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Originally published as JCO Early Release 10.1200/JCO.2008.20.0741 on December 8 2008 © 2009 American Society of Clinical Oncology.
In Reply
Department of Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru We are pleased to respond to Ciccarese et al regarding the article by Gomez et al.1 In the first part of their letter, Ciccarese et al evaluate the idea of administering fewer daily doses of lapatinib than the number approved, and using a different schedule or taking the drug with a meal. The trial in which we participated, EGF 20009, was a randomized study that included 138 patients, and compared the efficacy and tolerability of two lapatinib administration schedules—1,500 mg once daily versus 500 mg twice daily—as first-line treatment for patients with ErbB2-amplified locally advanced or metastatic breast cancer. The rationale for the study was based on previous studies2-4 that suggested less variability in plasma drug levels with fractionated daily doses, and on the expectation that the area under the curve with the fractionated schedule would be greater than that with the once-daily regimen. However, in this group of patients, we found a similar profile of safety and efficacy between both doses as monotherapy, but results of pharmacokinetics are still pending. Moreover, this trial used fasting conditions, which by definition are reproducible, rather than the taking of pills with meals, which is an obvious source of heterogeneity in terms of interpatient and/or intrapatient pharmacokinetic variability. The combination of lapatinib with a meal is described by a phase I, open-label trial developed by Reddy et al.5 This trial included only 27 patients, and found an increase in the amount of drug entering the blood after a standardized meal (identical food), with changes between low- and high-fat content, in comparison with the amount in a fasting state. To conclude that adding meals allows the dose to be reduced to 500 mg every 12 hours, without affecting safety or efficacy, we need to perform additional and larger studies, and show that the food effect is consistent and occurs continuously. Moreover, we should prove that this schedule is reproducible in the real world. Finally, the information we have as of now supports the need to use 1,250 mg of lapatinib when combined with capecitabine; this is the only indication approved by the US Food and Drug Administration for lapatinib. Even if we would like to administer lapatinib as individualized monotherapy treatment, the use of lapatinib as a single drug has not yet been approved. More studies need to be performed, and the pharmacokinetic results of the EGF 20009 trial need to be reviewed, before a twice-daily schedule is administered. However, the use of a lapatinib monodrug could become a reality in the next few years, because there are two large ongoing adjuvant trials (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation and Tykerb [GlaxoSmithKline, Philadelphia, PA; Research Triangle Park, NC] Evaluation After Chemotherapy) that plan to enroll a total of 11,000 women. In conclusion, we still need to define the best schedule or strategy for administering lapatinib as a single agent. 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. Clark KJ, Keith BR, Alligood K, et al: Pharmacokinetics and pharmacodynamics of GW572016 following oral administration to female BT474-bearing CB-17SCID mice. 2002 Annual Meeting of the American Association of Pharmaceutical Scientists, Toronto, Ontario, Canada, November 11-14, 2002 (abstr W5286) 3. Koch KM, Lee D, Jones S, et al: Pharmacokinetics of GW572016 in an ascending dose tolerability study of phase I cancer patients. Eur J Cancer 1:S169, 2003 (suppl) 4. 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 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)
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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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