ArticleJournal of clinical oncology : official journal of the American Society of Clinical Oncology2014
Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer.
Article in Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00544804 (A Phase I Dose Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer), which is not on this map. Cited by 22 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase I Dose Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer
Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Clinical data mining reveals analgesic effects of lapatinib in cancer patients.Scientific reports · 2021Pooled it
- Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.PloS one · 2015Trial
- Exploring tyrosine kinase inhibitors for HER2-positive breast cancer: comprehensive review on a complete pharmacology-molecular mechanisms, safety profiles, and insights from preclinical and clinical studies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Neratinib plus dasatinib is highly synergistic in HER2-positive breast cancer in vitro and in vivo.Translational oncology · 2024Article
- Repurposing antifungal drugs for cancer therapy.Journal of advanced research · 2023Review
- Pharmacokinetic Boosting of Kinase Inhibitors.Pharmaceutics · 2023Review
- Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells.Journal of Cancer · 2023Article
- Inactivating Amplified HER2: Challenges, Dilemmas, and Future Directions.Cancer research · 2022Article
- Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.Cell reports · 2022Article
- Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I exposure escalation study.Cancer chemotherapy and pharmacology · 2020Article
- Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes.International journal of molecular sciences · 2020Article
- Dual HER2 Blockade versus a Single Agent in Trastuzumab-Containing Regimens for HER2-Positive Early Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.Journal of oncology · 2020Article
- Phase I Study of Intermittent High-Dose Lapatinib Alternating with Capecitabine for HER2-Positive Breast Cancer Patients with Central Nervous System Metastases.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Phase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2019Article
- Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer.American journal of cancer research · 2019Review
- Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities.OncoTargets and therapy · 2018Review
- Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer.Oncotarget · 2017Article
- Alternative scheduling of pulsatile, high dose sunitinib efficiently suppresses tumor growth.Journal of experimental & clinical cancer research : CR · 2016Article
- Translating neoadjuvant therapy into survival benefits: one size does not fit all.Nature reviews. Clinical oncology · 2016Review
- Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer.Journal of cancer research and clinical oncology · 2015Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeThe highly effective treatment of human epidermal growth factor receptor (HER) 2-amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis. PATIENTS AND
methodsWe conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring.
resultsForty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL.
conclusionLapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.