Mucosal Subtypes Research Articles

Eosinophilic gastroenteritis: Imaging spectrum on intestinal ultrasonography and CT enterography

Rationale and objectivesDiagnostic delays are common in eosinophilic gastroenteritis (EGE). This study aimed to evaluate the value of imaging modalities in facilitating the diagnosis of EGE. Materials and methodsPatients diagnosed with EGE who underwent either intestinal ultrasound (IUS) or computer tomography enterography (CTE) were retrospectively recruited. Medical records were reviewed for clinical information, while IUS and CTE images were reviewed to summarize characteristic findings. Imaging characteristics of EGE subtypes were also evaluated. ResultsA total of 51 patients were included, with 30 undergoing IUS examinations and 42 undergoing CTE examinations. Positive findings were observed in 22 (73.3 %) patients on IUS and 32 (76.2 %) on CTE. In both modalities, the small intestine was the most commonly involved site (88.9 % on IUS and 90.6 % on CTE), with lesions predominantly diffuse (72.2 % on IUS and 75.0 % on CTE). IUS also revealed clear bowel wall stratification in 94.4 % of patients and identified a specific “piano key sign” in 22.2 % of patients. Thirty-six (70.6 %) patients were categorized into the mucosal subtype, 4 (7.8 %) muscular subtype, and 11 (21.6 %) serosal subtype. Most patients with the muscular and serosal subtypes exhibited typical manifestations (100 % and 81.8 %, respectively), while 63.9 % of patients with the mucosal subtype showed unremarkable or nonspecific imaging findings. No significant differences of baseline imaging characteristics were found between relieved and relapsed groups (P = 0.13). ConclusionCharacteristic imaging findings of EGE include small intestine involvement, diffuse lesions, clear bowel wall stratification, and the “piano key sign”. Imaging modalities can be useful tools to facilitate the diagnosis of EGE, especially for the muscular and serosal subtypes.

Stromal Expression Profiling Reveals Immune-Driven Adaption to Malignancy in Canine Melanoma Subtypes.

Canine mucosal melanoma (CMM) is the most common oral malignancy in dogs and is significantly more aggressive than its cutaneous counterpart (CCM), yet the reasons for this disparity remain unclear. Cancer-associated stroma (CAS) plays a crucial role in tumour progression, but a detailed understanding of CAS in canine melanoma is missing. To assess stromal reprogramming, we analysed CAS from 21 CMM, 14 CCM and normal stroma from 10 skin and 9 oral mucosa samples by laser-capture microdissection followed by RNA sequencing. Results were assessed in relation to subtypes, prognostic factors including mitotic count (MC), ulceration, necrosis, pigmentation and immune cell infiltration (CD3, CD20 and CD68), scored using immunohistochemistry and RNA in situ hybridisation. Stromal reprogramming was evident in both subtypes but significantly more pronounced in CMM. Immune-excluded tumours exhibited higher MC than desert/cold ones. MC strongly correlated with genes associated with B-cells, T-helper cells and CTLA4 in CCM, suggesting CAS reprogramming to depend on tumour malignancy. Finally, we identify an immune-suppressive stromal signature in a subset of CMM characterised by the downregulation of key immune checkpoints and pathways. Together, these findings provide a solid foundation for understanding the role of CAS in canine melanoma, specific to cutaneous and mucosal subtypes.

Predominance of hyperprogression in mucosal melanoma during anti-PD-1 monotherapy treatment.

A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005). A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

Three-Year Analysis of Adjuvant Therapy in Postoperative Melanoma including Acral and Mucosal Subtypes.

Adjuvant therapy has improved the clinical prognosis for postoperative melanoma patients. However, the long-term efficacy of this therapy on the melanoma acral and mucosal subtypes has not been fully evaluated in previous trials. This study assessed the 3-year recurrence-free survival and overall survival of patients with melanoma, including the acral and mucosal subtypes, treated with anti-PD-1 antibody (Ab) or with the combination of the BRAF and MEK inhibitors dabrafenib and trametinib. We retrospectively analyzed both the 3-year time to relapse (TTR) and overall survival (OS) of 120 patients treated with anti-PD-1 antibody (Ab), or with the combination of dabrafenib and trametinib. The overall median TTR was 18.4 months, with a range of 0.69 to 36 months. The 3-year TTR of the acral and mucosal types was 28.1% and 38.5%, respectively. Baseline tumor thickness (TT) and acral type were associated with the TTR in subgroup analysis. Moreover, we classified 104 acral and non-acral cutaneous patients into the anti-PD-1 Abs or dabrafenib plus trametinib combined therapies cohort in multiple analyses. The acral subtype and TT were detected as important prognostic factors. In the 3-year OS, only tumor ulceration was associated with the OS in both univariate and multiple analyses. There was no significant difference in baseline or treatment-related factors of the mucosal type (p > 0.05). This study suggests that adjuvant therapy is more effective with non-acral cutaneous melanoma than either the acral or mucosal types at the 3-year TTR endpoint.

