Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor

Abstract

Purpose: The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors.

Experimental design: Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.

Results: In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.

Conclusion: Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors.

Clinical trial registration: NCT00359190.

Conflict of interest statement

Competing Interests: The authors have the following interests: Funding for this study was provided by GSK. Editorial support in the form of development of the first draft, editorial suggestions to draft revisions, assembling tables/figures, collating author comments and referencing was provided by Guissou Dabiri, PhD, and was funded by GSK. Sarah Bacus is employed by Quintiles, Deborah A Smith, Kelli Glenn, Leanne Cartee and Kevin M Koch by GlaxoSmithKline, Jennifer Harris by Pivot Oncology Consulting and Peter Beitsch by Dallas Surgical Group. GlaxoSmithKline markets the drug lapatinib under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe). There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Schema of EGF10027.

Twenty-eight patients were randomized to the following treatment groups: lapatinib 500 mg PO BID; lapatinib 1000 mg PO QD; lapatinib 1500 mg PO QD. Patient follow up and data analysis were conducted as indicated.

Fig 2. Lapatinib in human breast cancer xenograft tissue.

Steady-state (Day 3) lapatinib concentrations in blood, tumor, kidney, and liver measured in CB-17 SCID female mice bearing established HER2+ BT474 breast cancer xenografts (n = 45) following treatment with lapatinib (100 mg/kg BID) administered by oral gavage x 5 doses. Results represent the mean +/- standard error.

Fig 3. The relationship between lapatinib concentrations in tumor and plasma from clinical samples.

Women with early stage HER2+ breast cancer were randomized to oral lapatinib monotherapy at 500 mg twice daily (BID), 1000 mg once daily (QD), or 1500 mg QD. Lapatinib concentrations (μM) in plasma (CP) and tumor (CT) tissue samples obtained simultaneously 9–15 days after initiating therapy (steady state) concentrations (Cmin). (A). Lapatinib concentrations for each patient in the indicated treatment groups. The dotted blue line represents the reported IC90 value for lapatinib in HER2+ breast cancer cell lines. Large circles represent group medians. (B) The complex relationship between lapatinib concentration in tumor and plasma showing a speculative model that suggests determinants: target protein binding (lower Emax curve), and net uptake/efflux (upper Emax curve): grey circle (patient with dysfunctional ABCB1 SNP C3435T); open circle (patient taking lapatinib 500 mg BID also taking grape seed oil), shown with simulation and deviations (dashed lines) illustrating speculation of diminished efflux (left shift) and increased EGFR target binding (right shift). The horizontal dotted line at 4 μM represents the IC50 for the ABCB1 transporter.

Fig 4. Phosphorylation of HER receptors relative to tumor and plasma concentrations of lapatinib.

Changes (post-/pre-treatment ratios of optical density (OD values)) in EGFR, HER2, and HER3 phosphorylation in response to lapatinib in clinical tumor samples, and their relationship to tumor (left panel) and plasma (right panel) concentrations of lapatinib.