Symposium article. Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: Pivotal trial data

Transcription

1 Annals of Oncology 12 (Suppl. I): S57-S62, Kluwer Academic Publishers. Primed in the Netherlands. Symposium article Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: Pivotal trial data W. Eiermann, on behalf of the International Herceptin Study Group Frauenklimk vom Rolen Kreuz, Munich, Germany Summary A pivotal, randomized, multicenter, phase III trial was conducted to compare chemotherapy in combination with trastuzumab (Herceptin) vs. chemotherapy (anthracycline plus cyclophosphamide [AC] or paclitaxel) alone as first-line treatment for HER2-positive metastatic breast cancer. Results from a total of 469 patients, randomized to receive either chemotherapy alone or chemotherapy plus trastuzumab, revealed that the addition of trastuzumab improved time to disease progression significantly (7.6 vs. 4.6 months, P = ) compared with chemotherapy alone. The increase was higher in the trastuzumab plus paclitaxel subgroup (6.9 vs. 3.0 months, P = ) than in the trastuzumab plus AC subgroup (8.1 vs. 6.1 months, P = ). Patients receiving combination therapy also had a greater overall response rate (49% vs. 32%, P = ) and a longer median response duration (9.3 vs. 5.9 months, P ) than those who received chemotherapy alone. Most importantly, median follow-up of 29 months revealed a significantly increased median survival in patients receiving trastuzumab plus chemotherapy (25.4 vs months, P < 0.025) compared with those receiving chemotherapy alone. Trastuzumab plus chemotherapy was well tolerated; adverse events were typically mild-to-moderate chills and fever and occurred in approximately 40% of patients, primarily following the first administration only. Key words: first-line treatment, HER2, Herceptin, metastatic breast cancer, survival, trastuzumab Introduction Human epidermal growth factor receptor-2 (HER2) is a growth factor receptor protein encoded by the HER2 oncogene [1, 2]. HER2-receptor expression occurs in many normal tissues, although clear overexpression is detected in a high percentage of many tumor types [2]. HER2-receptor overexpression is almost invariably a consequence of HER2 gene amplification and results in oncogenic transformation of normal cells to form tumor cells [3-5]. HER2-positive tumors are detected in approximately 30% of metastatic breast cancer patients resulting in worse prognosis, including more aggressive disease and shortened disease-free and overall survival, compared with patients who have HER2-negative tumors [6, 7]. Accurate determination of HER2 status may be of prognostic and predictive value for the patient and physician. Indeed, a positive HER2 status has been shown to predict for reduced responses to some conventionally used anticancer agents. The development of routine assays to accurately determine patients' HER2 status is allowing physicians to determine the most appropriate therapeutic approach for patients with HER2-positive tumors. Identification of HER2 and its significance for breast cancer patients has led to the development of targeted biologic therapies. The HER2-receptor protein is now considered a valid target for therapy because it provides an extracellular target for novel and specific anti-cancer treatment. A range of experimental and investigational therapeutic strategies has been studied, including anti- HER2 monoclonal antibodies. Trastuzumab (Herceptin) is a humanized anti-her2 monoclonal antibody and early clinical trials have confirmed its value in HER2-positive patients who have relapsed following treatment for their metastatic disease [8-10]. The successful outcome of these trials prompted a series of new trials to evaluate the efficacy and safety of trastuzumab in combination with other anti-cancer agents given as first-line treatment in HER2-positive metastatic breast cancer. This paper reports on the results of a pivotal trial comparing trastuzumab plus chemotherapy vs. chemotherapy alone as first-line treatment in HER2-positive metastatic breast cancer patients. The data from this trial have been previously presented, in part, during the ASCO 1998 and 1999 meetings [11,12] and are the subject of an original article currently in preparation by Slamon et al. Study design A pivotal, ^andomized^multicente-fr-phase-jil-trialwas conductedto'compare chemotherapy in combination

