 0.003) vs 0-5% poverty on univariable analysis. Male gender was associated with a lower BT on multivariable analysis (diff = -0.12, 95% CI -0.20 to -0.04, p = 0.005) and lower risk of death on univariable analysis (HR = 0.50, 95% CI 0.31 to 0.82, p = 0.006). Conclusions: We found no difference in median BT during and post- vs pre-lockdown. We also identified at-risk populations (female, unmarried, and living in greater poverty areas) who could benefit from proactive melanoma care. Time to surgery from initial diagnosis during and post vs pre-lockdown would be of interest to study further.

A phase 3 trial of IMC-F106C (PRAME x CD3) plus nivolumab versus standard nivolumab regimens in HLA-A*02:01+ patients with previously untreated advanced melanoma (PRISM-MEL-301).

TPS9602 Background: Current standard of care in newly diagnosed patients with metastatic cutaneous melanoma (CM) include anti-PD1 as monotherapy or in combination with other immune checkpoint inhibitors (ICI). However, most patients will eventually progress and the 5-year survival rate remains low, necessitating new therapies with novel mechanisms of action to combine with anti-PD1. T cell receptor (TCR) bispecifics have shown overall survival (OS) benefit with tebentafusp (gp100 ´ CD3) in a phase (Ph) 3 trial in metastatic uveal melanoma [1]. IMC-F106C is the first TCR bispecific protein targeting CD3 and PRAME (PRAME ´ CD3), redirecting T cells towards cancer cells presenting a PRAME peptide on the cell surface by HLA-A*02:01 proteins. PRAME is expressed in the vast majority of melanoma. In an ongoing Ph 1 study (NCT04262466), IMC-F106C monotherapy was well tolerated and demonstrated evidence of durable clinical activity in heavily pre-treated, advanced melanoma patients, including those who progressed on prior ICI and targeted therapy [2]. Two doses, 40 mcg and 160 mcg, were selected for further study based on exposure response modeling. Safety of combination TCR bispecifics with ICI has been demonstrated in the ongoing IMC-F106C Ph 1 study and in a prior study of tebentafusp + ICI [3]. Combining IMC-F106C with the anti-PD1 ICI nivolumab has the potential to improve progression free survival (PFS), OS, and response rate (RR). Methods: PRISM-MEL-301 is a randomized, global, open-label, Ph 3 study in previously untreated HLA-A*02:01+ patients with unresectable or metastatic non-uveal melanoma; up to 10% of patients can have a diagnosis of mucosal, acral, or other non-CM melanoma. The first 90 patients will be randomized 1:1:1 to receive IMC-F106C 40 mcg + nivolumab (Arm A), IMC-F106C 160 mcg + nivolumab (Arm B), or a nivolumab regimen (Arm C) from which a final IMC-F106C dose (Arm A or B) will be selected. Subsequently, approximately 590 additional patients will be randomized to Arm (A or B) vs. control Arm C, either nivolumab monotherapy or nivolumab + relatlimab, dependent on the country. Randomization will be stratified by 1) American Joint Committee on Cancer (8th Edition) M stage with lactate dehydrogenase (LDH; M0 or M1 with normal LDH vs M1 with elevated LDH); 2) prior anti-PD[L]1 adjuvant therapy (yes vs no); and 3) BRAF V600 mutation status (positive vs negative). Primary endpoint is PFS per RECIST 1.1 by blinded independent central review. Secondary endpoints include OS, ORR, and safety. Enrollment is ongoing globally. Clinical trial registration: NCT06112314 Nathan et al. N Engl J Med 2021; 385:1196 Hamid et al. Ann Oncol 2022; 33 (Supp7): S875 Hamid et al. J Immunother Cancer 2023; 11(6): e006747. Clinical trial information: NCT06112314 .

Lenvatinib (len) plus pembrolizumab (pembro) in patients with advanced melanoma that progressed on anti–PD-(L)1 therapy: Over 4 years of follow-up from the phase 2 LEAP-004 study.

