This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Paoletti, P. Search for Related Content PubMed PubMed Citation Articles by Paoletti, P. Social Bookmarking                            What's this?

Drug Development in the Targeted Therapy Era

Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA

To the Editor:

The editorial published in Journal of Clinical Oncology by Drs Seruga and Tannock¹ alludes to a lack of transparency surrounding dose selection for the approved indication of lapatinib and capecitabine in HER2-positive metastatic breast cancer and the delayed publication of studies relating to the original dose selection.

As Head of the Medicine Development Center for GlaxoSmithKline Oncology, I would like to address these concerns. Dose selection for therapeutic agents is often an imprecise science and is particularly complex with targeted agents. In traditional models, doses were selected by dose-limiting toxicities and a maximum-tolerated dose. For targeted molecules, such as lapatinib, the best dose chosen for clinical development is often the optimally tolerated dose. It is inaccurate to suggest that no dose recommendation was made for single-agent lapatinib after phase I studies. The clinical investigators and GlaxoSmithKline were being responsible in not recommending the maximum-tolerated dose for additional testing, which was much higher than the dose evaluated in clinical trials and approved for use on the label. Dose-redefinition for oncology agents has been the rule rather than the exception (for example, witness the development history of the following oncology compounds: fluorouracil, gemcitabine, paclitaxel, and doxorubicin).

Few small-molecule tyrosine kinase inhibitors have shown a therapeutic advantage when combined with chemotherapy versus chemotherapy alone. Among the success stories are combinations of erlotinib and gemcitabine in pancreatic cancer² and lapatinib and capecitabine in HER2-positive metastatic breast cancer.³ One reason for failure of these combined treatment regimens is the use of suboptimal doses of targeted therapies. The approved dose of lapatinib (1,250 mg daily) in combination with capecitabine used in the phase III study was based on results of a phase I study in patients with solid tumors.⁴

After a planned interim analysis (April 2006) of data from EGF100151, the phase III trial of lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer, the Independent Data Monitoring Committee recommended halting the trial and giving patients in the control arm the opportunity to cross over to experimental therapy. Resources and efforts were subsequently devoted to submitting applications to the US Food and Drug Administration, Committee for Medicinal Products for Human Use, and other regulatory authorities. A global expanded-access program was opened in tandem, providing lapatinib in combination with capecitabine to patients who would not have otherwise had access to this therapy (more than 3,500 patients are enrolled globally to date). Though we concur that publication of phase I and II data should generally precede that of phase III, to do so in this case would have delayed publication of the pivotal phase III lapatinib data and dissemination of information about a treatment regimen that could potentially benefit thousands of patients. I am sure that the patients and their loved ones appreciate this.

The recent publication by Gomez et al⁵ of the phase II monotherapy lapatinib study in first-line metastatic breast cancer that led to the editorial (1,500 v 500 mg daily) is a demonstration of transparency. Drs Seruga and Tannock in their editorial discussing this article state, "These response rates are similar to those observed for trastuzamab." Indeed, these findings have been the basis for the continued development of lapatinib. Observations from the study by Gomez et al highlight the importance of testing new targeted agents in earlier disease settings.

In response to the comment in the editorial about whether a comparable therapeutic effect may be observed with a 500-mg twice daily dose of lapatinib and capecitabine (as opposed to the studied and approved dose of 1,250 mg daily), it is plausible; however, this regimen has not been tested or proven in combination with capecitabine. Therefore, it would be irresponsible for prescribers and not in the best interest of patients at present to substitute a 500-mg twice daily dose of lapatinib with that of the 1,250-mg dose. We are committed to defining the optimum dose and schedule as much as we are committed to developing new drugs for cancer patients and having them available based on demonstrated efficacy and safety. If, after approval, doses and schedules are defined that retain or increase efficacy and tolerability, we will develop these further—this is an ongoing process and in the obvious interest of patients.

AUTHOR'S 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: Paolo Paoletti, GlaxoSmithKline (C) Consultant or Advisory Role: None Stock Ownership: Paolo Paoletti, GlaxoSmithKline; Does your study have any NIH funding? No Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Seruga B, Tannock IF: Mathematics in the realm of lapatinib: 500 + 500 = 1,500? J Clin Oncol 26:2940-2942, 2008[Free Full Text]

2. Kulke MH, Blaszkowsky LS, Ryan DP, et al: Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 25:4787-4792, 2007[Abstract/Free Full Text]

3. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive breast cancer. N Engl J Med 355:2733-2743, 2006[Abstract/Free Full Text]

4. Chu Q, Schwartz G, de Bono J, et al: A phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies. J Clin Oncol 25:3753-3758, 2007[Abstract/Free Full Text]

5. 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[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Paoletti, P. Search for Related Content PubMed PubMed Citation Articles by Paoletti, P. Social Bookmarking                            What's this?