2 58 / Metastatic breast cancer (MBC) / HER2 (2+ and 3+) Eligible patients (n = 469) / No prior chemotherapy for MBC ' \ Measurable disease \ KPS 60% J No prior anthracyclines (AC) Herceptin* + AC (n=143) AC fn=138; AC, doxorubicin/epirubicin + cydophosphamide Figure 1. Trial design \ Prior anthracyclines (AC) Herceptin* + paclitaxel (n=92) Paclitaxel with trastuzumab vs. chemotherapy alone as first-line therapy for HER2-positive, metastatic breast cancer [11, 12]. This open-label trial was conducted in 150 centers across 12 countries, including the USA, Canada, Australia, New Zealand, and several in Europe. A total of 469 HER2-positive metastatic breast cancer patients were enrolled in the trial between June 1995 and March Each patient had a measurable, acceptable performance status and had received no prior chemotherapy for metastatic disease. HER2 overexpression was determined by immunohistochemistry and all enrolled patients had 2+ or 3+ HER2 overexpression. Treatment Study endpoints The primary study endpoint for the trial was time to disease progression (TTP) measured as the time from Table 1. Demographics of patients enrolled in the pivotal phase III trial of trastuzumab. Age (years) Mean KPS > 80 (%) Metastatic sites > 3 (%) Liver or lung (%) HER2 3+(%) ER negative (%) > 4+ nodes (%) Median DFI (months) Prior anthracyclines (%) Prior adjuvant CT (%) Prior transplant (%) Prior hormonal (%) Prior radiotherapy (%) a P < Patients were randomized to receive either chemotherapy alone or trastuzumab plus chemotherapy (Figure 1). Those who had received no prior anthracyclines in the adjuvant setting received either anthracyclines (doxorubicin 60 mg/m 2 or epirubicin 75 rag/m 2 ) plus cyclophosphamide 600 mg/m 2 (AC) alone or AC in combination with trastuzumab. Patients received AC by i.v. bolus or infusion over a maximum of two hours. Those who had previously been given anthracyclines in the adjuvant setting received paclitaxel 175 mg/m 2 alone or in combination with trastuzumab. Paclitaxel was administered by i.v. infusion over three hours after premedication with dexamethasone, diphenhydramine and cimetidine. Chemotherapy was repeated every three weeks for six cycles, and additional cycles could be administered at the discretion of the investigator. Trastuzumab was administered in an outpatient setting as an initial 4 mg/kg dose followed by 2 mg/kg weekly i.v. until disease progression. At first, the infusion lasted 90 minutes, 24 hours prior to chemotherapy. However, if the initial dose was well tolerated, subsequent infusion periods were shortened to 30 minutes and given on the same day immediately prior to chemotherapy. Trastuzumab + AC (n = 143) ~~34 ' AC (n = 138) a Trastuzumab + paclitaxel (n = 92) a Paclitaxel (n = 96) a assignment to therapy until disease progression defined as a > 25% increase in any measurable lesion. Secondary endpoints for the study were objective response rate, response duration, time to treatment failure (TTF) and one-year survival. An independent response evaluation committee (REC) determined disease progression and response. A complete response was defined as disappearance of all radiographically and/or visually apparent tumor and a partial response as a > 50% decrease in size of all measurable lesions. In addition, patients' overall survival was recorded over a 29-month median followup period. Other assessments included physical examinations, vital signs, chest X-rays, and standard laboratory tests, which were performed at baseline, predetermined timepoints, and study discontinuation. Adverse events and health-related quality of life (QoL) were also monitored. QoL was measured at baseline and at specified intervals during treatment using the European Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ-C30 [13]. Pharmacokinetic analysis of serum trastuzumab concentrations, levels of shed extracellular domain (ECD) of the HER2-receptor protein, and measurement of any neutralizing antibodies to trastuzumab were performed at the end of the study. Results Patient characteristics Of the 469 patients enrolled, 216 of 234 (92%) received at least 80% of the planned number of trastuzumab infusions. Fewer than 5% of patients required delayed or reduced doses of chemotherapy, although five patients were not treated for the following reasons: patient request (n - 2); death (n - 1); disease progression (n = 1);

