Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm

Khattak, Muhammad A.; Fisher, Rosalie; Turajlic, Samra; Larkin, James

doi:10.1177/1758834012466280

Cited by 46 publications

(37 citation statements)

References 98 publications

(190 reference statements)

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“…Despite the discovery of new cancer therapeutics (170,171,172,173,174,175,176,177), there are existing limitations to the targeted-and immune-therapy approaches (178,179) including the development of drug resistance (180). Data depicting an association of GH action and chemo-and radiotherapy refractoriness in human cancers have been scarce(141).…”

Section: Role Of Gh-ghr In Cancer Therapy Resistancementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Basu

Qian

Kopchick

2018

European Journal of Endocrinology

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Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 40-50 years. Work on the GH receptor (R) knock-out (GHRKO) mice and results of studies on GH resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition, and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.

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Section: Role Of Gh-ghr In Cancer Therapy Resistancementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Basu

Qian

Kopchick

2018

European Journal of Endocrinology

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“…8 ) cancers, and NRAS mutations prevalent in melanoma (20%; ref. 9 ). Mutations in RAF family genes, most notably BRAF at codon V600, are frequent, particularly in malignant melanomas (50%; ref.…”

Section: Introductionmentioning

confidence: 99%

First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study

et al. 2018

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Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF-and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatmentrelated adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF -mutant solid tumors. SIGnIFICAnCE:Here, we describe the fi rst-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profi le with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS -and BRAF V600-and non-V600-mutant solid-tumor malignancies. Cancer Discov; 8(2);

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“…The rationale behind this approach is twofold: to prolong the progression-free survival (PFS) by delaying or preventing the development of MAPK-dependent resistance mechanisms (reviewed in this journal) [Khattak et al 2013]; and to reduce BRAF inhibitor related toxicities as a result of paradoxical activation of the MAPK pathway in nonmelanoma BRAF wild-type cells.…”

Section: Combination Braf and Mek Inhibitorsmentioning

confidence: 99%

“…A rapidly evolving understanding of tumor biology and immunity has provided the basis for a revolution in systemic therapies for melanoma, in particular, the identification of immune checkpoints and prevalent driver oncogenes. Drugs targeting the mitogen-activated protein kinase (MAPK) pathway and CTLA4 have entered routine clinical practice, and were the subject of a recent review in this journal [Khattak et al 2013]. Building upon the early success of these therapies, trials involving new classes of drugs and combinations of these drugs already in clinical use are underway.…”

Section: Introductionmentioning

confidence: 99%

New combinations and immunotherapies for melanoma: latest evidence and clinical utility

Menzies

Long

2013

Ther Adv Med Oncol

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Until recently there was no effective systemic therapy for metastatic melanoma. Increased understanding of tumor biology and immune regulation has led to the development of drugs targeting the mitogen-activated protein kinase (MAPK) pathway (BRAF inhibitors and MEK inhibitors) and T-cell regulation (CTLA4 antibodies). These drugs are the new standard of care, however barriers to better patient outcomes include limited responses and significant toxicities (CTLA4 antibodies) and lack of durability in the majority of cases (BRAF and MEK inhibitors). This review discusses the next stages of development of treatments in melanoma, including immune checkpoint blocking drugs targeting the PD-1/ PD-L1 axis, and the use of BRAF and MEK inhibitors in combination. Both approaches lead to a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes even further, clinical trials of combinations of MAPK inhibitors, immunotherapies and other signal pathway inhibitors are underway. Adjuvant studies of many of these drugs have commenced, with the hope of also improving outcomes in patients with early-stage melanoma.

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Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm

Cited by 46 publications

References 98 publications

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study

New combinations and immunotherapies for melanoma: latest evidence and clinical utility

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