9559 Background: PD-1 inhibitors such as pembro are a standard-of-care option for advanced melanoma, and effective treatments are needed for disease that progresses on anti–PD-(L)1–based therapy. Previous results from the single-arm, open-label, phase 2 LEAP-004 study (NCT03776136) showed that len + pembro had antitumor activity in patients (pts) with advanced melanoma that progressed on prior anti–PD-(L)1–based therapy. With a median follow-up of 15.3 mo, the ORR was 21.4% and median DOR was 8.3 mo. Results from LEAP-004 led to the inclusion of len + pembro in treatment guidelines for pts with advanced melanoma and confirmed progression on a PD-(L)1 inhibitor. Here, we present results from LEAP-004 with over 4 years of follow-up. Methods: Eligible pts were aged ≥18 years, had unresectable stage III or IV melanoma, had ≥1 measurable lesion, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had confirmed disease progression within 12 weeks of the last dose of anti–PD-(L)1 therapy given alone or in combination for ≥2 doses. All pts received len 20 mg PO QD + ≤35 doses of pembro 200 mg IV Q3W. The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Results: 103 pts were enrolled and received treatment. Median time from first dose to data cutoff (Oct 11, 2023) was 52.0 months (range, 48.8-55.7). ORR in the overall population was 24.3% (95% CI, 16.4-33.7), with 5 pts (4.9%) having a complete response and 20 (19.4%) a partial response. In key subgroups, ORR was 33.3% (10/30; 95% CI, 17.3-52.8) in pts with progression on prior anti–PD-1 + anti–CTLA-4 therapy and 10.7% (3/28; 95% CI, 2.3-28.2) in pts with BRAF-mutant tumors who received prior BRAF/MEK-directed therapy for metastatic disease. Median DOR in the overall population was 8.5 mo (range, 3.2-40.8) and an estimated 35% of responders remained in response at ≥12 mo. Median PFS was 4.2 mo (95% CI, 3.5-6.3); 24-mo PFS rate was 10.1%. Median OS was 14.0 mo (95% CI, 10.8-18.3); 24-mo OS rate was 29.7%. Efficacy outcomes in pts with mucosal (n = 11) and acral lentiginous (n = 8) melanoma were consistent with the overall population. Any-grade treatment-related AEs occurred in 99 pts (96.1%). Grade 3-5 treatment-related AEs occurred in 51 pts (49.5%). No new treatment-related deaths occurred since prior analysis (1 pt had died because of treatment-related decreased platelet count). Conclusions: With over 4 years of follow up, len + pembrocontinued to show antitumor activity in pts with advanced melanoma and confirmed progression after ≥2 doses of anti–PD-(L)1-based therapy. Safety remained consistent with previous reports, with no new or unexpected safety signals. These results support len + pembro as a potential treatment option for advanced melanoma after anti–PD-(L)1-based therapy. Clinical trial information: NCT03776136 .

Incidence and risk factors for central nervous system (CNS) metastasis (met) in patients (pts) with stage III melanoma treated with adjuvant (ADJ) anti-PD1 immunotherapy (IMT).

9581 Background: The identification of risk factors for CNS met in stage III melanoma pts will facilitate the development of personalized surveillance strategies. Previously we characterized the incidence (3.6%, 9.6%, and 15.8% at 1, 2, and 5 yrs) and risk factors for CNS met in pts diagnosed with stage III melanoma from 1998 to 2014. It is unknown if the incidence of CNS met has changed in the ADJ IMT era. Methods: We performed an institutionally approved retrospective chart review of pts diagnosed with stage III melanoma treated with ADJ IMT between 1/1/2018 and 12/31/2020 at MD Anderson Cancer Center (MDA) or the Melanoma Institute of Australia (MIA). Exclusion criteria included mucosal or uveal melanoma or prior systemic therapy (other than ADJ interferon). Pts had to have CNS imaging within 1 month before or 4 months after stage III diagnosis. Pt and tumor features, treatments, and distant recurrence events (CNS met; non-CNS met) were captured. Time-to-CNS and time-to-non-CNS met were computed from start date of ADJ IMT to date of CNS/non-CNS met. Cumulative incidence of distant met events was determined using competing risks (death) and pts alive with no met at last follow-up were censored. Associations were determined using proportional sub-distribution hazards regression models; group differences were assessed using Gray’s test. Results: 361 pts were included in the analysis (MDA, 212; MIA, 149). With a median FU of 34.1 months (range 1.7-61.9), 128 (35.5%) of pts were diagnosed with distant mets. Among pts with distant mets, 56 had CNS met (15.5% of full cohort; 43.8% of pts with distant met); 24 (18.8% of pts with distant mets) pts had CNS met at initial diagnosis of stage IV disease. The 1-, 2-, and 5-yr rates of CNS met in the full cohort were 7%, 12%, and 17%. There was no difference in CNS met incidence between MDA and MIA. On univariate analysis, risk of CNS met was associated with AJCC stage IIID (Hazard Ratio [HR] 6.4; 95% Confidence Interval [CI] 2.2 – 18.8, p<0.001); increased primary tumor Breslow thickness (HR 1.1, CI 1.1 – 1.2, p<0.001), ulceration (HR 2.8; CI 1.5 – 5.1, p<0.001), and mitotic rate > 9/mm (HR 2.3; CI 1.1 – 4.6, p=0.025). There was a trend for decreased risk of CNS met in pts that stopped ADJ IMT due to toxicity (HR 0.4; CI 0.2 – 1.1, p=0.08). Multivariable (MV) model with these features did not identify any significant (p<0.05) associations with CNS met. Primary tumor ulceration and mitotic rate were significantly associated with non-CNS met on MV analysis. Conclusions: Despite the established impact of ADJ IMT on distant met free survival, the incidence of CNS met in stage III melanoma pts treated with ADJ IMT remains high. The results support the need for continued investigation of risk factors, prevention strategies and optimal surveillance for CNS met in stage III melanoma pts.