3 59 Table 2. Efficacy of trastuzuraab when given in combination with chemotherapy in metastatic breast cancer. Trastuzumab AC alone Trastuzumab Paclitaxel Herceptin + Chemotherapy + AC (n = 143) (n = 138) + paclitaxel alone (n = 96) chemotherapy alone {n = 234) («= 92) (n = 235) Median TTP (months) Response rate (%) Median duration of response (months) 9.1 Median TTF (months) One-year survival (%) (P = ) (Z 3 = ) 6.5 (P = ) (P = ) (P = ) (P < ) {P = ) (P = ) {P = ) (/> = ) (/> = ) Abbreviations: AC - anthracyclines (doxorubicin or epirubicin + cyclophosphamide); TTP - time to disease progression; TTF - time to treatment failure. and inadvertent enrolment (n - 1). The REC assessed tumor response in 99% (446 of 452) of patients who had a baseline tumor assessment, and in 95% (446 of 469) of patients who were enrolled in the study. As of the cut-off date of 31 December 1997, 83% (388 of 469) of patients had discontinued the study, including 74% (173 of 235) of those receiving trastuzumab plus chemotherapy and 92% (215 of 234) of patients receiving chemotherapy alone. Patients were evenly distributed between the trastuzumab plus chemotherapy vs. the chemotherapy alone groups. However, stratification to chemotherapy based on patients' prior anthracycline treatment resulted in differences between the AC and paclitaxel subgroups (Table 1). For example, patients who received paclitaxel had a greater number of involved lymph nodes at diagnosis and/or increased likelihood of having received high-dose chemotherapy with stem cell or marrow rescue than those receiving AC. Improvement in time to disease progression After a 14-month follow-up, addition of trastuzumab to chemotherapy was associated with 65% improvement in median TTP from 4.6 to 7.6 months (Table 2). The median study time was 43 weeks for patients receiving chemotherapy plus trastuzumab compared with 30 weeks for those receiving chemotherapy alone, reflecting the improved TTP for the combined therapy. The increase in TTP was higher in the trastuzumab plus paclitaxel subgroup than in the trastuzumab plus AC subgroup (Table 1). This finding is noteworthy because patients in the AC and paclitaxel subgroups represented two very different strata: those in the paclitaxel subgroups were more likely to have had poor prognostic factors, prior therapy and a shorter disease-free interval than patients treated with AC. Enhanced tumor responses Patients receiving trastuzumab plus chemotherapy had a greater overall response rate and a longer median response duration than those who received chemotherapy alone (Figure 2). Addition of trastuzumab to paclitaxel significantly improved the response rate from 16% to 42%, equivalent to a 163% increase (P < ), and median response duration from 4.4 to 11.0 months, equivalent to a 150% increase (P ), compared with paclitaxel alone. Similarly, addition of trastuzumab to AC improved the response rate from 43% to 52% and median duration of response from 6.5 to 9.1 months compared with AC alone. Combining trastuzumab with chemotherapy also prolonged the median TTF in the entire group and in each subgroup (Table 1). Improved median survival Trastuzumab in combination with chemotherapy significantly improved median survival from 20.3 to 25.4 months (Figure 3). This survival benefit occurred despite a significant proportion of the chemotherapy alone patients (65%) being subsequently treated with trastuzumab following disease progression. Addition of trastuzumab to chemotherapy significantly reduced mortality at one year from 33% to 22% as compared with those receiving chemotherapy alone (P ). Trastuzumab reduced the relative risk of mortality by 22.4%. In both subgroups, trastuzumab in combination with either AC or paclitaxel resulted in a clear trend towards improved survival, reflecting the survival benefit observed in the entire chemotherapy group. Intent-to-treat analysis of patients treated with trastuzumab plus AC showed a median survival of 26.8 months compared with 22.8 months in those who received AC alone (Figure 4). A similar trend was obtained in the paclitaxel subgroup: the median survival rates were 22.1 in patients receiving trastuzumab plus paclitaxel vs months in those treated with paclitaxel alone. In this case, it is

4 60 P P = P= AC group Paclitaxel group H + CT CT H + CT CT H + CT CT H, Herceptin*. CT, chemotherapy Figure 2 Time to disease progression, one-year response rate, and one-year survival following chemotherapy ± trastuzumab Time (months) Time (months) H, Herceptin*. AC, anthracycline + cyclophosphamide. P. paclitaxel Figure 4 Kaplan-Meier plot of overall survival duration in the chemotherapy subgroups receiving either AC or paclitaxel ± trastuzumab ] I 0.8- «06- 'o it" 0.4- RR = 0 76 P= months (i25%) CT patients treated with Herceptin* after disease progression H, Herceptin*. CT, chemotherapy 24% Time (months) 62% 65% Figure 3 Kaplan-Meier plot of overall survival duration in patients receiving chemotherapy ± trastuzumab. H + CT CT Median response duration H, Herceptin*. CT, chemotherapy H + CT CT Median survival Figure 5. Median response duration and survival in patients responding to chemotherapy ± trastuzumab. noteworthy that a trend towards increased survival was seen despite patient numbers in the