Key Words. FDA summary Metastatic breast cancer Multidrug resistant Lapatinib Capecitabine

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1 The Oncologist Regulatory Issues FDA Drug Approval Summary: Lapatinib in Combination with Capecitabine for Previously Treated Metastatic Breast Cancer That Overexpresses HER-2 QIN RYAN, AMNA IBRAHIM, MARTIN H. COHEN, JOHN JOHNSON, CHIA-WEN KO, RAJESHWARI SRIDHARA, ROBERT JUSTICE,RICHARD PAZDUR Division of Drug Oncology Products, Office of Oncology Drug Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA Key Words. FDA summary Metastatic breast cancer Multidrug resistant Lapatinib Capecitabine Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers. LEARNING OBJECTIVES After completing this course, the reader should be able to: 1. Describe the clinical trial that led to the approval of lapatinib in combination with capecitabine for the treatment of previously treated patients with HER-2 overexpressing metastatic breast cancer. 2. Determine appropriate patients to receive lapatinib plus capecitabine treatment. 3. Assess and manage the toxicities of lapatinib plus capecitabine treatment. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb tablets; Glaxo- SmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2 overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab. One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3 or 2 with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function. Patients received either lapatinib (1,250 mg once daily on days 1 21) plus capecitabine (1,000 mg/m 2 every 12 hours on days 1 14) every 21 days or capecitabine alone (1,250 mg/m 2 every 12 hours on days 1 14) every 21 days. The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. Af- Correspondence: Qin Ryan, M.D., Ph.D., Division of Oncology Drug Products, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, USA. Telephone: ; Fax: ; qin.ryan@fda.hhs.gov Received January 23, 2008; accepted for publication August 6, 2008; first published online in THE ONCOLOGIST Express on October 10, AlphaMed Press /2008/$30.00/0 doi: /theoncologist The Oncologist 2008;13:

2 Ryan, Ibrahim, Cohen et al ter TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled). The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p.00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7 (lapatinib plus capecitabine) versus 13.9 (capecitabine alone). Survival data were not mature. Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. 3 or 4 adverse reactions that occurred with a frequency of >5 in patients on the combination arm were diarrhea (13) and palmar plantar erythrodysesthesia (12). There was a 2 incidence of reversible decreased left ventricular function in the combination arm. The Oncologist 2008;13: INTRODUCTION Following therapy with an anthracycline, a taxane, and trastuzumab, treatment options for human epidermal growth factor receptor (HER)-2 overexpressing advanced or metastatic breast cancer are limited [1 3]. Lapatinib (Tykerb ; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1 (epidermal growth factor receptor) has demonstrated noncrossresistance with trastuzumab in both preclinical and clinical studies and is thus a possible therapeutic option [4, 5]. Moreover, in vitro data suggest that the combination of capecitabine and ErbB inhibitors can have synergistic activity in both high and low ErbB-expressing breast cancer cell lines [6, 7]. Capecitabine is already approved for the treatment of metastatic breast cancer resistant to both paclitaxel and anthracycline-containing chemotherapy regimens. To define the efficacy of lapatinib and support the proposed use of lapatinib plus capecitabine for the treatment of patients with HER-2 overexpressing metastatic breast cancer, a randomized, open-label study tested lapatinib in combination with capecitabine in the setting of ErbB-2 positive metastatic breast cancer that has been treated with an anthracycline, a taxane, and trastuzumab. A report of the study results was recently published [8]. PATIENTS AND METHODS The safety and efficacy of lapatinib in combination with capecitabine for the treatment of patients with HER-2 overexpressing metastatic breast cancer previously treated with an anthracycline, a taxane, and trastuzumab were evaluated in a single multicenter, open-label, two-arm randomized trial conducted by GlaxoSmithKline. One hundred forty-one sites participated, with the majority of patients enrolled within the European Union (57) and U.S. (19). Eligibility criteria included histologically or cytologically proven breast cancer (stage IIIb or IV disease), documented ErbB-2 overexpression (immunohistochemistry [IHC] 3 or IHC 2 with fluorescence in situ hybridization [FISH] confirmation), prior therapy that included an anthracycline, a taxane (for adjuvant and/or metastatic disease), and trastuzumab (for advanced and/or metastatic disease), progression after hormone therapy for hormone receptor positive tumors, measurable lesion(s), age 18, an Eastern Cooperative Oncology Group performance status score of 0 or 1, normal cardiac ejection fraction, and adequate renal, hepatic, and bone marrow function. Women who were pregnant or lactating were excluded, as were women of childbearing potential unless adequate contraception was used. Patients were stratified at randomization by the site of metastasis (visceral versus nonvisceral) and stage of disease (stage IIIb versus IV) and received either lapatinib (1,250 mg once daily on days 1 21) plus capecitabine (1,000 mg/m 2 every 12 hours on days 1 14) every 21 days or capecitabine alone (1,250 mg/m 2 every 12 hours on days 1 14) every 21 days. The primary endpoint was time to progression (TTP), defined as time from randomization to tumor progression or death related to breast cancer. Progression was determined by a blinded independent review panel using the Response Evaluation Criteria in Solid Tumors. Tumor assessment was conducted every 6 weeks for the first 24 weeks, then every 12 weeks and at the end of treatment. Additional safety assessments were to be performed on all subjects every 3 weeks and at the end of treatment. Subjects withdrawn from the investigational drug who had not progressed were assessed every 12 weeks until progression. Thereafter, subjects were followed for survival at approximately 12-week intervals until death. The study was originally designed to have an 80 power to detect a 30 difference in overall survival with a planned sample size of 528 patients. RESULTS In total, 399 patients were randomized between March 29, 2004 and April 3, After the results of a prespecified interim analysis of 324 patients (cutoff date of November 15, 2005) were made available, further enrollment was discontinued after 399 patients were enrolled, 76 of the planned 528 patients. The final analysis includes 198 pa-

3 1116 Lapatinib and Capecitabine for HER-2 Overexpressing Metastatic Breast Cancer Table 1. Efficacy analyses: TTP November 15, 2005 cutoff n 324 April 3, 2006 cutoff n 399 a IND INV IND INV LC C LC C LC C LC C TTP n 163 n 161 n 163 n 161 n 198 n 201 n 198 n 201 Total events () 49 (30) 72 (45) 59 (36) 74 (46) 82 (41) 102 (51) 121 (61) 126 (63) Median TTP, weeks Improvement in median TTP, weeks HR (95 CI) 0.49 ( ) 0.59 ( ) 0.57 ( ) 0.72 ( ) p-value a Eighty-seven percent (347 of 399) of patients tumor assessment data were evaluable for the independent review committee. Abbreviations: C, capecitabine; CI, confidence interval; HR, hazard ratio; IND, independent reviewer analysis; INV, investigator s analysis; LC, lapatinib plus capecitabine; TTP, time to tumor progression. tients randomized to the lapatinib and capecitabine combination and 201 patients randomized to capecitabine alone (cutoff date of April ). The treatment groups were comparable for demographic characteristics at baseline: the median age was 53 years, with years old. Ninetyone percent were white. The two treatment groups were also comparable for tumor characteristics at inclusion. Ninety-seven percent of patients had stage IV disease, 77 had visceral stage IV and 20 had nonvisceral stage IV. Only 4 were stage IIIb or IIIc. Seventy-seven percent of patients were postmenopausal (lapatinib plus capecitabine, 81; capecitabine, 72). Forty-seven percent were estrogen receptor or progesterone receptor positive and 48 had received prior hormonal therapy. Ninety-five percent were ErbB-2 IHC 3 or IHC 2 with FISH confirmation. Approximately 95 of patients had prior treatment with a taxane, an anthracycline, and trastuzumab. Forty-six percent had received prior vinorelbine and 14 had received gemcitabine. Ninety-nine percent of patients had at least one measurable lesion. The mean duration of treatment was approximately 20 weeks for patients in the lapatinib plus capecitabine arm and approximately 15 weeks for patients receiving capecitabine alone. The daily dose of capecitabine was 20 higher in the control arm than in the lapatinib combination arm. As noted above, the study enrollment was discontinued early based on an independent data monitoring committee recommendation. Patient disposition and TTP results based on the two data cutoff dates are summarized in Table 1. TTP data were more mature at the clinical cutoff date of April 3, 2006, with 247 events identified by the investigators and 184 events identified by the independent review committee (planned final TTP analysis was at 266 events). TTP analyses by both the