Phase I study of continuous and intermittent schedules of lapatinib in combination with vinorelbine in solid tumors

• Published in: Annals of oncology Vol. 23; no. 4; pp. 1023 - 1029
• Main Authors: Chew, H.K., Somlo, G., Mack, P.C., Gitlitz, B., Gandour-Edwards, R., Christensen, S., Linden, H., Solis, L.J., Yang, X., Davies, A.M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2012; Oxford University Press
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Disease-Free Survival; Dose-Response Relationship, Drug; EGFR (epidermal growth factor receptor); Female; HER2; Humans; Kaplan-Meier Estimate; Lapatinib; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - mortality; PTEN; PTEN Phosphohydrolase - metabolism; Quinazolines - administration & dosage; Treatment Outcome; Tumors; Vinblastine - administration & dosage; Vinblastine - analogs & derivatives; Vinorelbine; vinorelbine; lapatinib; PTEN; EGFR (epidermal growth factor receptor); HER2; Antineoplastic agent; Solid tumor; erbB2 Gene; Epidermal growth factor receptor; Alkaloid; Intermittent; PTEN Gene; Lapatinib; Antimitotic; Protein-tyrosine kinase; Protooncogene; Tumor suppressor gene; Human; Drug combination; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Malignant tumor; Human Epidermal growth factor Receptor 2; Growth factor receptor; Treatment; C-Onc gene; Phase I trial; Vinorelbine; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdr328

Chemotherapy in combination with small-molecule epidermal growth factor receptor inhibitors has yielded inconsistent results. Based on preclinical models, we conducted a phase I trial of two schedules of lapatinib and vinorelbine. Patients had advanced solid tumors and up to two prior chemotherapeutic regimens. Patients were enrolled on two dose-escalating schedules of lapatinib, continuous (arm A) or intermittent (arm B), with vinorelbine on days 1, 8, and 15 of a 28-day cycle. Tumors from a subset of patients were evaluated for gene mutations and expression of targets of interest. Fifty-one patients were treated. The most common grade 3/4 toxic effects included leukopenia, neutropenia, and fatigue. Dose-limiting toxic effects were grade 3 infection, febrile neutropenia, and diarrhea (arm A) and bone pain and fatigue (arm B). The maximum tolerated dose was vinorelbine 20 mg/m2 weekly and lapatinib 1500 mg daily (arm A) and vinorelbine 25 mg/m2 weekly and lapatinib 1500 mg intermittently (arm B). One patient on each arm had a complete response; both had human epidermal growth factor receptor 2-positive breast cancer. In a subset of patients, lack of tumor PTEN expression correlated with a shorter time to progression. In an unselected population, two schedules of lapatinib and vinorelbine were feasible and well tolerated.