Efficacy and toxicity of KIT targeted therapy in elderly patients with melanoma.

e23269 Background: Most cases of malignant melanoma are cutaneous, with ≈50% having a BRAF driver mutation that predicts response to MAPK pathway inhibitors. A small minority of melanoma cases harbor an activating KIT mutation, most notably in mucosal and acral melanomas (15-20%) and occasionally in those arising from chronic sun-damaged skin (2-3%). Only about a third of KIT mutated melanomas respond to targeted therapy with Imatinib, yet data is scarce and limited, especially in older patients. We sought to characterize the efficacy and toxicity of Imatinib in KIT-mutated melanoma patients over 65. Methods: We identified electronic medical records of patients over 65 that were treated with Imatinib for KIT mutated melanoma at our institution over the years 2017-2023. Data was retrospectively collected including demographics, disease characteristics, response patterns and toxicity. Results: 10 patients were identified, 50% were males. The median age at treatment initiation was 75 years (71-100). 3 patients had cutaneous primary, 3 had Vulvar/vaginal primary, 3 had acral primary and 1 had anal canal primary. All patients had normal Lactate dehydrogenase at treatment initiation and ECOG performance status was 0-2 (median 0). 9 patients received Imatinib for stage IV disease with an overall response rate (ORR) of 55% (44% partial response, 11% complete response). Median duration of response was 4 months. Responses were seen in acral melanoma (67%), vulvar/vaginal melanoma (67%) and cutaneous melanoma (33%). Median Progression free survival was 4.3 months (1.8-44), median overall survival from treatment initiation was 22.6 months (4-64). 6 patients were treated as 2nd line with an ORR of 67% and 3 were treated as 3rd line with an ORR of 33%. There was one patient with M1d disease who did not respond to treatment either systematically or intracranially. 6 patients had Exon 11 mutations (V560D/G/E, N564S and L576P) of which 4 responded (67%). 2 had Exon 17 mutations (N822C/K) of which 1 responded (50%) and the 2 others had an Exon 14 (F681I) and Exon 13 (K642E) mutation that did not respond to treatment at all. Toxicity was moderate with 90% of patients experiencing any grade AE, yet only 1 experienced toxicity requiring dose interruption with two Grade 3 toxicities - Pneumonitis and decreased neutrophil count, leading to temporary treatment interruption, dose reduction and a course of corticosteroids. The rest of the patients experienced only Grade 1-2 toxicity. 4 patients needed dose reductions, there were no treatment discontinuations due to toxicity. Conclusions: Treatment with Imatinib for elderly KIT mutated melanoma patients is safe and well tolerated with no treatment discontinuations recorded. The response rate is encouraging yet seems to vary according to the KIT mutation present as previously reported. The duration of response is usually short-lived and alternative/combination treatments are still needed for this patient population.