Five-Year Follow-Up of POLARIS-01 Phase II Trial: Toripalimab as Salvage Monotherapy in Chinese Patients With Advanced Melanoma.

To investigate the efficacy and toxicity after long-term follow-up of anti-PD-1 antibody in advanced melanoma with predominantly acral and mucosal subtypes. In the POLARIS-01 phase II trial, 128 Chinese patients with advanced melanoma refractory to standard therapy received toripalimab until disease progression or unacceptable toxicity for ≤2 years. For those who progressed after discontinuation due to 2-year treatment completion, rechallenge was allowed. The primary objectives were safety and overall response rate (ORR). As of February 8, 2021, ORR was 17.3% (95% CI: 11.2-25.0) evaluated by the independent radiologic review committee. The median overall survival (OS) for patients with known melanoma subtypes was 16.3 m for acral, 41.5 m for nonacral cutaneous, and 10.3 m for mucosal melanoma. Thereafter, the evaluation was continued by investigators. As of November 4, 2022, 5 years after the last enrollment, median duration of response was 15.6 months (range, 3.7-64.5+), median progression-free survival (PFS) was 3.5 months (95% CI, 2.2-5.3), and 60-month OS rate was 28.5% (95% CI: 20.2-37.2). Thirteen patients completed a 2-year treatment of toripalimab, with the subtypes of acral (2/13), non-acral cutaneous (4/13), mucosal (3/13) and unknown primary (4/13). Five patients were rechallenged. Four of them, all of whom were non-mucosal, completed the rechallenge course of 2 years with PFS ≥ 24 months. This is the largest prospective anti-PD-1 trial with mature data in advanced melanoma in China. Toripalimab demonstrated a manageable safety profile and durable clinical response in Chinese patients with metastatic melanoma who had failed in standard therapy. Immunotherapy seems less efficacious for long-term responders with mucosal primaries as rechallenge therapy.

Abstract 5563: Novel approaches to measuring tumor-mutational burden provide insights into tumor-immune interaction in primary melanoma

Abstract Background: Tumor mutation burden (TMB) has been widely explored in metastatic melanoma as a proxy of neoantigenic load. In contrast, the role of TMB on the biology of primary melanoma disease progression is less understood. In this study, we explored the associations between the immune context of melanoma subtypes and TMB as measured by several standard and novel criteria. Methods: Whole-genome-sequencing and multiplex immunohistochemistry (mIHC) were used to characterize the genomic and immune landscape of a cohort of 116 primary melanomas, including cutaneous non-acral (n=59), acral (n=39) and mucosal (n=18) subtypes, as well as 5 mucosal metastases. mIHC was used to identify intratumoral CD8+ T-cells, memory T-cells, macrophages, dendritic cells, B-cells and PD-L1 expression. Standard measures of TMB -total mutational burden (tTMB) and non-synonymous (ns) mutational burden (nsTMB)- as well as novel measures that incorporate multiplicity and clonality -ns persistent mutation burden (ns-pTMB), and ns mutation dosage (ns-dosTMB) were calculated, and their association with immune profiles and clinical-pathological factors established. Results: In cutaneous non-acral melanomas, ns-pTMB and ns-dosTMB were positively associated with CD8+ T cell proportions (p=0.02 for both comparisons). Clonal, but not subclonal ns-pTMB from mutations present in single-copy regions of the genome were positively associated with higher tumor-resident CD103+CD8 T-cell (p=0.01) and B-cell proportions (p=0.02). Higher single-copy ns-pTMB was also associated with tumors presenting early/intermediate regression compared to late regression. In mucosal melanomas, clonal ns-dosTMB had the strongest positive association with the presence of macrophages (CD68, p=0.005). Additionally, macrophages (p=0.01), tissue resident memory T-cells (p=0.02), PDL1+ cells (p=0.03) and B-cells (p=0.048) were found to be positively associated with clonal ns-pTMB from mutations present in multiple copies, which was also positively associated with the presence of lymphatic invasion (p=0.03). Mucosal patients who recurred had lower levels of single-copy ns-pTMB (p=0.03). In acral melanomas, all measures of TMB were positively associated with the presence of dendritic cells (CD11c), with no particular role for clonality observed. In both cutaneous non-acral (p=0.046) and acral melanomas (p=0.03), but not mucosal (p=0.4), clonal ns-dosTMB was found positively associated with tumor mitotic rate. Conclusion: Novel TMB measures reveal associations between tumor and immune context that are not captured by standard TMB measures alone in primary melanomas. Different TMB measures are linked to distinct immune populations across melanoma subtypes that harbor unique genomic and immune landscapes. Clonal mutations play a dominant role in the associations of TMB with immune cell populations. Citation Format: Eva R. Shteinman, Nigel Maher, Jordan W. Conway, Grace H. Attrill, Felicity Newell, Nic Waddell, Nicholas Hayward, John V. Pearson, Georgina V. Long, Richard A. Scolyer, James S. Wilmott, Ismael A. Vergara. Novel approaches to measuring tumor-mutational burden provide insights into tumor-immune interaction in primary melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5563.

