Combinatorial effects of azacitidine and trametinib on <i>NRAS</i>‐mutated melanoma

Hanft, Klara‐Maria; Hamed, Ebrahem; Kaiser, Max; Würtemberger, Julia; Schneider, Michaela; Pietsch, Torsten; Feige, Ursula; Meiß, Frank; Krengel, Sven; Niemeyer, Charlotte M.; Hettmer, Simone

doi:10.1002/pbc.29468

Cited by 8 publications

(9 citation statements)

References 41 publications

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“…For the most commonly used therapies, such as trametinib-or temozolomide-based regimens, we observed short-term clinical improvement in some patients, both in patients in the STEP registry and in published case reports. 8,13,14,19 However, the overall survival rates did not differ. While the combination of dual immunotherapy (anti-PD1 and anti-CTLA-4) and stereotactic radiosurgery is aimed for in adults with CNS melanoma, the efficacy of immunotherapy in pediatric patients with CNS melanoma based on NCM is unclear.…”

Section: Discussionmentioning

confidence: 88%

Melanoma of the central nervous system based on neurocutaneous melanocytosis in childhood: A rare but fatal condition

Abele,

Forchhammer,

Eigentler

et al. 2024

Pediatric Blood & Cancer

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BackgroundMelanomas of the central nervous system (CNS) based on neurocutaneous melanocytosis (NCM) are exceptionally rare in childhood and have been described only sporadically. Rapidly progressive disease may represent a major challenge for treating physicians, especially given the limited knowledge about this condition. This analysis aimed to increase knowledge about the occurrence and treatment of these malignancies.ProcedureData on diagnosis, treatment, and outcome of patients aged 0–18 years with CNS melanoma based on NCM recorded in the German Registry for Rare Pediatric Tumors (STEP registry) were analyzed. Additionally, published case reports on this condition were analyzed.ResultsIn STEP, five patients with leptomeningeal melanoma based on NCM were identified, with a median age at melanoma diagnosis of 3.7 years. Various multimodal treatments were performed: (partial) resection (n = 4), irradiation (n = 2), trametinib (n = 3), different cytostatics (n = 2), and anti‐GD2 immunotherapy (n = 1). All patients died between 0.3 and 0.8 years after diagnosis. Including published case reports, 27 patients were identified with a median age of 2.8 years at melanoma diagnosis (range: 0.2–16.6). Fourteen of 16 cases with reported data had a NRAS alteration (88%), particularly NRAS p.Q61K (85%). In the expanded cohort, no patient survived longer than 1 year after diagnosis despite multimodal therapy (including trametinib; n = 9), with a median survival of 0.4 years (range 0.1–0.9).ConclusionsCNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets.

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Section: Discussionmentioning

confidence: 88%

Melanoma of the central nervous system based on neurocutaneous melanocytosis in childhood: A rare but fatal condition

Abele,

Forchhammer,

Eigentler

et al. 2024

Pediatric Blood & Cancer

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“…Figure 1 illustrates all patients' OS and PFS. The median OS was 6.5 months (2-24), and the median PFS was 2 months (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). At the first evaluation (about 2 months following the beginning of treatment), eight patients (36%) had an objective disease control using RECIST criteria on computed tomography scan: six stable diseases and two partial responses.…”

Section: Resultsmentioning

confidence: 99%

“…In a paediatric population, a combination of trametinib and azacytidine has been evaluated in NRAS -mutant melanomas occurring on congenital melanocytic nevus [15]. Azacytidine is a DNA methyltransferase inhibitor with action on ERK1/2 inhibition, downstream RAS protein.…”

