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Originally published as JCO Early Release 10.1200/JCO.2008.20.0758 on December 8 2008 © 2009 American Society of Clinical Oncology.
In Reply
Karmanos Cancer Institute, Wayne State University, Detroit, MI
Sarah Cannon Research Institute, Nashville, TN
Oncology Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC
Clinical Pharmacokinetics Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC The letter from Ciccarese et al raises questions about how to dose lapatinib on the basis of data emerging from recently reported trials. These data fall outside of the approved indication for which a dosing recommendation exists, but reveal some unique characteristics of the drug that are scientifically interesting and therapeutically challenging. In addition to these questions, Ciccarese et al critique the design of a phase I study we described in a report that assessed the tolerability and pharmacokinetics of lapatinib combined with docetaxel.1 The lapatinib-docetaxel combination study began before completion of several phase I lapatinib trials, at a time when less was known about the clinical pharmacology of the drug. The food effect had been quantified as a 60% increase in bioavailability at a low dose under extreme conditions (ie, after a high-fat meal). Given these data, it seemed reasonable to allow patients the option of a low-fat breakfast to facilitate treatment. Later, it was discovered that a standard low-fat meal increased bioavailability three-fold at a higher dose.2 However, there was no evidence of a food effect in the data we reported,3 indicating that patients who chose to have breakfast consumed less than the standard low-fat breakfast. This is consistent with surveys showing the average breakfast of choice is smaller than the standard low-fat meal that increased bioavailability of lapatinib.4 The letter states that emerging data have contributed to confusion about how to dose lapatinib, and repeats the misinterpretations of Ratain et al5 that administering lapatinib with food would improve bioavailability, reduce toxicity, and lower the cost of treatment by requiring fewer tablets (a lower dose). These assertions ignore data showing that administering lapatinib with food increases variability and does not reduce toxicity.3,6 As for cost savings, drug pricing is not simply determined by the cost of a drug substance, but also by the cost of development, and most importantly, by the value to patients. However, concern about the cost of drugs is not confined to lapatinib, which is not the most expensive agent in this class. We agree with Ciccarese et al that studies assessing targeted agents should not follow the cytotoxic paradigm equating maximum tolerated dose (MTD) with optimal therapeutic dose (OTD). The OTD should be defined using objective, quantitative measures. However, such measures are often elusive for novel agents, because valid surrogate markers are rarely developed in parallel with the drug. Biomarkers that reflect the biologic or clinical activity of a drug are sometimes available; however, in many cases, they do not exist or are not technically or ethically feasible. Agents with intracellular targets encounter additional barriers. Serial biopsies are difficult for patients to endure, imaging techniques (if applicable) are inconvenient and expensive, and the technical requirements of sample processing and handling are unwelcome additions to the demands on clinic staff involved in patient care. Defining the OTD can then default to demonstrating clinical activity or efficacy later in development, adding expense and risk. The development of lapatinib included several studies that attempted to obtain intracellular phosphorylation biomarkers and circulating human epidermal growth factor receptor 2 extracellular domain, but for a number of reasons, including those cited in this letter, none provided sufficient data to define the OTD. As a result, quantitative dose selection has proved elusive, and emerging data may indeed seem confusing. In this context, pharmacokinetic data alone cannot provide sufficient rationale for dose selection. Our study, which evaluated the combination of a targeted agent and a cytotoxic agent, required a design that suited both. Our assessment of the MTD for lapatinib as part of this combination should not be confused with a determination of the OTD, which was not an objective. The MTD is equally relevant for targeted agents to define a therapeutic window. Developing a drug for patient use requires an understanding of the potential toxicities in likely scenarios, such as concomitant use of other drugs (or food) that could increase exposure beyond the equivalent of the MTD. The MTD for lapatinib had not been determined when we initiated our study, but was subsequently shown to exceed 1,800 mg once daily. The MTD for docetaxel could be considered 100 mg/m2 in a curative setting. The highest doses administered in our study did not reach these levels, because tolerability of the combination was limited by an unexpected enhancement of neutropenia. This toxicity appeared to be mediated by a pharmacokinetic-pharmacodynamic interaction that we characterized using absolute neutrophil count. Contrary to the comments of Ciccarese et al, the limit of tolerability was quantified using pharmacokinetic and pharmacodynamic end points. Ultimately, we identified the optimally tolerated regimen for this combination as 1,250 mg of lapatinib (consistent with the OTD defined in later studies and the approved indication) and 75 mg/m2 of docetaxel (with growth factor support to offset the enhanced neutropenia). The dose levels tested in our study provided an estimate of the optimally tolerated regimen as a starting point to assess clinical activity in a more select phase II population. The criticism that our design was inappropriate for a targeted agent seems to be based on the presumption that it was intended to define the OTD, despite acknowledgment that the primary objectives were to assess tolerability and pharmacokinetics. These study objectives were achieved more efficiently in a relatively small population of patients with various tumor types. Adequate assessment of clinical activity to define an OTD for a targeted agent would require a larger phase II trial in a more select patient population. But it would be incorrect to infer that patients in the phase I study had derived less benefit than those in phase II studies by disregarding the presence of the cytotoxic agent and the potential for synergy through nontarget mechanisms. In this regard, the mechanism that we speculated underlay the enhanced neutropenia could have equally enhanced antitumor activity. Therefore, we disagree with the criticism that we failed to find any evidence of potential synergy with this combination. We agree with the concepts that phase I studies should be designed to take advantage of the opportunity to observe clinical activity early in drug development, and that biologic markers of clinical activity should be used to help with identification of the OTD. However, proven biomarkers for human epidermal growth factor receptor 2 inhibition are still not readily available.7 Intracellular phosphorylation markers require serial biopsies and tissue sample processing, which are difficult to execute. In the absence of a valid or technically feasible biomarker, assessing a targeted drug may seem to follow the cytotoxic paradigm until sufficient clinical activity data are obtained to enable more rational study design and dose definition. The optimal design of clinical trials with targeted agents, alone or in combination with cytotoxic agents, requires a balance between the theory of best practice and the reality of the limitations of what patient volunteers can accommodate, available technology, and resources for implementation. Hurdles in drug development need to be understood by health care providers, especially those involved as investigators, who are in a position to help overcome them, so we can achieve our common goal of improving patient care. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Ronald A. Fleming, GlaxoSmithKline (C); Kevin M. Koch, GlaxoSmithKline (C) Consultant or Advisory Role: Patricia M. LoRusso, GlaxoSmithKline (C) Stock Ownership: Ronald A. Fleming, GlaxoSmithKline; Kevin M. Koch, GlaxoSmithKline Honoraria: Patricia M. LoRusso, GlaxoSmithKline; Howard A. Burris III, Sanofi-aventis, GlaxoSmithKline Research Funding: Patricia M. LoRusso, GlaxoSmithKline Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES
1. 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 2. 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) 3. 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 4. Haines PS, Guilkey DK, Popkin BM: Trends in breakfast consumption of US adults between 1965 and 1991. J Am Diet Assoc 96:464-470, 1996[CrossRef][Medline] 5. 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 6. Koch KM, Beelen AP, Ho PTC, et al: The value of label recommendations: How to dose lapatinib. J Clin Oncol 25:5331-5332, 2007 7. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287-5312, 2007
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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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