Long-term survival with systemic therapy in the last decade: Can melanoma be cured?

Immune checkpoint inhibitors have been shown to prolong survival of patients with several types of cancer, and the finding was first established in melanoma. Previously, systemic therapy for advanced melanoma aimed only at tumor control and palliation of symptoms. However, in recent years, some patients who received systemic therapy have achieved a complete response and survived without continuous treatment for more than several years. This review discusses the long-term survival rates achieved with currently used systemic therapies and their future perspectives. Long-term survival is currently most likely to be achieved with the use of the standard-dose combination of nivolumab plus ipilimumab, however, this regimen is associated with a high frequency of serious or persistent immune-related adverse events. Several new anti-PD-1-based combination therapies with a better risk-benefit balance are currently under development. Although the acral and mucosal subtypes tend to be less responsive to immune checkpoint inhibitors, anti-PD-1-based combination therapy should continue to be investigated for these subtypes owing to its potential for better long-term survival. With the development of efficacious immunotherapy and targeted therapy, it is important to determine the optimal duration of systemic therapy to avoid unnecessary health and financial burdens as well as to improve efforts to support long-term cancer survivors. As the goal of systemic therapy shifts from tumor control to long-term survival, in future clinical trials, long-term clinical outcomes should be evaluated to assess the benefits of novel agents.

Benefit, recurrence pattern, and toxicity to adjuvant anti-PD-1 monotherapy varies by ethnicity and melanoma subtype: An international multicenter cohort study

Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. A retrospective study. Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.

Real-world efficacy of nivolumab in Peruvian patients with advanced melanoma.

e18849 Background: Malignant melanoma in Latin American (LATAM) population has aggressive features as higher rates of Acral lentiginous (ALM) subtype and shorter survival. Immunotherapy has improved prognosis among patients with cutaneous melanoma; however, there is scarce reports of the effectiveness in LATAM population. We describe our experience with management and survival of Peruvian patients with advanced melanoma treated whit nivolumab. Methods: A retrospective study based on cases review evaluated the efficacy of nivolumab. Eligible patients were metastatic, recurrent or unresectable malignant melanoma undergoing treatment with nivolumab as first-line for at least 3 consecutive months between 2020 and February 2021 in two institutions (Instituto Nacional de Enfermedades Neoplasicas, Oncosalud). Clinical pathologic features and immune inflammatory blood markers (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and prognostic nutritional index (PNI)) were evaluated. Efficacy was measured as progression-free survival (PFS), objective response rate (ORR), Clinical benefit rate (CBR) and overall survival (OS). A p < 0.05 value (SPSS) will be considered for a significant difference. Results: 57 patients were analyzed; median age was 63 yo (range 34-83); 59.6% were female. 77.2% had a Zubrod 0-1. Regarding histology, 37% (n = 21) had acral subtype, 38% (n = 22) non-acral, 17% (n = 10) mucosal and 8% (n = 4) unknown primary (UP). 81.1% had negative BRAF mutation status, and the median lactate dehydrogenase (LDH) level was 257 U/L (130-1281). 63.2% had visceral metastasis, the most common site being lung (42%) and liver (9%). Central nervous system (CNS) metastases was reported in 5%. After a median follow-up was 25 months, the median OS reported was 51.43 months (95% CI, 14.23-88.62). Median OS was 28.93 for acral melanoma (95% CI, 14.66-43.19) and not reached for other subtypes. Median PFS was 7.93 months (95% CI, 2.49-13.36); 4.93, 14.73 and 5.26 months in patients with acral, non-acral and mucosal melanoma, respectively. A significant difference was founded in OS (p = 0.024) and PFS (p = 0.001) between acral and non-acral melanoma. ORR was reached in 28.1% of patients; 19%, 31.8% and 20% in acral, non-acral and mucosal subtype, respectively. However, global CBR was 64.9%, with the higher and lower rate for non-acral (81.82%) and mucosal melanoma (50%). The overall incidence of immune related adverse effects (irAEs) was 69.5%, the most common were skin reactions (14%), followed by asthenia (12%); not grade 3-4 AEs were reported. Regarding immune inflammatory blood markers, no association between PFS with NLR (p = 0.49), PLR (p = 0.3) and PNI (p = 0.71) were founded. Conclusions: Nivolumab showed efficacy in improving OS for patients with advanced melanoma, however ALM had shorter OS and PFS. No prognostic immune blood markers were reported. New biomarkers are necessary, especially in acral melanoma.

