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Originally published as JCO Early Release 10.1200/JCO.2008.20.0345 on December 8 2008 © 2009 American Society of Clinical Oncology.
How Should We Prescribe Lapatinib to Our Patients: Once Daily or Twice Daily, and at What Dose?
Department of Oncology, Vito Fazzi Hospital, Lecce, Italy To the Editor: The results of two studies have contributed to increased confusion on the lapatinib dose to be prescribed to patients. Gomez et al1 randomly selected patients with locally advanced or metastatic breast cancer to receive, as first-line therapy, 1,500 mg of lapatinib once daily, or 500 mg twice daily. This study proceeded from the assumption that twice-daily dosing causes less variability in plasma drug levels, and the area under the curve would be greater for twice-daily rather than for once-daily administration.2,3 No differences were observed across the two groups in terms of response rate and progression-free survival, but no data were reported on pharmacokinetics or pharmacodynamics, and no indication was given about the best schedule to be used. The question still to be answered concerns the best schedule of lapatinib as a single agent as well as in association, especially in light of data showing the influence of a meal on bioavailability of the drug.4,5 Indeed, the consumption of lapatinib with a meal (especially a high-fat meal) seems to be better both in terms of increased bioavailability and reduced toxicity, and in terms of cost, because fewer pills would be taken. Conversely, the lapatinib package insert recommends consuming lapatinib while fasting, because this modality was carried by the sponsor in the phase III registration trial.6 This is a crucial point, especially for economic implications, because the monthly cost of lapatinib is $2,900 if the drug is taken while fasting, whereas consuming it with food could lead to a 60% savings of $1,740 a month.7 It is becoming urgent that a study be performed comparing the consumption of lapatinib with food with the consumption of the dose indicated on the package insert—five tablets of 250 mg—while fasting. LoRusso et al8 investigated the association of lapatinib and docetaxel in a phase I study. In this study, lapatinib was administered with a low-fat breakfast, with the aim of assessing the optimally tolerated regimen of lapatinib and docetaxel plus pegfilgrastim in patients with advanced solid tumors through the identification of dose-limiting toxicity, according to the classic end point of phase I studies for cytotoxic agents. This study demonstrated that this combination is feasible at dosages of 1,250 mg daily for lapatinib, and 75 mg/m2 (every 3 weeks) for docetaxel, provided that pegfilgrastim is given 24 hours afterward. We think that this methodology is incorrect for evaluating targeted agents in combination with classical chemotherapeutic agents. In fact, traditional phase I studies for chemotherapeutic agents are designed to find the maximum tolerated dose (MTD) and dose-limiting toxicity of the drugs. With biologic agents acting on highly specific targets expressed in cancer cells, the MTD may not be reached if the drugs have a much wider therapeutic ratio. Therefore, an increase of the doses to toxic levels may be not necessary to achieve maximum activity, and it may be an irrelevant end point. There are alternative end points for these agents that can be usefully employed in phase I studies: the identification of a molecular drug effect (the target effect), the measurement of surrogates for biologic activity, and the assessment of drug plasma levels. In particular, the identification of the target effect through pharmacodynamic assays is proof of principle and can be proof of drug activity. The main application of pharmacodynamic studies is to help in the selection of the minimum target-inhibiting dose (MTID) and the optimal schedule of administration of a drug.9,10 If the design of the study by LoRusso et al is suitable enough for cytotoxic chemotherapy (ie, docetaxel), it may be not appropriate for lapatinib, because, as in the study by Burris et al,11 it does not follow the methodology used to design studies of targeted agents. In addition, when patients affected by different tumors are included in these studies, as in the study by LoRusso et al, the risk of not having target-oriented results increases. In modern times, when new drugs undergo continuous investigation, we cannot continue using traditional phase I studies to assess dose. Instead, we should design phase I trials to measure the MTID through pharmacokinetic and pharmacodynamic assays. The optimal trial design in the early development of molecular targeted agents should be such that the MTD and MTID coincide. When they differ, it is necessary to analyze the range between the two parameters before providing recommended doses for phase II trials. In conclusion, in our opinion, the aim of LoRusso et al8 was more to define the tolerability and feasibility of the combination of lapatinib and docetaxel plus pegfilgrastim at the MTD, than to investigate the real synergism between the agents. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES
1. Gomez HL, Doval DC, Chavez MA, et al: Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 26:2999-3005, 2008 2. Moy B, Kirkpatrick P, Kar S, et al: Lapatinib. Nat Rev Drug Discov 6:431-432, 2007[CrossRef][Medline] 3. Bence AK, Anderson EB, Halepota MA, et al: Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects. Invest New Drugs 23:39-49, 2005[CrossRef][Medline] 4. US Food and Drug Administration Center for Drug Evaluation and Research: Application 22-059. http://www.fda.gov/cder/foi/nda/2007/022059s000_ClinPharmR.pdf 5. Reddy N, Cohen R, Whitehead B, et al: A phase I, open-label, three-period, randomized crossover study to evaluate the effect of food on the pharmacokinetics of lapatinib in cancer patients. Clin Pharmacol Ther 81:S16-S17, 2007 (suppl) 6. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 7. Ratain MJ, Cohen EE: The value meal: How to save $1,700 per month or more on lapatinib. J Clin Oncol 25:3397-3398, 2007 8. LoRusso PM, Jones SF, Koch KM, et al: Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J Clin Oncol 26:3051-3056, 2008 9. Hidalgo M, Messersmith W: Pharmacodynamic studies in drug development. Am Soc Clin Oncol Ed Book 160-163, 2004 10. Morabito A, Di Maio M, De Maio E, et al: Methodology of clinical trials with new molecular-targeted agents: Where do we stand? Ann Oncol 17:vii128-vii131, 2006 (suppl 7) 11. Burris HA III, Hurwitz HI, Dees EC, et al: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305-5313, 2005
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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