Efficacy and safety of combined anti-angiogenic chemoradiotherapy with PD-1 monoclonal antibody in advanced melanoma: A retrospective study.

e21516 Background: Malignant melanoma, characterized by its aggressiveness and early metastasis, poses significant challenges in terms of treatment efficacy. This retrospective study aimed to assess the efficacy and safety of the integrated treatment regimen in patients (pts) with advanced melanoma. Methods: 42 pts with histologically confirmed inoperable stage III or IV melanoma and ECOG PS 0 or 1 were included in this retrospective study conducted from September 2020 to August 2023. Pts received combination therapy with albumin-bound paclitaxel, bevacizumab (bev), and toripalimab (tor) (Q3W). Maintenance therapy with bev and tor was given after 6-8 cycles without disease progression or intolerable adverse reactions. Personalized radiotherapy was delivered. Radiological evaluations were performed every 2 cycles during combination therapy and every 3 cycles during maintenance therapy using RECIST 1.1 criteria. Adverse events were graded according to NCI-CTCAE version 4.03. Results: All pts underwent at least one efficacy evaluation. The male-to-female ratio was 1:1, with a median age of 61.5 years (range: 34-80 years). Treatment-naïve pts accounted for 47.6% (n = 20), second-line pts for 35.7% (n = 15), third-line pts for 11.9% (n = 5), and fourth-line pts for 4.8% (n = 2). There were 25 cases (59.5%) of acral melanoma, 4 cases (9.5%) of cutaneous melanoma, 12 cases (28.6%) of mucosal melanoma, and 1 case (2.4%) with an unknown primary site. During the treatment period, 66.7% (n = 28) of pts received radiotherapy. As of December 2023, 26 out of 43 pts showed tumor shrinkage, including 2.4% (n = 1) achieving CR through conversion surgery following PR, maintaining it for 30 months. The ORR was 61.9%, with a confirmed ORR of 57.1%, and a DCR) of 92.9%. The median PFS was 14.4 months, and the median OS has not yet been attained. Common adverse events included alopecia (100%), hypertriglyceridemia (61.9%), elevated transaminases (59.5%), anemia (59.5%), leukopenia (52.4%), hypercholesterolemia (52.4%), peripheral neuropathy (50%). No treatment-related deaths were reported. Conclusions: This study demonstrates that PD-1 monoclonal antibody in combination with chemotherapy, anti-angiogenic therapy and radiotherapy offers a promising therapeutic option for advanced melanoma. Keywords:Malignant melanoma; Albumin-bound paclitaxel; Bevacizumab; PD-1 monoclonal antibody; Radiotherapy.

Endoscopic surgery combined chemoradiotherapy and PD-1 blockade in patients with sinonasal mucosal melanoma.

e21552 Background: Primary sinonasal mucosal melanoma (SNMM) is a rare and aggressive disease different from cutaneous melanoma. The best treatment modality including the role of immune checkpoint blockade in SNMM has not been defined. Methods: Between 2021 and 2023, patients with previously untreated sinonasal melanoma were enrolled by three single-center investigator-initiated phase II clinical trials (ChiCTR2100046498 / ChiCTR2100045797/ ChiCTR2100049031). Eligible patients in ChiCTR2100045797 trial received postoperative radical chemoradiotherapy combined with toripalimab (a PD-1 inhibitor) for a year or until the disease progressed. Eligible participants in ChiCTR2100046498 study received surgery combined with radiation without immunotherapy. And for patients in ChiCTR2100049031 study, preoperative radiation was carried out firstly. The locoregional control, distant metastasis-free survival (DMFS), and overall survival (OS) were the main efficacy goals. Results: Fifty-four patients were enrolled (mean age 62 years, 33 males [61.1%] and 21 women [38.9%]) with 2y-OS rate 62.3±7.9%, 2y-RFS rate 67.1±8.2%, and 2y-DMFS rate 63.9±8.1%. Patients with T3 (n = 23), T4a (n = 14), and T4b (n = 17) stages, including12 patients with node-positive disease, were included at baseline. During a median follow-up of 11 months, 19 patients ultimately died, 10 experienced relapses, and 17 developed metastases. Tumor T staging was demonstrated to be an independent prognostic predictor according to the Cox univariate analysis. The primary factor contributing to a poor prognosis and the primary cause of death for 73.7% of patients was distant metastases. Preoperative radiation had an improved long-term survival with 2y-OS rate of 85.7±13.2%, and it can considerably lower the risk of distant metastases (p≤0.05). The overall survival rate for patients receiving postoperative chemoradiotherapy combined with immunotherapy was higher than that for patients not receiving immunotherapy (2y-OS rate 74.1±11.4% vs. 39.3±15.8%), although the difference was not statistically significant due to a small number of patients (p = 0.16). No immune-related adverse effects grade≥3 was recorded. Conclusions: The primary cause of the poor prognostic performance of SNMM is distant metastasis. The risk of distant metastases might be considerably decreased by preoperative radiation treatment. Surgery combined with radiation and immunotherapy could bring promising survival benefit. The way forward may involve investigating the combination of immunotherapy and preoperative radiotherapy. Clinical trial information: NCT04879654 ; NCT05009446 .

