No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

Guida, Michele; Bartolomeo, Nicola; Quaglino, Pietro; Madonna, Gabriele; Pigozzo, Jacopo; Giacomo, Anna Di; Minisini, Alessandro Marco; Tucci, Marco; Spagnolo, Francesco; Occelli, Marcella; Ridolfi, Laura; Queirolo, Paola; Risi, Ivana De; Quaresmini, Davide; Gambale, Elisabetta; Chiarion-Sileni, Vanna; Ascierto, Paolo A.; Stigliano, Lucia; Strippoli, Sabino

doi:10.3390/cancers13030475

Cited by 23 publications

(17 citation statements)

References 30 publications

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“…Especially for NRAS, mutant melanoma combination therapy is essential [61]. Patients with metastases to the brain also benefitted from the combination therapy, with an intracranial response in 46% of patients who received the combination and 20% intracranial response rate for the single agent nivolumab, irrespective of their mutational status [59,62,63].…”

Section: Discussionmentioning

confidence: 99%

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

Baumgartner

Stepien

Mayr

et al. 2021

JPM

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Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.

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Section: Discussionmentioning

confidence: 99%

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

Baumgartner

Stepien

Mayr

et al. 2021

JPM

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“…In the anti-PD(L)1 monotherapy subgroup, the corresponding RR of ORR was 1.13 (95% CI: 0.87-1.47, I 2 = 52.5%, P=0.122; Figure 2B ) with moderate heterogeneity. The hazard ratio (HR) of PFS in 2 studies ( 16 , 17 ) and overall survival (OS) in 2 studies ( 14 , 17 ) were 0.73 (95% CI: 0.58-0.93, I 2 = 0%, P=0.930; Figure 2C ) and 1.01 (95% CI: 0.52-1.96, I 2 = 89.3%, P=0.002; Figure 2D ), respectively. However, studies with opposite results were not included because of different objectives, such as TTF ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

“…Six retrospective studies and 1 randomized clinical trial were relevant to our analyses (11)(12)(13)(14)(16)(17)(18). Study design, drug, number of patients, efficacy of immunotherapy (ORR, DCR, PFS, OS, TTF, et al) for NRAS mutant and wild-type advanced melanoma patients, and univariate and multivariate factors analyzed along with NRAS status were listed in Supplementary Table S1.…”

Section: Meta-analysismentioning

confidence: 99%

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

et al. 2021

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BackgroundAnti-PD-1 monotherapy is the standard therapy for advanced melanoma patients, including those with NRAS mutations. The influence of NRAS mutation on immunotherapy, especially in noncutaneous melanoma, is largely uncharacterized.Materials and MethodsWe analyzed clinical data of four clinical trials for advanced melanoma patients treated with anti-PD-1 monotherapy between 2016 and 2019. The impact of NRAS mutation on efficacy and outcome of immunotherapy were analyzed in cutaneous and noncutaneous groups separately.ResultsA total of 206 patients were assessed, including 92 cutaneous melanoma patients with 12 NRAS mutations and 114 noncutaneous melanoma patients with 21 NRAS mutations. In cutaneous melanoma, the response rates of NRAS mutant patients were lower than patients without NRAS mutations (9.5% vs. 23.9%), the median progression-free survival (PFS) and median overall survival (OS) were shorter for patients with NRAS mutations, although without significant difference for OS (P=0.081). In noncutaneous melanoma, the response rates were 0 and 13.7% for NRAS mutant and wild-type patients, the median PFS were 3.6 months (95% CI: 0.9-6.3) and 4.3 months (95%CI: 2.9-5.7) (P=0.015), and the median OS were 10.8 months (95% CI: 1.5-20.1) and 15.3 months (95% CI: 13.2-17.4) (P=0.025), respectively. In multivariate analysis, NRAS mutation, along with ECOG performance score and LDH level, was negatively associated with both PFS (HR 1.912, P=0.044) and OS (HR 2.210, P=0.025) in noncutaneous melanoma.ConclusionIn advanced Asian melanoma treated with anti-PD-1 monotherapy, NRAS mutant patients had lower response rates and poorer prognoses compared to wild-type patients, especially in noncutaneous subtypes.

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“…Still, Johnson et al reported an overall better response to immunotherapies in patients harboring NRAS mutations (n = 60) versus those with NRAS wt melanomas [56]. The recent study also demonstrated the association of longer PFS and the presence of NRAS mutations in melanoma patients who received anti-PD1 as a first-line monotherapy [57]. Combined anti-PD-1 and anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab has also been assessed in first-line administration in NRAS mut melanoma [54] with conflicting results [55,58,59].…”

Section: Current Clinical Treatmentsmentioning

confidence: 93%

NRAS mutant melanoma: Towards better therapies

Randic

Kozar

Margue

et al. 2021

Cancer Treatment Reviews

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Genetic alterations affecting RAS proteins are commonly found in human cancers. Roughly a fourth of melanoma patients carry activating NRAS mutations, rendering this malignancy particularly challenging to treat. Although the development of targeted as well as immunotherapies led to a substantial improvement in the overall survival of non-NRAS mut melanoma patients (e.g. BRAF mut ), patients with NRAS mut melanomas have an overall poorer prognosis due to the high aggressiveness of RAS mut tumors, lack of efficient targeted therapies or rapidly emerging resistance to existing treatments. Understanding how NRAS-driven melanomas develop therapy resistance by maintaining cell cycle progression and survival is crucial to develop more effective and specific treatments for this group of melanoma patients. In this review, we provide an updated summary of currently available therapeutic options for NRAS mut melanoma patients with a focus on combined inhibition of MAPK signaling and CDK4/6-driven cell cycle progression and mechanisms of the inevitably developing resistance to these treatments. We conclude with an outlook on the most promising novel therapeutic approaches for melanoma patients with constitutively active NRAS. Statement of significance: An estimated 75000 patients are affected by NRAS mut melanoma each year and these patients still have a shorter progression-free survival than BRAF mut melanomas. Both intrinsic and acquired resistance occur in NRAS-driven melanomas once treated with single or combined targeted therapies involving MAPK and CDK4/6 inhibitors and/or checkpoint inhibiting immunotherapy. Oncolytic viruses, mRNA-based vaccinations, as well as targeted triple-agent therapy are promising alternatives, which could soon contribute to improved progression-free survival of the NRAS mut melanoma patient group.

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No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

Cited by 23 publications

References 30 publications

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

NRAS mutant melanoma: Towards better therapies

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