paclitaxel subgroup being relatively small. The increased median survival seen in patients receiving trastuzumab plus chemotherapy may be due to several processes. If trastuzumab works merely by increasing the percentage of patients responding to chemotherapy, the median survival time would be expected to increase, although the survival of responders would be the same whether or not they had received trastuzumab. The more likely explanation is that trastuzumab has other effects, contributing to an increase in median survival and response duration in responding patients. Indeed, among the responding patients in this trial, both the response duration and survival time were increased following the addition of trastuzumab to chemotherapy (Figure 5). However, this observation does not allow determination of whether the effects of trastuzumab are additive or synergistic, secondary to the delay in tumor development or on the tumor regrowth rate. It is hoped that the results from several proposed adjuvant trials will help to address these points in the future. Quality of life Patients receiving trastuzumab plus chemotherapy showed maintenance of QoL endpoints compared with those receiving chemotherapy alone [13]. A comparison of QLQ-C30 scores during treatment revealed no statistically significant differences between the trastuzumab plus chemotherapy vs. the chemotherapy alone population. Analysis of response by patient characteristics The efficacy of trastuzumab was observed consistently across patient subgroups with only two exceptions. Firstly, patients with 3+ overexpression benefited from trastuzumab to a greater degree than those with 2+ overexpression. However, since 74% of the patients had 3+ overexpression in this study, the 2+ overexpression sample size is too small to draw a definitive conclusion regarding the benefits of trastuzumab in 2+ vs. 3+ patients. Secondly, the improvement in response rate and TTP following addition of trastuzumab to paclitaxel was greater if patients had a Karnofsky score of > 90% at baseline. Clinical safety The combination of trastuzumab and chemotherapy was well tolerated; trastuzumab-related adverse events were typically mild-to-moderate chills and fever and occurred in approximately 40% of patients, primarily following the administration of the first dose of trastuzumab. The main severe adverse event (defined as causing severe discomfort, severely limiting or preventing normal function, and a definite health hazard) was an increased risk of cardiac dysfunction in women receiving

5 61 trastuzumab and AC. The side-effect profile of trastuzumab, including special reference to cardiac dysfunction, is covered in the article by Gianni in this supplement [14]. Discussion and conclusion Over the past decade, HER2 overexpression has been shown to play an important role in the pathogenesis of breast cancer and is a marker of poor prognosis. Consequently, strategies directed toward HER2 overexpression or the function of the overexpressed HER2 protein have been anticipated to have therapeutic value. Extensive preclinical studies revealed that murine anti- HER2 monoclonal antibodies inhibit the growth of HER2-overexpressing tumor cells [15-19]. However, the development of neutralizing human anti-mouse antibodies was a recurring problem during the clinical use of murine antibodies. For this reason, development of monoclonal antibodies for long-term use in humans has centered on the use of humanized antibodies. Trastuzumab is a humanized anti-her2 monoclonal antibody and early clinical trials have confirmed its value in HER2-positive patients having relapsed following treatment for their metastatic disease [8-10]. The successful outcome of these trials prompted a series of new trials to evaluate the efficacy and safety of trastuzumab in combination with other anti-cancer agents given as first-line treatment in HER2-positive metastatic breast cancer. This pivotal, phase III, multinational, combination trial enrolled a total of 469 patients, who were randomized to receive either chemotherapy alone or trastuzumab plus chemotherapy. The results demonstrate that the addition of trastuzumab to chemotherapy improved median TTP significantly (7.6 vs. 4.6 months, P = ) compared with chemotherapy alone. Patients receiving combination therapy also had a significantly higher overall response rate (49% vs. 32%, P ) and a longer median response duration (9.3 vs. 5.9 months, P ). Furthermore, the addition of trastuzumab to chemotherapy prolonged the median TTF in the entire group and in each subgroup. Follow-up after 29 months revealed a significantly increased overall survival in patients receiving trastuzumab plus