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Background: Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.Methods: A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety.Results: A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.Conclusions: Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing. [ABSTRACT FROM AUTHOR]

LL‐37 is a naturally occurring 37‐amino‐acid peptide that is part of the innate immune system in human skin. Preclinical studies have showed that intra‐tumoral injections of LL‐37 stimulate the innate immune system by activation of plasmacytoid dendritic cells, which mediate tumor destruction. LL‐37 intra‐tumoral injections have been utilized in a phase 1 clinical trial for melanoma patients with cutaneous metastases. We report dermatologic toxicity in a 63‐year‐old woman with stage IIIC melanoma of the right calf and inguinal lymph nodes. She was previously treated with nivolumab and combination chemotherapy (cisplatin, vinblastine and dacarbazine) and subsequently treated with LL‐37 injections upon progression of both prior regimens. She received a total of 8 weekly LL‐37 injections, with interval clinical shrinkage of injected lesions. However, approximately 45 days after initiation of this therapy, she presented with multiple verrucous papules and a vesiculo‐bullous lesion on the trunk and extremities. Clinically, most of these lesions were thought to be either squamous cell carcinoma or inflamed seborrheic keratosis. Histologically, 11 of the total 12 skin biopsies showed similar histopathologic features, with a prominent lichenoid inflammatory infiltrate admixed with eosinophils and an overlying atypical squamous epithelial proliferation with verrucous and keratoacanthoma‐like features and varying degrees of keratinocytic atypia. Interestingly, a majority of the lesions did not show spongiosis (11/12). All lesions resolved within 2 months of cessation of LL‐37 injection therapy. This case highlights adverse dermatological manifestations of LL‐37 therapy, similar to the consequences of other novel therapies. [ABSTRACT FROM AUTHOR]

Background: BRAFV600 , NRAS, TP53, and BRAFNon-V600 are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAFV600 and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAFNon-V600 mutations.Methods: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926).Results: The prevalence of BRAFV600 , NRAS, TP53, and BRAFNon-V600 mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAFNon-V600 mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAFNon-V600 mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAFNon-V600 mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy.Conclusions: These results add to the understanding of the clinical features associated with TP53 and BRAFNon-V600 mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed. [ABSTRACT FROM AUTHOR]

The article offers information on the updates for advanced melanoma treatment. It mentions that melanoma, the seventh most common diagnosed malignancy in females and fifth most common in men, was a curable malignancy. It states that the immune-related adverse events (IRAES) include hypophysitis, hepatitis, and enterocolitis.

Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.

The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma. [ABSTRACT FROM AUTHOR]

Objective: We aim to evaluate outcomes for patients with resectable SNMM treated in the immunotherapy era., Methods: Thirty-seven patients with resectable SNM were identified using our institutional database between 2016 and 2023., Results: Patients receiving neoadjuvant Ipi/Nivo (46%, n = 17) were more likely to have disease involving the sinuses and/or the skull base (71% vs. 35%, p = 0.05). The overall response rate to Ipi/Nivo was 24%. Two-year LRFS from the start of therapy was 63%, and from the end of local therapy was 78%. Two-year PFS was 49%. The patients who received Ipi/Nivo with evidence of response (n = 4, 24%) had better PFS (2-year PFS 100% vs. 15%, p = 0.02) and LRFS (2-year LRFS 100% vs. 31%, p = 0.08)., Conclusions: Outcomes for resectable SNMM patients continue to be poor in the immunotherapy era. In the context of selection bias, neoadjuvant Ipi/Nivo was not associated with better outcomes in all-comers. However, those with evidence of response to Ipi/Nivo had better prognosis., (© 2025 Wiley Periodicals LLC.)

Clinical stage III melanoma, defined as resectable RECIST measurable nodal disease with or without in-transit metastases, represents approximately 15% of new melanoma diagnoses every year with additional cases presenting as recurrent nodal disease following previous treatment of a primary melanoma. The standard of care for patients with resectable clinical stage III melanoma is surgical resection, consisting of therapeutic lymph node dissection and/or resection of in-transit disease and consideration of adjuvant systemic therapy and occasionally adjuvant radiation. These patients have high rates of regional recurrence and progression to metastatic disease postsurgery, highlighting the need for better treatment options. With the success of immune checkpoint inhibitors in both the adjuvant and metastatic settings, the use of these agents in the neoadjuvant setting has been an emerging area of research interest. In this chapter, we will discuss the rationale for neoadjuvant immunotherapy; review impactful clinical trials; and define response monitoring, surgical considerations, emerging therapies, and unanswered questions for neoadjuvant therapy as a recent paradigm shift in the management of clinical stage III melanoma.

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS -mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556-67. ©2018 AACR. See related commentary by Sullivan, p. 532 See related article by Teh et al., p. 568 This article is highlighted in the In This Issue feature, p. 517 ., (©2018 American Association for Cancer Research.)

Background: BRAF V600 , NRAS, TP53, and BRAF Non-V600 are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAF V600 and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAF Non-V600 mutations., Methods: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926)., Results: The prevalence of BRAF V600 , NRAS, TP53, and BRAF Non-V600 mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAF Non-V600 mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAF Non-V600 mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAF Non-V600 mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy., Conclusions: These results add to the understanding of the clinical features associated with TP53 and BRAF Non-V600 mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

High-dose interleukin-2 has been used for the treatment of metastatic melanoma since 1998 based on data proving durable complete responses in up to 10% of treated patients. The immunomodulatory effects of this critical cytokine have been instrumental in the development of immunotherapy for melanoma and other cancers. However, with the advent of new therapies, its use as a front-line agent has come into question. Nonetheless, there is still a role for interleukin-2 as monotherapy, as well as in combination with other agents and in clinical trials. In this article, we review preclinical and clinical data regarding interleukin-2, its pharmacology and mechanism of action, its toxicity profile, and its use in ongoing and planned clinical trials. We also explore the future of this agent within the treatment landscape for melanoma.

Melanoma remains a major cause of morbidity and mortality worldwide, however tremendous advances have been made in its treatment over the past several years. The discovery of genomic alterations that contribute to oncogenicity has ushered in a new era of molecularly-targeted therapy. Importantly, over half of melanomas harbor a mutation in the BRAF gene that leads to constitutive signaling down the MAPK pathway and multiple subsequent deleterious effects. Pharmacologic agents targeting this mutation have been developed and several are now FDA-approved, having yielded high response rates to therapy although these are tempered by a short duration of response. Multiple molecular mechanisms of resistance have been identified; however until recently few studies had delved into the immune effects of BRAF inhibitors. The effect of BRAF inhibition on anti-tumor immunity will be discussed herein, as will potential implications of these findings in the treatment of melanoma.