MELANOMA OF ORAL CAVITY: A CASE REPORT OF AN UNUSUAL PRESENTATION

Oral mucosal melanoma is a rare malignancy with the tendency to metastasize and locally invade tissues more readily than other malignant tumor of the oral cavity. It occurs approximately four times more frequently in the oral mucosa of the upper jaw usually on the palate or alveolar gingiva. The chameleonic presentation of malignant melanoma, its asymptomatic condition, rarity of the lesion, poor prognosis and the necessity of a highly specialized treatment are factors that should be seriously considered by the involved health care provider. We report a rare and interesting case of oral malignant melanoma of the upper gum, which was clinically and histopathologically diagnosed with a brief review of literature, has been discussed.

Clinicopathological and Molecular Features of Penile Melanoma With a Proposed Staging System.

Penile melanomas (PM) are an exceedingly rare subtype of mucosal melanoma (MM), and we reviewed the clinicopathologic features and molecular profile in 8 PMs. The patient ages ranged from 46 to 78 (mean: 62.8) years with involvement on the glans (n=5; 62.5%), penile urethra (n=2; 25%), and foreskin (n=1, 12.5%). Tumor depth ranged from 1.6 to 10.0 (mean: 5.25) mm. Most of the patients underwent partial penectomy (n=6; 75%) and sentinel lymph node (LN) biopsy N=7; 87.5%). Seven patients had metastatic disease at diagnosis, 6 involving LNs and 1 the adrenal gland, and 4 died of disease with a mean follow-up period of 40.5 (2 to 95) months. Five of 7 (71%) cases identified 15 molecular alterations within KIT , CDKN2A , NF1 , PTEN , and APC (n=2 each), and NRAS , MAP3K1 , CDH1 , MSH6 , and TERT (n=1 each). Two cases were not found to harbor genetic aberrations, and 1 case failed testing. In addition, we reviewed the English literature and included 93 cases with a reported depth of invasion and follow-up. A total of 101 PMs were analyzed for prognostic parameters, and the overall survival was significantly worse in patients with LN metastasis (P=0.0008), distant metastasis (P=0.0016), and greater depth of invasion (P=0.0222) based upon T-stage. While T4 conferred substantially worse survival, the delineation of the survival curves between T2 and T3 was less clear, and combining T2+T3 disease had a strong prognostic impact ( P =0.0024). Prognostic parameters used in the staging of cutaneous melanomas may also be used in PMs. An alternative staging system expanding the inclusion criteria for T2 might provide a more accurate prognostic stratification.

The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification

BackgroundMucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification.MethodsThe anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsDalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494–0.957) and 51.6% (95% CI, 0.307–0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue.ConclusionsDalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration.Trial registrationChiCTR2000031608.

Comparative Epigenetic Profiling Reveals Distinct Features of Mucosal Melanomas Associated with Immune Cell Infiltration and Their Clinical Implications.

