Originally published as JCO Early Release 10.1200/JCO.2008.16.5282 on May 5 2008

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

Bostjan Seruga, Ian F. Tannock

Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada

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,¹ 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.² 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,³ 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.^4,5

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,⁶ 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 al⁷ 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 dosing⁸ 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.⁹ 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 twice- and 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.^10,11 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 al⁷ 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 once- or twice-daily dosing.^12,13 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.¹² 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 dose escalation of lapatinib started at 1,250 mg once daily, but this became the recommended phase II dose to be used in the combination.¹⁴ Interestingly, this phase I study was published 9 months after the pivotal phase III study⁶ that resulted in the approval of lapatinib in combination with capecitabine. In phase II studies of women with advanced breast cancer, single-agent lapatinib was used commonly at a dose of 1,500 mg once daily. Responses were restricted to patients with HER-2–overexpressing cancers, the majority of whom were trastuzumab resistant.^15,16 However, until now, there have been no published dose-ranging phase II studies for lapatinib in the treatment of breast cancer. In two ongoing large adjuvant trials (ALTTO and TEACH), which plan to enroll together 11,000 women, lapatinib is administered for up to 12 months as a once-daily dose of 1,500 mg as monotherapy and as a once-daily dose of 1,000 mg in combination with trastuzumab.

The same treatment regimens of single-agent lapatinib as evaluated by Gomez et al⁷ (500 mg twice daily v 1,500 mg once daily) have been compared in a phase II study of patients with advanced non–small-cell lung cancer. This trial was stopped for futility after inclusion of 131 patients, but similar, mainly low-grade toxicities were reported for both treatment regimens, adding further support for the safety of the 500-mg twice-daily regimen.¹⁷

Unfortunately, the benefits of expensive new treatments are out of reach of many women with breast cancer and are restricted largely to subsets of women in wealthy countries. To maximize the overall benefit from new treatments, it is essential to use them at maximal cost effectiveness. The cost of lapatinib 1,250 mg daily is approximately $2,900 per month. Of note, the lapatinib label indicates that divided daily doses are not recommended because of an approximately two-fold higher exposure at steady-state compared with the same total daily dose administered once daily.¹⁸ Although the company label has to follow guidelines set by the regulatory bodies, it argues against a strategy that would halve the cost of the drug and thereby make it available to more women with breast cancer worldwide. Moreover, Ratain and Cohen¹⁹ described recently the marked effects of food to increase the bioavailability of lapatinib, which indicated that taking the medication with food might reduce substantially the number of daily pills that are required. Concerns have been raised about pharmacokinetic variability of lapatinib when taken with food and the possibility of an increased risk of serious toxicity²⁰; however, a clinical trial in which pharmacokinetics are studied in patients receiving a lower dose of lapatinib together with a standard meal could address this and might lead to lower cost and greater availability of the drug. If lapatinib in combination with food is hazardous, twice-daily dosing in the fasting state seems to be another approach to increase drug exposure. Pharmacokinetics should be more predictable, and the total daily dose and costs of treatment could be reduced. The data on safety and clinical activity of the 500-mg twice-daily regimen reported by Gomez et al⁷ are reassuring. Taking a drug once daily may be more convenient, but a cost of approximately $1,200 per month for that convenience seems a trifle high.

The fairy tale of lapatinib is evolving with increasing evidence of its activity, but we may be paying too high a price for the happy ending. The pivotal phase III trial by Geyer et al⁶ was published before the phase I trial of the combination of lapatinib and capecitabine and before publication of the other early-phase clinical trials with lapatinib, which are still accessible only in abstract form^13,15 or are about to be published.¹⁶ We do not have evidence that the higher single daily dose of lapatinib that has been approved in combination with capecitabine by regulatory agencies or the single daily doses being used in ongoing clinical trials are superior to a lower total dose administered in divided doses. This difference is not trivial because there are cost implications that may put this drug within or out of reach for many women who might benefit from it. In the future development of innovative targeted cancer therapies, it is important that phase III trials are designed on the basis of transparent data relating to dosing and efficacy from early-phase clinical trials. In our opinion, such trials (and regulatory decisions based on them) should require demonstration not only of effectiveness but also of cost effectiveness.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Bostjan Seruga, Ian F. Tannock

Financial support: Ian F. Tannock

Administrative support: Ian F. Tannock

Collection and assembly of data: Bostjan Seruge, Ian F. Tannock

Data analysis and interpretation: Bostjan Seruga, Ian F. Tannock

Manuscript writing: Bostjan Seruga, Ian F. Tannock

Final approval of manuscript: Bostjan Seruga, Ian F. Tannock

ACKNOWLEDGMENTS

We thank Natasha Leighl, MD, and Lillian Siu, MD, for their helpful comments about an earlier draft of this editorial.

NOTES

published online ahead of print at www.jco.org on May 5, 2008.

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