Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma

LoRusso, Patricia; Schalper, Kurt A.; Sosman, Jeffrey A.

doi:10.1111/pcmr.12847

Cited by 21 publications

(21 citation statements)

References 98 publications

(140 reference statements)

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“…Now, a combination of the BRAF inhibitor (BRAFi) and the MEK inhibitor (MEKi) has shown an overall response rate of up to 70% and has become the standard targeted treatment for BRAF V600 -mutated melanomas [ 6 ]. However, even though long-term responses have been reported, most patients develop resistance and relapse [ 7 , 8 ].…”

Section: Brief Overview Of Melanoma and Its Treatmentsmentioning

confidence: 99%

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An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Soysouvanh

Giuliano

Habel

et al. 2021

JCM

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The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research have been investigated to find new therapeutic targets for improving patient outcomes. Because of the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to pharmacological targeting, much attention has been paid to the role of this process in melanoma development and resistance to therapies. In this review, we summarize the latest data on ubiquitination and discuss the possible impacts on melanoma treatments.

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Section: Brief Overview Of Melanoma and Its Treatmentsmentioning

confidence: 99%

“…Now, the combination of CTLA-4, and PD-1 checkpoint blockades has been proven as a highly efficient treatment for patients with advanced melanomas [ 13 , 14 ]. However, more than half of the patients do not respond to ICT [ 8 , 15 ].…”

Section: Brief Overview Of Melanoma and Its Treatmentsmentioning

confidence: 99%

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Soysouvanh

Giuliano

Habel

et al. 2021

JCM

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“…The increased availability of DNA sequencing techniques has altered the therapeutic landscape in clinical oncology, now allowing identification of patient-specific (somatic) or oncogenic driver genetic mutations (akin to BRAF V600E mutant) which may act as biomarkers in the development of future targeted therapies. Apart from those discussed in this review, these include C-KIT and NRAS among other targets, and a new generation of targeted oncogenic driver inhibitors may promote more precise treatment algorithms in melanoma [109]. Furthermore, neoantigens exposed after treatment with targeted therapy or immunotherapy may alter the clinical approach to treatment.…”

Section: Discussionmentioning

confidence: 99%

Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

Chacon

Melucci

Qin

et al. 2021

IJMS

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Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.

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“… 13 Given the increased toxicity associated with combination immunotherapy, it is of great interest to clinicians to be able to identify those patients who could derive sufficient prolonged benefit from anti-PD1 monotherapy, and be spared the increased toxic side effects of combination immunotherapy. 14 …”

Section: Introductionmentioning

confidence: 99%

Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy

Rose

Armstrong

Hogg

et al. 2021

J Immunother Cancer

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PurposeAnti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.MethodsWe performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).ResultsWe identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.ConclusionsIn our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype—including NRAS—should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.

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Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma

Cited by 21 publications

References 98 publications

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy

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