Mucosal melanoma exhibits limited responsiveness to anti-PD-1 therapy. However, a subgroup of mucosal melanomas, particularly those situated at specific anatomical sites like primary malignant melanoma of the esophagus (PMME), display remarkable sensitivity to anti-PD-1 treatment. The underlying mechanisms driving this superior response and the DNA methylation patterns in mucosal melanoma have not been thoroughly investigated. We collected tumor samples from 50 mucosal melanoma patients, including 31 PMME and 19 non-esophageal mucosal melanoma (NEMM). Targeted bisulfite sequencing was conducted to characterize the DNA methylation landscape of mucosal melanoma and explore the epigenetic profiling differences between PMME and NEMM. Bulk RNA sequencing and multiplex immunofluorescence staining were performed to confirm the impact of methylation on gene expression and immune microenvironment. Our analysis revealed distinct epigenetic signatures that distinguish mucosal melanomas of different origins. Notably, PMME exhibited distinct epigenetic profiling characterized by a global hypermethylation alteration compared to NEMM. The prognostic model based on the methylation scores of a 7-DMR panel could effectively predict the overall survival of PMME patients and potentially serve as a prognostic factor. PMME displayed a substantial enrichment of immune-activating cells in contrast to NEMM. Furthermore, we observed hypermethylation of the TERT promoter in PMME, which correlated with heightened CD8+ T cell infiltration, and patients with hypermethylated TERT were likely to have improved responses to immunotherapy. Our results indicated that PMME shows a distinct methylation landscape compared with NEMM, and the epigenetic status of TERT might be used to estimate prognosis and direct anti-PD-1 treatment for mucosal melanoma.

Targeting canine mammary neoplastic epithelial cells with a reengineered anthrax toxin: first study.

Mammary tumors are the most frequent type of neoplasms in intact female dogs. New therapies that target neoplastic cells without affecting normal cells are highly sought. The Bacillus anthracis toxin has been reengineered to target tumor cells that express urokinase plasminogen activators and metalloproteinases. In previous studies carried out in our laboratory, the reengineered anthrax toxin had inhibitory effects on canine oral mucosal melanoma and canine osteosarcoma cells. In this study, five canine neoplastic epithelial cell lines (four adenocarcinomas and one adenoma) and one non-neoplastic canine mammary epithelial cell line were treated with different concentrations of reengineered anthrax toxin components. Cell viability was quantified using an MTT assay and half-maximal inhibitory concentration (IC50) values. Cell lines were considered sensitive when the IC50 was lower than 5000ng/ml. One canine mammary adenocarcinoma cell line and one mammary adenoma cell line showed significantly decreased viability after treatment, whereas the non-neoplastic cell line was resistant. We conclude that the reengineered anthrax toxin may be considered a targeted therapy for canine mammary neoplasms while preserving normal canine mammary epithelial cells.

Frequent Immunohistochemical Expression of Transcriptional Repressor GATA Binding 1 in Salivary Gland Neoplasms: A Sensitive but Nonspecific Marker.

Salivary gland (SG) neoplasms (SGNs) display considerable immunophenotypic diversity. A significant proportion of SG carcinomas develop metastases with increased diagnostic difficulty at metastatic sites. Transcriptional repressor GATA binding 1 (TRPS1), a novel immunohistochemical marker for breast cancer, has been found to stain certain SGNs. To investigate TRPS1 and SRY-related HMG-box 10 (SOX10) immunoexpression in various SGNs and non-SG carcinomas, head and neck paragangliomas, and head and neck mucosal melanomas. TRPS1 immunoreactivity score (IRS) was determined as negative or low, intermediate, or high positive; SOX10 was reported as negative or positive. One hundred forty-eight SGNs, 5 breast carcinomas, 105 nonbreast-non-SG carcinomas, including 33 head and neck squamous cell carcinomas (HNSCCs), 6 head and neck paragangliomas, and 6 head and neck mucosal melanomas, were assessed for TRPS1. All 23 benign SGNs showed TRPS1 positivity, with the majority having high-positive IRS (17 of 23 cases; 74%). Among 125 SG carcinomas, 115 of 125 (92%) were TRPS1 positive, with high-positive IRS in 94 of 125 (75%), intermediate positive in 15 of 125 (12%), and low positive in 6 of 125 (5%). Among nonbreast-non-SG carcinomas, HNSCC, lung, thyroid, kidney, and ovarian carcinomas showed frequent TRPS1 staining. Nearly half of HNSCCs had high (11 of 18; 33%) or intermediate (4 of 18; 12%) positive IRS. Mean IRS in SG carcinomas was significantly higher than that in nonbreast-non-SG carcinomas (P < .001). None of the TRPS1-positive nonbreast-non-SG carcinomas expressed SOX10. TRPS1 is positive in most benign and malignant SGNs. Its expression in several nonbreast-non-SG carcinomas indicates that it lacks specificity for breast and SG carcinomas, even if considering only high-positive IRS. Addition of SOX10 can increase discriminatory utility of TRPS1.