Lichen planus

Lichen planus is an inflammatory disorder of the skin and/or mucosa. Immune dysregulation, infections, environmental and genetic factors play a role in its pathogenesis. Clinically, there are 6 important distinctive manifestations. The mucosal subtypes manifest inside the mouth, oesophagus, genitalia and - although less often - the nose, ear canal, tear duct and conjuctiva. The non-mucosal subtypes occur on the skin, scalp (hair follicles) and nails. Patients may suffer from several subtypes of lichen planus. Unfamiliarity with the different manifestations may lead to a delay in diagnosis and thus to insecurity and distress in patients. The advice to all healthcare providers is to ask patients with lichen planus about symptoms of all subtypes and clinically inspect the skin and mucosa, or to refer the patient to a dermatologist.

Comparative analysis of adjuvant therapy for stage III BRAF-mut melanoma: A real-world retrospective study from single center in China.

BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%-15% of acral or mucosal subtypes. Currently, immunotherapy with anti-PD-1 blockade and dual-targeted therapy with Dabrafenib plus trametinib (D + T) target therapy have been approved as adjuvant therapies for Stage III melanoma with BRAF V600 mutation. According to their phase III clinical trials, 3-year recurrence-free survival (RFS) is around 60% for both types of treatment. However, early disease control was slightly more effective with targeted therapy than immunotherapy. With different drug approval deadlines in China, anti-PD1 monotherapy, D + T combination, and Vemurafenib (V) monotherapy have all been used in real clinical practice as adjuvant settings for stage III BRAF-mut melanoma in recent years. We conducted this retrospective study to evaluate the efficacy of different treatments in the Chinese melanoma population. Patients who underwent radical surgery and were diagnosed as Stage III melanoma harboring BRAF V600 mutation by pathological report were retrospectively identified at Fudan University Shanghai Cancer Center from January 2017 to December 2021. Patients with mucosal melanoma, or with follow-up of <6 months, or receiving other adjuvant treatment were excluded. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different adjuvant groups. Log-rank analysis was used to identify prognostic factors for relapse-free survival (RFS). Ninety-three patients with resected stage III melanoma with BRAF V600E mutation were identified in our study, including 25 patients receiving adjuvant anti-PD-1 immunotherapy (PD-1), 25 receiving adjuvant D + T, 23 receiving V, and 20 patients with observation-only (OBS). There were no statistical differences between treatment groups in baseline characteristics including age, gender, subtypes, primary thickness, ulceration, and nodal involvement. Median relapse-free survival (RFS) time was not reached in the D + T group, 15 months in the V group, 15 months in the PD-1 group, and 10 months in the OBS group, respectively. Compared to OBS, all three other groups showed a tendency to benefit from RFS, while only D + T achieved a statistical difference (p = 0.002). However, compared to D + T, anti-PD-1 monotherapy also showed significantly worse relapse control (p = 0.032). For Chinese stage III melanoma with BRAF mutation, both novel targeted therapy and immunotherapy showed potential benefits in relapse-free survival compared to observation only. Dual-targeted D + T therapy may still be the best choice for adjuvant therapy because anti-PD-1 monotherapy has failed to report equivalent efficacy in real-world practice.

Efficacy and safety of interferon-alpha 1b combined with PD-1 monoclonal antibody in patients with unresectable stage IV melanoma: a retrospective study.

