Final overall survival analysis of EXAM, an international, double-blind, randomized, placebo-controlled phase III trial of cabozantinib (Cabo) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline.

Schlumberger, Martin; Elisei, Rossella; Schöffski, Patrick; Brose, Marcia S.; Shah, Manisha H.; Licitra, Lisa; Jarząb, Barbara; Медведев, В. С.; Kreißl, Michael C.; Cohen, Ezra E.W.; Wirth, Lori J.; Ali, Haythem; Hessel, Colin M.; Yaron, Yifah; Ball, Douglas W.; Nelkin, Barry D.; Sherman, Steven I.

doi:10.1200/jco.2015.33.15_suppl.6012

Cited by 32 publications

(22 citation statements)

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“…The ATP-competitive multikinase inhibitors vandetanib and cabozantinib effectively block activity and signaling of both full-length and fusion RET proteins and have been approved for use in patients with progressive unresectable MTC or treatment-resistant PTC (Wells et al 2012, Elisei et al 2013, Redaelli et al 2018. These drugs have significantly improved progression-free survival (PFS), leading to stable disease or increased duration of response in patients with advanced or metastatic MTC (Wells et al 2012, Karras et al 2013, Schlumberger et al 2015, Viola et al 2016. Importantly, treatment provides significant improvements in PFS and overall survival for MTC patients with RET M918T mutations, which respond very poorly to other chemotherapies, although some initial studies with cabozantinib suggest that benefits for other RET mutations may be more modest (Fox et al 2013, Schlumberger et al 2015.…”

Section: Ret-targeted Therapiesmentioning

confidence: 99%

“…These drugs have significantly improved progression-free survival (PFS), leading to stable disease or increased duration of response in patients with advanced or metastatic MTC (Wells et al 2012, Karras et al 2013, Schlumberger et al 2015, Viola et al 2016. Importantly, treatment provides significant improvements in PFS and overall survival for MTC patients with RET M918T mutations, which respond very poorly to other chemotherapies, although some initial studies with cabozantinib suggest that benefits for other RET mutations may be more modest (Fox et al 2013, Schlumberger et al 2015. Notably, some specific MEN2 RET mutations that affect the 'gate keeper' residue (V804) adjacent to the RET ATP-binding pocket, block binding of inhibitors to RET and confer resistance to these agents (Carlomagno et al 2004), making RET mutation genotype an important determinant of treatment success.…”

Section: Ret-targeted Therapiesmentioning

confidence: 99%

“…These are primarily ATP-competitive inhibitors that vary in their kinase targets and RET inhibitory profiles, and in their ability to inhibit RET gatekeeper mutants. However, all these multikinase inhibitors, including vandetanib and cabozantinib, are associated with significant toxicities, likely due to systemic effects of the 'off target' inhibition of other kinases such as EGFR or VEGFR family kinases (Wells et al 2012, Schlumberger et al 2015. Further, the recent report of an acquired V804M mutation in a metastatic MTC previously treated with multiple tyrosine kinase inhibitors (Subbiah et al 2018b), suggests the potential for development of drug resistance in response to extended treatment with these inhibitors, as has been seen for other targeted therapies.…”

Section: Ret-targeted Therapiesmentioning

confidence: 99%

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65 YEARS OF THE DOUBLE HELIX: Exploiting insights on the RET receptor for personalized cancer medicine

Mulligan

2018

Endocrine-Related Cancer

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The focus of precision cancer medicine is the use of patient genetic signatures to predict disease occurrence and course and tailor approaches to individualized treatment to improve patient outcomes. The rearranged during transfection (RET) receptor tyrosine kinase represents a paradigm for the power of personalized cancer management to change cancer impact and improve quality of life. Oncogenic activation of RET occurs through several mechanisms including activating mutations and increased or aberrant expression. Activating RET mutations found in the inherited cancer syndrome multiple endocrine neoplasia 2 permit early diagnosis, predict disease course and guide disease management to optimize patient survival. Rearrangements of RET found in thyroid and lung tumors provide insights on potential disease aggressiveness and offer opportunities for RET-targeted therapy. Aberrant RET expression in a subset of cases is associated with tumor dissemination, resistance to therapies and/or poorer prognosis in multiple cancers. The potential of RET targeting through repurposing of small-molecule multikinase inhibitors, selective RET inhibitors or other novel approaches provides exciting opportunities to individualize therapies across multiple pathologies where RET oncogenicity contributes to cancer outcomes.