independent and investigator assessments at both cutoff dates were statistically significant. However, the longer median TTP was variable in the lapatinib and capecitabine combination arm and depended on whether the assessment was performed by the investigator or by the independent review panel, or whether the earlier or later data cutoff date was used. The median TTP of the control arm was consistent regardless of the cutoff and whether the assessment was by the independent review panel or the investigator. At the more mature April 3 update, an 8.5-week longer median TTP was observed in the lapatinib combination arm compared with the capecitabine alone arm. It is noteworthy that the number of TTP events identified by the independent assessment was substantially less than the number of events identified by investigators (Table 1). This was because the independent TTP assessment was based only on objective tumor assessments (not all assessments were available) and cancer deaths, whereas the investigator TTP assessment also included symptomatic progression. Additional reasons for differences between the independent review committee and investigator assessments also included the interpretation of data and/or different lesions/ organ selected. The objective response rate (complete responses plus partial responses) by independent review was 23.7 (95 confidence interval [CI], ) for the lapatinib combination arm and 13.9 (95 CI, ) for capecitabine alone. There was one complete response in the lapatinib combination arm and none in the capecitabine alone arm. The median response duration was 31.2 weeks in

4 Ryan, Ibrahim, Cohen et al Table 2. Adverse reactions occurring in 10 of patients Lapatinib (1,250 mg/day) capecitabine (2,000 mg/m 2 /day) Capecitabine (2,500 mg/m 2 /day) (n 198) (n 191) Adverse reactions Gastrointestinal disorders Diarrhea Nausea Vomiting Stomatitis Abdominal pain Dyspepsia Constipation Skin and s.c. tissue disorders Palmar plantar erythrodysesthesia Rash b Dry skin General disorders and administrative site conditions Fatigue Mucosal inflammation Asthenia Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Pain in extremity Back pain Respiratory, thoracic, and mediastinal disorders Dyspnea Nervous system disorder Headache Psychiatric disorders Insomnia a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 3 dermatitis acneiform was reported in 1 of patients in the lapatinib plus capecitabine group. the lapatinib plus capecitabine arm and 30.6 weeks in the capecitabine alone arm. At the April 3, 2006 cutoff date, only 30 of the patients had died (55 patients, 28, in the lapatinib plus capecitabine group and 64 patients, 32, in the capecitabine group). Survival data are not mature enough to conduct a formal comparative analysis at this time. Clinical treatment emergent adverse reactions (regardless of relationship to study drug) are summarized in Table 2 and laboratory adverse reactions are summarized in Table 3. Although the toxicities observed in the lapatinib combination arm were similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination therapy. The most common adverse reactions ( 15) during therapy with lapatinib plus capecitabine were gastrointestinal (diarrhea, 65; nausea, 44; vomiting, 26) or dermatologic, such as palmar plantar erythrodysesthesia (PPE, 53) and rash (28). Fatigue was noted in 23 of patients and stomatitis occurred in 14 of patients. The most common grade 3 or 4 adverse reactions for the lapatinib and capecitabine combination were diarrhea (14) and PPE (12). Fourteen percent of

5 1118 Lapatinib and Capecitabine for HER-2 Overexpressing Metastatic Breast Cancer Table 3. Laboratory adverse reactions Adverse reactions Lapatinib capecitabine patients discontinued therapy because of any adverse event and 5 discontinued because of diarrhea. The important laboratory adverse reactions were anemia (56), neutropenia (22), thrombocytopenia (18), and abnormalities of transaminases (aspartate aminotransferase, 49; alanine aminotransferase, 37) and bilirubin (45), similar to those observed in the control arm. A 2 incidence of generally reversible decreased left ventricular function in the combination arm was noted. Although QT prolongation has been observed with lapatinib use, torsade de pointes has not been reported. DISCUSSION This phase III, randomized trial comparing lapatinib in combination with capecitabine with capecitabine alone provides support for the use of the lapatinib combination in the treatment of HER-2 overexpressing metastatic breast cancer by demonstrating a TTP advantage supported by an objective response rate improvement. TTP, the primary efficacy endpoint, included both disease progression and death resulting