The low objective response of immune checkpoint inhibitors (ICIs) remains a great challenge in advanced melanoma therapy. Interferon-alpha has been proven to be a promising combination regimen with ICI in a phase Ib/II trial. Herein, we evaluated the efficacy and safety of interferon-alpha 1b plus PD-1 monoantibody in a real-world Chinese metastatic melanoma cohort. Profiles of patients diagnosed with unresectable stage IV (AJCC 8th Edition) between December 1st, 2018 and February 28th, 2022 from the Department of Dermatology, Xijing Hospital were reviewed. All of them received the combination treatment of interferon-alpha 1b (600μg every other day) plus PD-1 monoantibody (Pembrolizumab 2mg/kg or Toripalimab 240mg or Sintilimab 200mg, every 3weeks) for at least 12weeks. The efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST V1.1). The safety data were identified according to Common Terminology Criteria for Adverse Events (CTC AE) V.5.0. In total, 70 patients were included. 50% were females. 52.9% were with ECOG performance status ≥ 1. The fraction of patients receiving Pembrolizumab, Toripalimab, and Sintilimab was 28.6%, 67.1%, and 4.3%, respectively. Acral and mucosal subtypes accounted for 48.6% and 20%. The median follow-up period is 15.1months. The objective response rate was 32.8%. The median time of overall survival was 18months (95% CI 14.2-21.8months), and the median time of PFS was 5.2months (95% CI 4.2-6.2months). The incidence of adverse events (any grade) was 98.6%, but only 8.6% of cases experienced grade 3 or 4 adverse reactions. The combination of interferon-alpha 1b and PD-1 monoantibody demonstrated promising anti-tumor effects and acceptable toxicity in Chinese metastatic melanoma patients with cutaneous, acral, and mucosal subtypes.

A Mysterious Case of Abdominal Pain

A Mysterious Case of Abdominal Pain

807P Adjuvant anti-PD-1 monotherapy benefit varies across different ethnicities and melanoma subtypes

Although anti-programmed cell death receptor-1 (PD-1) monotherapy is a standard adjuvant treatment for melanoma patients underwent definitive surgery, their efficacy is evaluated mostly in Caucasians and cutaneous melanoma, it remains unclear in other ethnic groups and melanoma subtypes. Clinical data for patients (pts) with resected stage II/III/IV melanoma treated with anti-PD-1 monotherapy both in and outside clinical trial settings between 2015 and 2021 was collected retrospectively from 6 independent institutions in the US, Australia, Japan and China. Survival outcomes (both recurrence free survival [RFS] and overall survival [OS]) were compared by ethnicity (Caucasian versus East-Asian/African) and by different melanoma subtypes (non-acral-cutaneous[NAC]/unknown primary[UP], acral and mucosal). In total 537 pts were included. Caucasians had significantly longer RFS and OS. Among different melanoma subtypes, NAC/UP had the best RFS and OS, followed by acral. Mucosal melanoma had the poorest survival outcomes. In NAC/UP subtypes, Caucasians had longer RFS (with significance) and OS (with marginal significance) than East Asian/African. In the multivariate analysis incorporating ethnicity, melanoma subtype, age, sex, stage, LDH, and BRAF mutation status, Caucasian ethnicity was independently correlated with significantly better RFS (HR 0.59; 95%CI 0.41-0.84; P=.004) and a trend towards better OS (HR 0.59, 95%CI 0.34-1.02; P=.06), while mucosal subtype independently associated with both poorer RFS (HR 2.43; 95%CI 1.55-3.80; P<.001) and OS (HR 2.97; 95%CI, 1.53-5.78; P=.001).Table: 807PEntire CohortNAC/UP subtypesEthnicityMel SubtypeEthnicityCaucasianEast-Asian /AfricanNAC/UPAcralMucosalCaucasianEast-Asian /African(n=262)(n=275)(n=352)(n=83)(n=102)(n=246)(n=106)RFS1-y rate (%, 95% CI)80 (76-86)67 (62-73)77 (73-82)79 (70-88)58 (49-69)81 (76-86)68 (60-78)2-y rate (%, 95% CI)70 (64-76)49 (44-56)66 (61-71)57 (46-70)40 (32-52)71 (65-77)53 (44-64)P value<.001<.001<.001OS2-y rate (%, 95% CI)92 (88-95)80 (75-86)90 (87-94)83 (74-92)75 (67-85)92 (89-96)85 (78-93)4-y rate (%, 95% CI)83 (78-89)55 (46-66)82 (77-87)57 (38-86)46 (36-60)84 (78-90)78 (69-88)P value<.001<.001.07 Open table in a new tab Ethnicity and melanoma subtype both contribute to survival discrepancies in melanoma patients undergoing adjuvant anti-PD-1 monotherapy. The somatic genetic and immunologic underpinning of these differences remain unclear and warrants further investigation.