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Section: Ret-targeted Therapiesmentioning

confidence: 99%

Section: Ret-targeted Therapiesmentioning

confidence: 99%

Section: Ret-targeted Therapiesmentioning

confidence: 99%

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65 YEARS OF THE DOUBLE HELIX: Exploiting insights on the RET receptor for personalized cancer medicine

Mulligan

2018

Endocrine-Related Cancer

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“…Historically, resection of advanced melanoma has been reserved for patients with local recurrence and in-transit, satellite, and oligometastatic disease, with improvement in OS [80, 81]. Retrospective data suggest that patients with metastatic melanoma who respond to BRAF inhibition but have an isolated focus of residual or progressive disease may benefit from metastatectomy [82]. Similarly, patients with metastatic GIST may benefit from metastatectomy after response or disease stabilization with imatinib [83].…”

Section: Multimodality Therapymentioning

confidence: 99%

Principles of Kinase Inhibitor Therapy for Solid Tumors

Cohen

Kim²,

DeMatteo³

2017

Annals of Surgery

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STRUCTURED ABSTRACT Objective We aimed to identify key principles of targeted therapy of protein kinases and their application to the management of solid tumors. Background Concurrent advances in tumor genomic analysis and molecular inhibitor development have dramatically impacted the diagnosis and treatment of solid tumors and common themes regarding the use of kinase inhibitors are developing. Methods The list of kinase inhibitors that have been approved by the FDA was reviewed and articles related to the agents were searched in the PubMed database up until December 2015. We included pivotal, randomized, controlled phase 2 and 3 trials as well as pertinent preclinical studies. Results Small molecule inhibitors targeted against driver kinases, overactive in selected subsets of solid tumors, elicit improved response rates and survival compared with standard chemotherapy. Disease control has been proven in the metastatic and, to a limited extent, the adjuvant setting. However, tumor eradication is rare, and duration of treatment response is limited by the development of drug resistance. Conclusions Kinase inhibitors induce response in diverse types of solid tumors. While the agents are often effective in defined molecular subsets, cure is rare and resistance is common. This broad review provides rationale for further investigation of multimodality therapy combining kinase inhibitors with additional systemic and local therapies, including surgery.

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“…Median PFS on cabozantinib was longer for patients with RET mutation than for patients with wild-type RET (60 weeks vs. 25 weeks, p = 0.0001), and RET M918T associated with longer PFS than any other RET mutation (61 weeks vs. 36 weeks, p = 0.009), suggesting that RET mutation, which correlates with worse outcome [6], and RET M918T in particular confer a survival benefit from cabozantinib treatment [7]. The secondary endpoint of this Phase 3 study was improved overall survival (OS) and not met with median OS of 26.6 months for cabozantinib and 21.1 months for placebo (HR = 0.85, p = 0.241); however, patients with RET M918T mutations experienced significantly longer median OS with cabozantinib (44.3 months vs. 18.9 months with placebo, HR = 0.60, p = 0.026) [8]. …”

Section: Introductionmentioning

confidence: 99%

Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma

Heilmann¹,

Subbiah

Wang³

et al. 2016

Oncology

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Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

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Final overall survival analysis of EXAM, an international, double-blind, randomized, placebo-controlled phase III trial of cabozantinib (Cabo) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline.

Cited by 32 publications

References 0 publications

65 YEARS OF THE DOUBLE HELIX: Exploiting insights on the RET receptor for personalized cancer medicine

65 YEARS OF THE DOUBLE HELIX: Exploiting insights on the RET receptor for personalized cancer medicine

Principles of Kinase Inhibitor Therapy for Solid Tumors

Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma

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