Mathematics in the Realm of Lapatinib: 500 + 500 = 1,500?

Once upon a time (ie, several decades ago), breast cancer was a disease with a dismal outcome. However, we now witness long-term overall survival rates of 80% to 90% in women with early breast cancer in North America and Europe, although metastatic breast cancer remains incurable. Exciting scientific discoveries help us to understand the biology of breast cancer, leading to the development of effective but costly new therapeutic approaches. A family of epidermal growth factor receptor (EGFR) tyrosine kinases (HER-1 [EGFR], HER-2, HER-3, and HER-4) has an important role in mediating the proliferation and survival of normal and malignant cells. Approximately 20% to 25% of breast cancers have an amplified HER-2 gene and/or overexpressed HER-2 protein, which is associated with poor outcome. Treatment with trastuzumab, a monoclonal antibody against the extracellular domain of the HER-2 receptor, has a profound impact on outcome of women with HER-2–positive breast cancer, but many women have intrinsic resistance or develop acquired resistance to trastuzumab. Because HER-2—the most common partner of HER-1–does not bind known ligands, its main biologic role as a signal transducer is in forming heterodimer receptor complexes with other tyrosine kinases from the same family. Lapatinib is an oral drug that targets reversibly intracellular tyrosine kinases of both HER-1 and HER-2 receptors. On the basis of a phase III study published in December 2006 by Geyer et al, regulatory agencies have approved lapatinib in a once-daily dose of 1,250 mg continuously in combination with capecitabine for patients with advanced or metastatic HER-2–positive breast cancer treated previously with anthracyclines, taxanes, and trastuzumab. In this issue, Gomez et al report the results of a randomized, open-label, phase II, company-sponsored trial comparing efficacy and tolerability of two schedules of lapatinib monotherapy (500 mg twice daily and 1,500 mg once daily) in 138 women with HER-2 gene– amplified, locally advanced or metastatic breast cancer who had not received chemotherapy or trastuzumab for their advanced or metastatic disease. This study had approximately 90% power to detect an absolute increase of 30% in overall response rate (the primary end point) of the 500-mg twice-daily regimen compared with the 1,500-mg once-daily regimen. The rationale for the study was based on preliminary pharmacokinetic data suggesting less variability in plasma drug levels with twice-daily dosing and on the expectation that the area under the curve with the 500-mg twice-daily schedule would be greater than with the 1,500-mg once-daily regimen. No significant differences in efficacy or toxicity were found between the treatment arms. Tumor responses, which were assessed by a blinded independent review committee, were observed in 26% and 22% of the patients receiving the twiceand once-daily schedules, respectively (P .69). These response rates are similar to those observed for trastuzumab when used as first-line therapy for a similar population of women. Several secondary end points of efficacy, including progression-free survival, showed no significant differences (and no consistent trends) between the treatment arms, although the trial was underpowered to detect such differences. Lapatinib-related adverse events, including diarrhea, were also similar, and the majority of adverse events were grade 1 or 2. Pharmacokinetic analysis is not yet available, and this is a major limitation given the results of this study. The authors of this article conclude that their data support further evaluation of lapatinib as first-line treatment for metastatic breast cancer but make no recommendations about dose or schedule. The study by Gomez et al confirms the activity of lapatinib, but only approximately 50% of the women in their study had received any adjuvant or neoadjuvant systemic therapy, and none had received adjuvant trastuzumab. Therefore, the patients are not representative of women with HER-2–amplified breast cancer who now develop (or will develop in the future) metastatic disease; most will have received adjuvant chemotherapy and trastuzumab. The activity of lapatinib in a more representative population is unknown, and single-agent lapatinib cannot be recommended as standard first-line treatment for patients with HER-2–amplified breast cancer who develop metastases or local progression. It is instructive to review the early-phase clinical trials of lapatinib. In phase I studies of heavily pretreated patients, single-agent lapatinib was administered at total doses ranging from 175 to 1,800 mg/d using either onceor twice-daily dosing. Toxicities were low grade and not dose limiting. In the only published phase I study of single-agent lapatinib in cancer patients, activity (ie, objective responses or stable disease lasting 6 months) was observed at daily doses ranging from 500 to 1,600 mg (most frequently at 900 to 1,200 mg) in patients expressing HER-1 and/or overexpressing HER-2, without evident relationship between drug dose and response. The frequency of diarrhea was related to dose but not to serum drug concentrations, suggesting that lapatinib toxicity may evolve partly from a local effect on gut epithelium. A phase II dose for single-agent lapatinib was not recommended in the report of this study, despite that being the major goal of a phase I trial. Lapatinib was combined with trastuzumab or chemotherapeutic agents in other phase I studies. In combination with capecitabine, the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 18 JUNE 2

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