Abstract 5764: Genomic profiling of cutaneous, acral and mucosal melanomas in Chinese populations

Abstract Background: Targeted therapies and immunotherapies have significantly improved the survival of patients with cutaneous melanoma. Nevertheless, patients with acral and mucosal melanomas show limited benefit. The proportion of acral and mucosal subtypes are much higher in Chinese populations than Caucasians. Therefore, it is of great interest to detail the genomic features of acral and mucosal melanomas and compare these with cutaneous melanoma. Methods: A total of 111 Chinese patients with melanoma treated in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were enrolled in this study, comprising 32 cutaneous(28.8%), 41 acral(36.9%) and 26 mucosal(23.4%) subtypes. NGS-based genomic profiling of major cancer-related genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens with matched blood samples. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. Results: The most commonly mutated genes of cutaneous melanoma include BRAF(48%), CDKN2A(41%), CDKN2B(41%), NRAS(22%) and PTEN(22%). In acral melanoma patients, the mutation rate of BRAF was 10% while NRAS(31%), CDKN2A(21%), EMSY(21%), KIT(18%), CCND1(18%)) and NF1(18%) were frequently mutated. Mucosal melanomas were found most commonly to have mutations in CDKN2A(36%), KIT(32%), CDKN2B(28%), PDGFRA(24%), KDR(20%) and BRAF(16%). In acral and mucosal subtypes, the overall mutation rates of BRAF were significantly lower while the relative proportions of non-V600 mutations were higher as compared to cutaneous subtype. These may explain the less significant survival benefit of BRAFi+/-MEKi in acral and mucosal melanomas. In contrast, KIT mutations including SNVs and amplification, were enriched in acral and mucosal melanomas. Acral melanomas had lower mutation load than mucosal melanomas(2.42 Muts/Mb vs 4.84 Muts/Mb, p=0.0002), while cutaneous melanomas(4.03 Muts/Mb) did not differ from other subtypes in mutation burden. Additionally, patients with TERT, APC and FAT1 gene mutations had a significantly higher TMB than patients with wild-type genes respectively, indicating more activated anti-tumor immune profiles and suggesting therapeutic benefit from immune checkpoint inhibitors. Conclusions: We conducted a direction comparison of comprehensive genomic profiles of different melanoma subtypes among Chinese patients. The genomic alterations identified in our study may provide reference to discover potential strategies for targeted therapy and immunotherapy in acral and mucosal melanomas. Citation Format: Jing Chen, Ting Ye, Li Fan, Jieying Zhang, Rubo Cao, Yanshen Liu. Genomic profiling of cutaneous, acral and mucosal melanomas in Chinese populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5764.

Anti-LAG-3 antibody LBL-007 in combination with toripalimab in patients with unresectable or metastatic melanoma: A phase Ⅰ, open-label, multicenter, dose escalation/expansion study.

9538 Background: LBL007 is a novel, fully human IgG4 monoclonal antibody targeting human Lymphocyte-activation gene3 (LAG-3). Dual inhibition of anti-programmed cell death protein 1 (PD-1) and LAG-3 is anticipated to synergistically increase immune response against tumor growth. Here we report the preliminary safety and efficacy of LBL-007 in combination with Toripalimab (an anti-PD-1 antibody has approved for treatment of melanoma in China) in patients (pts) with unresectable or metastatic melanoma. Methods: Pts with unresectable or metastatic melanoma with or without prior anti-PD-(L)1 therapy were enrolled. This trial comprised 2 parts, namely part 1 (dose escalation), pts received LBL-007 (0.25/1/3/6 mg/kg) /Toripalimab (3 mg/kg) both i.v., Q2W; and part 2 (expansion), pts received LBL-007 (3/6 mg/kg)/Toripalimab (3 mg/kg) both i.v., Q2W. The primary objective was safety, the second objectives included pharmacokinetics, pharmacodynamics and efficacy (per RECIST 1.1). Results: By Jan 2022, 37 pts (15 [40.5%] male, median age 59 [range 31-74] years, 9 pts [24.3%] with baseline LDH elevation, 18 [48.6%] with acral, 12 [32.4%] mucosal, 5 [13.5%] nonacral cutaneous, 2 [5.4%] primary site unknown) were enrolled, with 17 in part 1 and 20 in part 2. No dose-limiting toxicity was observed in part 1, and the MTD was not reached. Of all 37 pts, the most common treatment-emergent adverse events (TEAEs) included anemia (24.3%), creatine phosphokinase elevation (24.3%), hypothyroidism (21.6%), and aspartate aminotransferase elevation (21.6%). For 32 radiologically evaluable pts, ORR was 12.5%, DCR was 53.1%. In a preplanned subtype-specific analysis in anti-PD-(L)1 treatment-naïve pts, ORR was 27.3 % vs. 0%, and DCR was 81.8% vs. 50.0% in acral and mucosal melanoma subtypes, respectively. For anti-PD-(L)1-resistant pts (n = 11), DCR was 18.2%. Conclusions: LBL007/Toripalimab combination is well tolerated and promising efficacy in pts with unresectable or metastatic melanoma, especially in the acral type without prior anti-PD-(L)1 therapy. Clinical trial information: NCT04640545.

Magnetic Resonance Imaging findings in Primary Extracutaneous Melanoma from a Tertiary Cancer Care Centre: A Retrospective Cohort Study

Introduction: Extracutaneous melanomas are rare, aggressive type of tumour, clinically and biologically distinct from their cutaneous counterpart. The two large broad categories of the extracutaneous melanomas are ocular and mucosal subtypes. Melanomas are classically hyperintense on T1 weighted images and hypointense on T2 weighted images due to the paramagnetic effects of melanin and presence of paramagnetic elements. Aim: To describe the Magnetic Resonance Imaging (MRI) findings in primary extracutaneous melanomas at various anatomic sites. Materials and Methods: This was a retrospective study in which 13 cases of primary extracutaneous melanomas were identified from Picture Archiving and Communication System (PACS) archive over a period of eight years (January 2013 - December 2020). Location and morphology of the tumour, signal intensity characteristics in T1 weighted, T2 weighted (hyperintense/ isointense/hypointense to adjacent muscle) and Diffusion Weighted Imaging (DWI) (presence or absence of diffusion restriction) were analysed. Results: The ocular melanomas (n=2) were seen as well-defined small intraocular mass attached to the choroid. The mucosal melanomas of the nasal cavity (n=2), rectum (n=4), vagina (n=3) and cervix (n=2) presented as large intraluminal polypoidal masses. Three categories of MRI appearances emerged in this study. Majority of the cases (n=8) showed hyperintense signals in T1- weighted images and hypointense signals in T2 weighted images (category 1). Diffusion restriction was seen in all cases (n=13) with low Apparent Diffusion Coefficient (ADC) values which ranged from 439-966 mm/sec with an average value of 755 mm/ sec. Conclusion: T1 and T2 shortening are typical of melanoma, the absence of these does not exclude the diagnosis. Although diffusion restriction and low ADC values help in the diagnosis of these tumours, they do not tend to play a specific role in the diagnosis.

Abstract CT035: Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with PD-(L)1 refractory/resistant unresectable or metastatic melanoma from a phase 1b study

Abstract Background: While PD-(L)1 inhibitors have improved outcomes for melanoma, a substantial proportion of patients do not respond or develop resistance. Sitravatinib, a spectrum-selective TKI targeting TAM receptors (Tyro3/Axl/MerTK) and VEGFR2, reduces the number of myeloid-derived suppressor cells and regulatory T cells while increasing the ratio of M1/M2-polarized macrophages, which may overcome an immunosuppressive tumor microenvironment and augment antitumor immune responses. Tislelizumab, an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, has shown clinical activity as a single agent and in combination with chemotherapy in patients with advanced solid tumors, including melanoma. Methods: We report results from the melanoma cohort of an ongoing multicohort phase 1b study (BGB-900-103; NCT03666143) assessing safety/tolerability and preliminary antitumor activity of sitravatinib + tislelizumab in advanced solid tumors. Eligible patients had unresectable or metastatic melanoma refractory/resistant to PD-(L)1 inhibitors and had not received other prior immunotherapy (eg, anti-CTLA-4, -OXO40, or -CD137) or anti-BRAF/MEK therapy. Patients received oral sitravatinib 120 mg once daily and tislelizumab 200 mg IV Q3W until a discontinuation criterion was met. The primary endpoint was safety/tolerability; key secondary endpoints included investigator-assessed objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: As of Oct 13, 2020, 25 patients were enrolled; 16 patients (64%) remained on treatment. All patients received 1 prior line of PD-(L)1 therapy, median age was 51 years (range: 23-79), and baseline histology included cutaneous (n=12; 48%), acral (n=7; 28%), and mucosal (n=4; 16%) subtypes. Median duration of study follow-up was 5.5 months (range: 1.5-13.3). Adverse events (AEs) were reported in 25 patients (100%); the most commonly reported grade ≥3 AE was hypertension (n=3; 12%). Serious AEs were reported in 4% (n=1/25) of patients. Dose reductions of sitravatinib due to AEs occurred in 13 patients. No AEs led to death. Six patients achieved a confirmed partial response. Confirmed ORR was 24.0% (95% CI: 9.36-45.13); DCR was 88.0% (95% CI: 68.78-97.45). Median PFS was 6.7 months (95% CI: 4.07, not evaluable). Conclusions: Sitravatinib + tislelizumab was generally well tolerated, had a manageable safety/tolerability profile, and demonstrated preliminary antitumor activity in patients with refractory/resistant unresectable or metastatic melanoma. Further investigation of sitravatinib + tislelizumab in these patients is warranted. Citation Format: Chuanliang Cui, Hongming Pan, Matteo Carlino, Jiuwei Cui, Xuan Wang, Cheng Chen, Xiao Xiang, Liu Yang, Jun Guo. Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with PD-(L)1 refractory/resistant unresectable or metastatic melanoma from a phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT035.

Real-world analysis of clinicopathological characteristics, survival rates, and prognostic factors in patients with melanoma brain metastases in China.

We aimed to establish the clinicopathological characteristics and prognostic factors of patients with melanoma brain metastases (MBM) in the East Asian population. Overall survival (OS) and intracranial progression-free survival (PFS) were evaluated by Kaplan-Meier analysis. Cox regression analyses were used to determine prognostic factors associated with intracranial PFS and OS. Between July 2007 and December 2019, 431 patients diagnosed with MBM were enrolled. Mucosal subtype (p = 0.013), LDH level (p = 0.014), the number of MBM ≥ 4 (p = 0.02), local treatment (p < 0.0001) and the use of PD-1 inhibitors (p < 0.0001) were independent prognostic factors for intracranial PFS. Mucosal subtype (p = 0.022), LDH level (p = 0.005), no extracranial metastasis (p = 0.01), concurrent liver metastasis (p = 0.004), local treatment (p = 0.001) and the use of PD-1 inhibitors (p < 0.0001) were independent prognostic factors for OS. Mucosal subtype brain metastases had a poor response to PD-1 inhibitors (p = 0.007), with a shorter intracranial PFS than other subtypes. In BRAF mutation patients with MBM, the first-line BRAF/MEK inhibitor therapy group had an advantage in OS compared to the first-line anti-PD-1 therapy group (p = 0.043). Our findings depict clinical characteristics and prognostic factors of MBM in the East Asian population, suggesting the mucosal subtype as an adverse prognostic and predictive factor for patients with MBM. For BRAF mutation patients with MBM, first-line BRAF/MEK inhibitor therapy may bring a potential survival benefit compared to first-line anti-PD-1 therapy.

Safety, Efficacy, and Biomarker Analysis of Toripalimab in Previously Treated Advanced Melanoma: Results of the POLARIS-01 Multicenter Phase II Trial.

In contrast to the predominant chronic UV exposure-induced cutaneous melanoma in Caucasians, acral and mucosal comprise the majority of melanomas in Asia and respond less effectively to established treatments. The clinical application of PD-1 blockade is yet to be explored in metastatic melanoma in China. This phase II study was to evaluate safety and efficacy of toripalimab in advanced Chinese patients with melanoma who had failed in systemic treatments. Toripalimab was given at 3 mg/kg i.v. once every 2 weeks until disease progression or unacceptable toxicity. The primary objective was safety and objective response rate. 128 Patients with melanoma were enrolled, including 50 acral and 22 mucosal. As of August 15, 2019, 23 months after the last enrollment, 116 (90.6%) experienced treatment-related adverse events. ≥Grade 3 TRAEs occurred in 25 (19.5%) patients. Among 127 patients assessed, 1 complete response, 21 partial response, and 51 stable disease were observed for objective response rate of 17.3% and disease control rate of 57.5%. Median duration of response was not reached. Median progression-free survival was 3.6 months [95% confidence interval (CI) 2.7-5.3] and median overall survival was 22.2 months (95% CI, 15.3-NE). Patients with positive PD-L1 staining in tumor biopsies had significant better ORR (38.5% vs. 11.9%, P = 0.0065), PFS (7.7 months vs. 2.7 months, P = 0.013), and OS (not reached vs. 14.4 months, P = 0.0005) than PD-L1-negative patients. This is the largest prospective anti-PD-1 clinical study in advanced melanoma with predominantly acral and mucosal subtypes. Toripalimab demonstrated a manageable safety profile and durable clinical response in Chinese patients with metastatic melanoma refractory to standard therapy.See related commentary by Shoushtari et al., p. 4171.