N0675: NCCTG phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma (MM).

Dronca, R.; Perez, Daisy; Allred, Jacob B.; Maples, William J.; Creagan, Edward T.; Pockaj, BA; Kaur, Judith S.; Moore, T.; Marchello, Benjamin T.; Markovic, S. N.

doi:10.1200/jco.2010.28.15_suppl.8572

Cited by 14 publications

(17 citation statements)

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“…these inhibitors may also be beneficial for melanoma patients. However, phase II clinical trials in advanced melanomas have shown limited effects of mTOR inhibitors (20,21). Our study detected two new gain-of-function mutations of mTOR, that is, H1968Y and P2213S, in addition to S2215Y (27).…”

Section: Discussionmentioning

confidence: 75%

“…A phase II clinical trial using RAD001 in 24 cases of metastatic melanoma showed that the median progression-free survival (PFS) was about 3 months (20). Another phase II clinical trial using RAD001 in combination with temozolomide in 48 patients with advanced stage IV unresectable melanomas showed that the median PFS was only 2.4 months (21). Genetic selection of specific target may be useful for the establishment of therapeutic strategy for advanced melanoma patients.…”

Section: Introductionmentioning

confidence: 99%

“…Genetic selection of specific target may be useful for the establishment of therapeutic strategy for advanced melanoma patients. The two clinical trials using mTOR inhibitors have not screened the genetic mTOR nonsynonymous mutations (termed as mutation in this study if not specified) in the melanoma patients (20,21). Therefore, it remains to be determined whether melanoma patients bearing certain genetic mutations in mTOR will respond better to mTOR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K–AKT–mTOR Pathway Inhibitors

Kong

et al. 2016

Clinical Cancer Research

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Purpose: mTOR is a validated target in cancer. It remains to be determined whether melanoma patients bearing mTOR mutation could be selected for treatment with PI3K–AKT–mTOR pathway inhibitors. Experimental Design: A total of 412 melanoma samples were included. Gene aberrations in all exons of mTOR were detected by Sanger sequencing and confirmed by using Agilent's SureSelect Target Enrichment System. HEK293T cells stably expressing mTOR mutants were constructed by using transcription activator-like effector nucleases technique. Function of mTOR mutants and in vitro sensitivity of gain-of-function mTOR mutations to PI3K–AKT–mTOR pathway inhibitors were analyzed. Results: The overall incidence of somatic nonsynonymous mutations of mTOR was 10.4% (43/412). mTOR nonsynonymous mutations were relatively more frequent in acral (11.0%) and mucosal (14.3%) melanomas than in chronic sun-induced damage (CSD; 6.7%) and non-CSD (3.4%) melanomas. Of the 43 cases with mTOR mutations, 41 different mutations were detected, affecting 25 different exons. The median survival time for melanoma patients with mTOR nonsynonymous mutation was significantly shorter than that for patients without mTOR nonsynonymous mutation (P = 0.028). Transient expression of mTOR mutants in HEK293T cells strongly activated the mTOR–p70S6K pathway. In HEK293T cells with stable expression of H1968Y or P2213S mTOR mutants, LY294002 and AZD5363 showed higher potency than temsirolimus or BYL719 in inhibiting the PI3K–AKT–mTOR pathway and cell proliferation. Conclusions: mTOR nonsynonymous mutations are frequent in melanoma patients. mTOR nonsynonymous mutation may predict a worse prognosis of melanoma. Clinical trials with PI3K–AKT–mTOR pathway inhibitors may be beneficial for melanoma patients with specific mTOR mutations. Clin Cancer Res; 22(4); 1018–27. ©2015 AACR.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K–AKT–mTOR Pathway Inhibitors

Kong

et al. 2016

Clinical Cancer Research

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“…Unfortunately, clinical results did not prove an advantage of adding mTOR inhibitors to chemotherapy. In a phase II trial of 48 stage IV melanoma patients, only 4 of 48 (8%) patients showed a partial response when co-treated with temozolomide and RAD001 [55]. The median progression-free survival was 2.4 months, and the median overall survival was 8.6 months.…”

Section: Resistance To Chemotherapy Possible Combination Of Chemothementioning

confidence: 99%

Resistance to Chemotherapy and Molecularly Targeted Therapies: Rationale for Combination Therapy in Malignant Melanoma

Wu¹,

Singh²

2011

CMM

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Metastatic melanoma is one of the most intractable tumors, with all current regimens showing limited survival impact. Failure of most agents is attributed to development of therapy resistance. Accumulated evidence points to the apoptotic defect of melanoma cells and the surge of survival signals stimulated by cytotoxic drugs, as a way that tumors circumvent cytotoxic chemotherapy. An overview of inhibitors developed against these growth/survival factors, which are potential partners to be combined with systemic chemotherapy, will be discussed. The escape mechanism from molecular inhibitors also suggests a “vertical” or “horizontal” combination of molecularly targeted therapies. A better understanding of the interactions between simultaneously used regimens and of the rationale for combination therapy will provide new insights to improve survival and quality of life in patients with advanced melanoma.

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“…74 It failed to show significant objective responses in combination with TMZ over TMZ alone. 75 A phase II clinical study of Everolimus in combination with pasireotide didn't meet its primary endpoint in uveal metastatic melanoma. 76 …”

Section: Mtor-inhibitorsmentioning

confidence: 99%

Developments in targeted therapy in melanoma

Amann

Ramelyte

Thurneysen

et al. 2017

European Journal of Surgical Oncology (EJSO)

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Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent longterm outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy. AbstractMelanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations).The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

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N0675: NCCTG phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma (MM).

Cited by 14 publications

References 0 publications

Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K–AKT–mTOR Pathway Inhibitors

Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K–AKT–mTOR Pathway Inhibitors

Resistance to Chemotherapy and Molecularly Targeted Therapies: Rationale for Combination Therapy in Malignant Melanoma

Developments in targeted therapy in melanoma

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