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Originally published as JCO Early Release 10.1200/JCO.2008.21.3025 on March 2 2009 © 2009 American Society of Clinical Oncology.
In Reply
Sandro Pitigliani Medical Oncology Unit, Prato, Italy In Reply We have read with astonishment the letter by Amir et al1 in relation to our recently published article evaluating the combination of paclitaxel and lapatinib in a phase III clinical trial for patients with advanced breast cancer with human epidermal growth factor receptor 2 (HER-2) –untested or –negative primary tumors. Amir et al raise the issue that our article overemphasizes the clinical activity of the paclitaxel-lapatinib combination in HER-2–positive patients, while minimizing the treatment-related toxicity. We are disappointed because we believe that Amir et al1 have not shown attention in reading or correctly interpreting the study results. With regard to the clinical activity of this combination in the HER-2–positive cohort, we state clearly throughout the article that the presented results are preliminary and need to be confirmed. Specifically, the abstract conclusion states that "prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2 positive breast cancer patients."2 Moreover, the last paragraph of the discussion states that "these retrospective results in a limited number of (HER-2–positive) patients should be considered as hypothesis generating." We believe that these statements are made at critical parts of the article. We believe that they neither lead to misinterpretation, nor misrepresent the study findings. In reference to our reporting of the paclitaxel-lapatinib safety profile, it is astonishing to see how Amir et al1 interpret the article to support their view. We believe that the article provides an appropriate and detailed description of the toxicity profile of the paclitaxel-lapatinib combination. In particular, we report the following safety information: (1) The Results paragraph of the abstract states that "the incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm."2 (2) The reporting of clinical adverse events is the longest section in the article's results. In this section we report exhaustive data regarding the safety profile of the paclitaxel-lapatinib combination. We report that patients on paclitaxel-lapatinib had more serious adverse events than patients treated with paclitaxel-placebo. In addition, we report that fatal events were more frequently observed in the lapatinib arm than in the placebo arm and we provide the reader with detailed information on the possible cause of death for each of these patients. (3) Table 3 focuses entirely on adverse events by treatment arm and reports P values for the safety comparison between study arms. (4) Figure 2 focuses on fatal events aiming to correlate the occurrence of fatal events with time and number of patients on treatment. (5) Under Discussion, two paragraphs are dedicated to the issues of treatment tolerability and safety, with comparisons between treatment arms. In addition, these paragraphs attempt to provide potential explanations for the observed toxicity. Based on these considerations, we certainly believe that the article does not minimize the safety results of the present study. Furthermore, we disagree with Amir et al1 regarding lapatinib efficacy in the HER-2–positive subgroup. The findings reported by us2 and others3–5 do warrant the statement that lapatinib is efficacious in a subgroup of women with HER-2–positive breast cancer. The findings we report in our article are not presented as practice-changing findings. From the outset a primary goal of the Epidermal Growth Factor 30001 (EGF 30001) trial was to investigate the possibility that lapatinib, an inhibitor of both HER-2 and epidermal growth factor receptor (EGFR), might be efficacious in some women with metastatic disease whose breast cancers do not contain HER-2 amplification/overexpression. As an initial exploration of this issue, we evaluated HER-2 status in tumor tissue from the women entered in the EGF 30001 trial to define the HER-2 status of their tumors. We confirmed, as expected based on the study of patients with HER-2–positive breast cancer in a completed separate trial,3,4 that women whose breast cancers were HER-2 positive and who received lapatinib showed a significant improvement in clinical outcomes compared with similar women who received a placebo.2 In our opinion, our results demonstrate, once again, the importance of molecular markers in the evaluation of efficacy when using targeted therapeutic agents. Although the HER-2–positive subpopulation of women in the EGF 30001 trial was small, and women were not randomly assigned according to HER-2 status, these women were reasonably well balanced between the two different treatment arms as reported.2,5 In fact, the minor imbalance in extent of disease dissemination between treatment and control arms would have been expected to minimize, not enhance, any outcome difference in the treatment arms (Table 22). Our exploration of this clinical trial for other subpopulations, such as women with EGFR-positive disease, who might benefit from lapatinib treatment has begun.5 We disagree with the view that our collective work in these trials represents "overenthusiasm in the reporting of a company-sponsored trial."1 To have an approved indication for use of lapatinib in women who have not had prior treatment with trastuzumab/anthracycline/taxane would obviously require another clinical trial of lapatinib as a primary treatment for HER-2–positive, metastatic breast cancer. As we state in our article, these trials are in progress. Assertions made by Amir et al1 questioning the financial relationships between the article authors and the study sponsor are unfounded. The article authors2 clearly and correctly state their financial disclosures. Some of the authors, with critical roles in the writing of the article, disclose financial relationships with other competing pharmaceutical companies in addition to the study sponsor. These companies have been involved in the discovery, clinical development, and marketing of competing anti–HER-2 compounds. This aspect is not mentioned by Amir et al perhaps because it does not support their personal perspective. That six of the 14 article authors are employees of the study sponsor is, in our opinion, irrelevant. This was a complex trial in terms of logistics and regulatory issues and each author of the article had a well-defined role in the study, as is clearly stated in Author Contributions.2 In conclusion, we disagree with Amir et al1 in their noninformative interpretation of the study results. We believe that one of the most important findings of the study,2 if not the most important, is the observation that lapatinib's main mechanism of action involves HER-2 amplification/overexpression, at least when combined with cytotoxic agents. Ongoing trials will define the potential activity and safety of the paclitaxel-lapatinib combination and identify the place for this combination in current clinical practice. REFERENCES
1. Amir E, Seruga B, Freedman O, et al: Lapatinib plus paclitaxel as first-line therapy for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: inappropriate conclusions from a company-sponsored study? J Clin Oncol 27:1919; 2009. 2. Di Leo A, Gomez HL, Aziz Z, et al: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544–5552, 2008. 3. Cameron D, Casey M, Press M, et al: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543, 2008.[CrossRef][Medline] 4. Geyer C, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743, 2006. 5. Press M, Finn R, Cameron D, et al: HER2 gene amplification, HER2 and EGFR messenger RNA and protein expression and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 14:7861–7870, 2008.
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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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