Section: Discussionmentioning

confidence: 99%

Real-life use of trametinib after immunotherapy failure in BRAF wild-type advanced melanoma

et al. 2023

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BRAFV600 wild-type advanced melanomas quickly reach a therapeutic dead-end, after immunotherapy failure. Even if preclinical studies have suggested sensitivity to MEK inhibitors such as trametinib in NRAS, NF1 or GNA mutated melanoma, therapeutic options are limited for these patients. We present a retrospective monocentric study of 22 patients with advanced melanoma treated by trametinib after immunotherapy resistance. Melanomas harboured NRAS (20), NF1 (1) or GNA11 (1) mutations. For most of them (18), anti-PD1 was associated with trametinib. A disease-control was reported in 36% of patients (8/22), with six stable diseases and two partial responses according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median progression-free survival was 2 months (1–14) and median overall survival was 6.5 months (2–24). In patients with progressive disease (14/22), dissociated radiologic responses and clinical benefits such as pain reduction were seen in five patients. High blood level of lactate dehydrogenase (LDH) seemed associated with trametinib failure, without significance (P = 0.06). Adverse events (grade 1–3) occurred in 91% of patients during the first weeks of treatment, mainly papulo-pustular rashes (77%), leg oedemas (36%), asthenia (18%) and diarrhoea (14%). This real-life study showed that trametinib may benefit some metastatic melanoma that progressed after chemotherapy and immune checkpoint inhibitors. Objective disease control (partial response or stable disease) using RECIST criteria was observed in 36% of patients. Because of frequent side-effects which can alter the quality of life and the short response duration, this off-label option has to be discussed with the patient. Studies with combination therapy with trametinib to improve relapse-free survival and lower side-effects are ongoing.

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“…Of the 92 primary CNS melanoma cases in our compilation, 13 patients reported their genetic status (Burgos et al., 2021; de la Fouchardière et al., 2015; El Habnouni et al., 2018; Fortin Ensign et al., 2020; Goldman‐Lévy et al., 2016; Hanft et al., 2022; Kinsler et al., 2017; Schäfer et al., 2013) (Table 1). This included three cases with GNAQ mutations, five cases with NRAS mutations, one case with BAP1 deletion, one case with INPP4B Q204R mutation, and one case with BRAF V600E mutation.…”

Section: Molecular Pathologymentioning

confidence: 99%

“…Veronica, Niklas and Klara et al. reported on six cases of primary CNS melanoma treated with targeted therapy (Hanft et al., 2022; Kinsler et al., 2017; Schäfer et al., 2013) (Table 2): five with NRAS mutations, and one with a BRAF mutation. These patients exhibited varying degrees of improvement in symptoms and signs, with a median OS of 7.2 months (4.8–9.6 months).…”

Section: Treatmentmentioning

confidence: 99%

Clinicopathological features, current status, and progress of primary central nervous system melanoma diagnosis and treatment

Guo,

Wei,

Guo

et al. 2023

Pigment Cell Melanoma Res

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Primary central nervous system (CNS) melanoma is an extremely rare condition, with an incidence rate of 0.01 per 100,000 individuals per year. Despite its rarity, the etiology and pathogenesis of this disease are not yet fully understood. Primary CNS melanoma exhibits highly aggressive biological behavior and presents clinically in a distinct manner from other types of melanomas. It can develop at any age, predominantly affecting the meninges as the primary site, with clinical symptoms varying depending on the neoplasm’s location. Due to the lack of specificity in its presentation and the challenging nature of imaging diagnosis, distinguishing primary CNS melanoma from other CNS diseases. The combination of challenges in early detection, heightened tumor aggressiveness, and the obscured location of its origin contribute to an unfavorable prognostic outcome. Furthermore, there has been currently no consensus on a standardized treatment approach for primary CNS melanoma. Despite recent advancements in targeted therapy and immunotherapy for CNS melanoma, patients with primary CNS melanoma have limited treatment options due to their inadequate response to these therapies. Here, we provided a comprehensive summary of the epidemiology, clinical features, molecular pathological manifestations, and available diagnostic and therapeutic approaches of primary CNS melanoma. Additionally, we proposed potential therapeutic strategies for it.

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Combinatorial effects of azacitidine and trametinib on NRAS‐mutated melanoma

Cited by 8 publications

References 41 publications

Melanoma of the central nervous system based on neurocutaneous melanocytosis in childhood: A rare but fatal condition

Melanoma of the central nervous system based on neurocutaneous melanocytosis in childhood: A rare but fatal condition

Real-life use of trametinib after immunotherapy failure in BRAF wild-type advanced melanoma

Clinicopathological features, current status, and progress of primary central nervous system melanoma diagnosis and treatment

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