chemotherapy as compared with those receiving chemotherapy alone (25.4 vs months, P < 0.025). This enhanced survival rate was seen despite 65%> of the patients who were initially randomized to chemotherapy alone being subsequently treated with trastuzumab following disease progression. The combination of trastuzumab and chemotherapy was well tolerated; adverse events were typically mild-to-moderate chills and fever and occurred in approximately 40% of patients, primarily during administration of the first dose of trastuzumab. The results from this pivotal trial allow the conclusion that the addition of trastuzumab to chemotherapy as first-line treatment significantly improves the survival of HER2-positive metastatic breast cancer patients to a clinically meaningful degree. Initial use of trastuzumab as part of combination therapy resulted in a decrease in relative risk of death by approximately 25% at 29 months of follow-up. In addition to this survival benefit, trastuzumab significantly increased TTP, response rate and duration, and TTF. Of particular note is that addition of trastuzumab to paclitaxel therapy more than doubled median TTP. The survival advantage observed in patients treated with trastuzumab plus chemotherapy is exceptional, and possibly unique, in the metastatic breast cancer setting and is remarkable considering the high rate of crossover to trastuzumab following disease progression. This type of crossover design would normally bias against observing a survival advantage. The results from ongoing trials of trastuzumab in combination with a variety of agents in both the metastatic and adjuvant breast cancer settings are eagerly anticipated. Note The author has not reported any financial relationships with companies whose products are mentioned in the text. References 1. Coussens L, Yang-Feng TL, Liao Y-C et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985; 230: Hynes NE, Stern DF. The biology of erbb-2/neu/her-2 and its role in cancer. Biochim Biophys Acta Rev Cancer 1994; 1198: Di Fiore PP, Pierce JH, Fleming TP et al. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T 3 cells. Cell 1987; 51: Di Fiore PP, Pierce JH, Kraus MH et al. erbb-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 1987; 237: Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor pl85her2 causes transformation and tumorigenesis of NIH 3T 3 cells. Proc Natl Acad Sci USA 1987; 84: Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER2/ neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: Baselga J, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous recombinant humanized anti-pl85her2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996; 14: Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-her2 monoclonal antibody in,women who-have- HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17: Pegram MD, Lipton A, Hayes DF et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-pl85her2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-over-expressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16:

6 Slamon D, Leyland-Jones B, Shak S et al. Addition of Herceptin (humanized anti-her2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: A randomized multinational controlled phase III trial. Proc Am Soc Clin Oncol 1998; 17: 98a (Abstr 377). 12. Norton L, Slamon D, Leyland-Jones B et al. Overall survival (OS) advantage to Herceptin (H) in HER2-overexpressing (HER2+) metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 1999; 18: 127a (Abstr 483). 13. Osoba D, Burchmore M. Health-related quality of life in women with metastatic breast cancer treated with trastuzumab (Herceptin). Semin Oncol 1999; 26: Gianni L. Tolerability in patients receiving trastuzumab with or without chemotherapy. Ann Oncol 2001; 12 (Suppl 1): S63-S68 (this supplement). 15. Hancock MC, Langton BC, Chan Tet al. A monoclonal antibody against the c-erbb-2 protein enhances the cytotoxicity of cisdiamminedichloroplatinum against human breast and ovarian tumor cell lines. Cancer Res 1991; 51: Harwerth IM, Wels W, Schlegel J et al. Monoclonal antibodies directed to the erbb-2 receptor inhibit in vivo tumor cell growth. Br J Cancer 1993; 68: Hudziak RM, Lewis GD.Winget M et al. pl85her2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 1989; 9: McKenzie SJ, Marks PJ, Lam Tet al. Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, pl85. Oncogene 1989; 4: Stancovski I, Kurwitz E. Leitner O et al. Mechanistic aspects of the opposing effects of monoclonal antibodies to the erbb2 receptor on tumor growth. Proc Natl Acad Sci USA 1991; 88: Correspondence to: W. Eiermann, MD Frauenklinik vom Roten Kreuz Taxisstrasse Munchen Germany w.eiermann@gmx.net