Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma

Daud, Adil; Kluger, Harriet M.; Kurzrock, Razelle; Schimmöller, Frauke; Weitzman, Aaron; Samuel, Thomas A.; Moussa, Ali H.; Gordon, Michael; Shapiro, Geoffrey I.

doi:10.1038/bjc.2016.419

Cited by 61 publications

(54 citation statements)

References 52 publications

(71 reference statements)

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“…This inhibitor, developed by Exelixis [180], is an orally bioavailable small molecule inhibitor against various tyrosine kinases which include Axl, MET and VEGF. A phase II trial (NCT00940225) evaluating cabozantinib in patients with metastatic melanoma was discontinued as the study was underpowered to detect statistical significance [181]. A phase I/II trial (NCT03957551) evaluating the combination of cabozantinib and pembrolizumab as a front-line therapy has been initiated for patients with advanced metastatic melanoma [182].…”

Section: Cabozantinib/xl184/bms-907351 (Type Ii)mentioning

confidence: 99%

Current Advances in the Treatment of BRAF-Mutant Melanoma

Patel

Yacoub

Mishra

et al. 2020

Cancers

124

102

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Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

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Section: Cabozantinib/xl184/bms-907351 (Type Ii)mentioning

confidence: 99%

Current Advances in the Treatment of BRAF-Mutant Melanoma

Patel

Yacoub

Mishra

et al. 2020

Cancers

124

102

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“…Bevacizumab and aflibercept, which inhibit VEGF, have also failed to show any significant clinical benefit (Piperno‐Neumann et al., ; Tarhini et al., ). Cabozantinib, a nonspecific MET and tyrosine kinase inhibitor, was tested in a phase II trial, and the UM cohort showed 61% of patients (14/23) achieved stable disease at week 12, with median PFS of 4.8 months and median OS of 12.6 months (Daud et al., ). Thus, overexpression of RTKs in UM is not predictive of clinical response to RTK inhibition, and this presumably reflects the underlying mutation profile (i.e., GNAQ/GNA11 , PLCB , and CYSLTR2 ) and oncogenic signaling activity present in each tumor.…”

Section: Oncogenic Signalingmentioning

confidence: 99%

Oncogenic signaling in uveal melanoma

Park

Diefenbach

Joshua

et al. 2018

Pigment Cell Melanoma Res

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Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are actionable, and many ongoing clinical trials are targeting these pathways. Additional cytogenetic and genetic changes, however, including chromosome 3 monosomy, mutations in the BAP1 tumor suppressor gene, alterations in the splicing factors SRSF2/SF3B1, and mutations in the translation initiation factor EIF1AX, modulate signaling output in uveal tumors and modify the risk of metastases. Here, we review the complex interactions between genetic, molecular signaling, and prognostic profiles in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy.

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“…In this regard, our data and others (28) suggest that this phenomenon is attributable to MET overexpression mediated by VEGF inhibition. We will continue to investigate the effects of combination therapy with VEGF inhibitor and MET inhibitor for GBM as has been conducted in melanoma (16).…”

Section: Discussionmentioning

confidence: 99%