Targeting precision medicine toxicity: recent developments

Mallarkey, Gordon; Mangoni, Arduino A.

doi:10.1177/2042098614560737

Cited by 4 publications

(3 citation statements)

References 42 publications

(42 reference statements)

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“…The mechanism of MAPKi‐mediated cardiotoxicities (heart failure, left ventricular dysfunction) is not well characterized, but preclinical data suggest that the MAPK pathway has a role in cardiac hypertrophy and cell survival . It has been understood since the early development of this drug class that cardiomyopathy is associated with MEKi, either alone or in combination with BRAFi .…”

Section: Current Management Strategies For Brafi‐ and Meki‐associatedmentioning

confidence: 99%

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma

Daud

Tsai

2017

The Oncologist

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Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage V600-mutant metastatic melanoma. To provide optimal therapeutic benefit to patients, clinicians need a keen understanding of the toxicity profiles of these drugs. Prompt identification and an understanding of which adverse events are most likely BRAF or MEK inhibitor associated provide a rationale for appropriate therapy adjustments. Practical recommendations derived from clinical experience are provided for management of key drug-related toxicities.

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Section: Current Management Strategies For Brafi‐ and Meki‐associatedmentioning

confidence: 99%

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma

Daud

Tsai

2017

The Oncologist

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“…Cardiac‐related adverse events have been observed with both BRAFi and MEKi therapies , although they appear to be more strongly associated with MEKi. Initial studies with trametinib reported left ventricular ejection fraction (LVEF) dysfunction in 8% of patients compared with 5% of patients using combination therapy in the COMBI‐d trial in patients with BRAF V600‐mutant metastatic melanoma.…”

Section: Adverse Events and Managementmentioning

confidence: 99%

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

2018

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Therapies for advanced non‐small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600‐mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression‐free survival of 10–11 months. BRAF mutations are a high‐frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical‐trial and real‐world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. Implications for Practice The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E‐mutant non‐small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.

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“…For instance, a review reported that only 2% of 296 patients who received 10 mg/kg of nivolumab exhibited hypotension. Similarly, only 7% of 135 melanoma patients who received 10 mg/kg of pembrolizumab showed a development of hypertension [ 160 ]. Cardiotoxic mechanisms are still to be elucidated, but mouse models suggest that heart dysfunction and dilation occur as an autoimmune response to cardiac troponin I in PD-1 deficient mice through chronic stimulation of Ca2+ influx [ 161 ].…”

Section: Reviewmentioning

confidence: 99%

Cardio-Oncology: Cancer Therapy-related Cardiovascular Complications in a Molecular Targeted Era: New Concepts and Perspectives

Hurtado-de-Mendoza

Loaiza‐Bonilla

Bonilla-Reyes

et al. 2017

Cureus

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Cardio-oncology is a medical discipline that identifies, prevents, and treats the cardiovascular complications related to cancer therapy. Due to the remarkable proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia, we provide an extensive, comprehensive revision of the most up-to-date scientific information available on the cardiovascular complications associated with the use of newer, novel chemotherapeutic agents, including their reported incidence, suggested pathophysiology, clinical manifestations, potential treatment, and prevention. The authors consider this topic to be relevant for the clinicians since cardiovascular complications associated with the administration of recently approved drugs are relatively underappreciated.The purpose of this article is to provide a state-of-the-art review of cardiovascular complications associated with the use of newer, novel chemotherapeutic agents and targeted therapies, including their reported incidence, suggested pathophysiology, clinical manifestations, potential treatment, and prevention. Ongoing efforts are needed to provide a better understanding of the frequency, mechanisms of disease, prevention, and treatment of cardiovascular complications induced by the newer, novel chemotherapeutic agents. Development of a cardio-oncology discipline is warranted in order to promote task forces aimed at the creation of oncology patient-centered guidelines for the detection, prevention, and treatment of potential cardiovascular side effects associated with newer cancer therapies.

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Targeting precision medicine toxicity: recent developments

Cited by 4 publications

References 42 publications

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

Cardio-Oncology: Cancer Therapy-related Cardiovascular Complications in a Molecular Targeted Era: New Concepts and Perspectives

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