from breast cancer as assessed by an independent review committee. Advantages of TTP as an endpoint include earlier reporting of results, no confounding effect of treatment subsequent to progression, and a smaller sample size required to show a longer TTP than to show longer survival. However, TTP is a softer endpoint that depends on the time of tumor evaluation and does not necessarily represent the natural time when progression occurs. Irregularities in the frequency or interval of clinical and radiological assessments to document progression and missing data can introduce bias. Another disadvantage in using TTP is that a large number of scans can markedly increase the cost of the study. In this study, TTP was evaluated by a blinded independent review committee. The advantage of blinded review is Capecitabine Hematologic Hemoglobin Platelets Neutrophils Hepatic Total bilirubin Aspartate aminotransferase Alanine aminotransferase a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. that it can potentially decrease bias in an open-label study design. However, it is dependent on investigator data collection. Thus, when an investigator believes that a patient s disease has progressed, further diagnostic evaluation may not be performed. In this situation, if the independent reviewer does not concur with the investigator s assessment of progression, then the independent reviewer can choose to censor the patient (no event) on the date of the last complete diagnostic evaluation, because further tumor assessments may not be available. This may lead to an overestimation of the treatment effect for both arms, assuming the errors are evenly distributed. If there is a large amount of missing or censored data, especially compared with the investigator reported assessment, then this may lead to an erroneous result. In this study, although the protocol-specified duration between two tumor assessments was at most 6 weeks, the time from the last tumor evaluation to the data cutoff date was 100 days in 31 of evaluable patients (see Table 1 footnote) in the independent assessment compared with 13 of patients in the investigator assessment. This suggests that either the independent reviewer did not concur with the investigator assessment or that not all scans were available to the independent reviewer at the time of the data cutoff date. Early termination of a study can introduce some major problems. A smaller sample size and crossover of patients from the capecitabine alone arm to the lapatinib combination arm may reduce the chance of detecting a survival difference. However, a follow-up survival analysis is planned when 75 of events have occurred and is projected to be completed in Because of the early termination and differences in the investigator and independent assessments of progression, an accurate determination of the magnitude of the TTP difference cannot be made. Although statistically significant differences between the treatment arms were observed consistently, the initially longer TTP was

6 Ryan, Ibrahim, Cohen et al lower when analyzed approximately 4 months later (the difference in the median TTP decreased from 17.6 weeks to 8.5 weeks, Table 1). Based on the result of this study, regular approval was granted on March 13, The approved indication is for lapatinib to be used in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER-2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. ACKNOWLEDGMENTS The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration. AUTHOR CONTRIBUTIONS Conception/design: Qin Ryan, Amna Ibrahim, Martin H. Cohen, John Johnson, Chia-wen Ko, Rajeshwari Sridhara Data analysis and interpretation: Qin Ryan, Amna Ibrahim, Chia-wen Ko, Rajeshwari Sridhara Manuscript writing: Qin Ryan, Amna Ibrahim, Martin H. Cohen, John Johnson, Chia-wen Ko, Rajeshwari Sridhara, Robert Justice Final approval of manuscript: Robert Justice, Richard Pazdur REFERENCES 1 Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344: Marty M, Cognetti F, Maraninchi D et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 2005;23: Montemurro F, Donadio M, Clavarezza M et al. Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumabbased therapy. The Oncologist 2006;11: Konecny GE, Pegram MD, Venkatesan N et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 2006;66: Spector NL, Xia W, Burris H 3rd et al. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol 2005;23: Mandelblat J, Bashir T, Budman DR. Capecitabine-docetaxel combination treatment. Expert Rev Anticancer Ther 2006;6: Budman DR. New directions with capecitabine combinations in advanced breast cancer. Oncology (Williston Park) 2002;16(suppl 12): Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355: