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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2786-2792 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.1764 Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer
From US Oncology Research Inc, Houston, TX; Departments of Oncology and Medicine, McGill University, Montreal, Quebec, Canada; Rush-Presbyterian-St Luke's Medical Center, Chicago; Loyola University Medical Center, Maywood, IL; and the University of California, Los Angeles, School of Medicine,Los Angeles, CA Address reprint requests to Nicholas Robert, MD, 8503 Arlington Blvd, Suite 400, Fairfax, VA 22031; e-mail: nicholas.robert{at}usoncology.com
PURPOSE: This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2–overexpressing metastatic breast cancer (MBC). PATIENTS AND METHODS: HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2–overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone. RESULTS: Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01). CONCLUSION: The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2–overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.
HER2 gene amplification and protein overexpression occurs in approximately 25% of breast cancer patients, resulting in a clinically aggressive tumor type that is associated with shortened disease-free and overall survival (OS).1-9 The monoclonal antibody trastuzumab, which is directed against an epitope on the external domain of the HER-2 protein, has clinical activity in women with HER-2–overexpressing metastatic breast cancer (MBC) when used as a single agent and, of particular interest, when used in combination with chemotherapy.10-12 Given the findings of earlier studies,11-13 the combination of trastuzumab and paclitaxel was adopted for clinical use. Investigations to improve further the clinical benefit of the combination focused on the addition of nonanthracycline agents. Much interest centered on the platinum agents based on in vitro data that indicated highly synergistic activity between trastuzumab and cisplatin or carboplatin as well as the combination of paclitaxel and carboplatin.14-18 Pietras et al19 conducted a series of elegant in vitro studies using recombinant humanized anti-HER2 monoclonal antibody (rhuMAb HER-2), the basis of trastuzumab, revealing that the combination of the antibody with either cisplatin or doxorubicin resulted in significantly greater growth inhibition. The combination with cisplatin produced the greatest cytotoxic response. Complete tumor remission was achieved after two to three cycles of therapy. Enhanced tumor killing occurred only if the antibody and cisplatin were given in close temporal proximity, confirming that the rhuMAb HER-2 antibody blocked the repair of cisplatin-damaged DNA.19 The combination of a platinum agent with trastuzumab in HER-2–overexpressing MBC has been shown to be clinically active and without unexpected toxicities. A 24% objective response rate (ORR) for this combination was reported in a phase II trial in women with chemotherapy-refractory HER-2–overexpressing MBC.20 This response rate was higher than previously reported for cisplatin alone in this group of patients, and was suggestive of clinical synergism. Of importance, toxicities were consistent with those expected for cisplatin alone. Given these data, the addition of a platinum agent to the combination of paclitaxel and trastuzumab seemed rational. Although the combination of paclitaxel and carboplatin is often used for the treatment of a number of solid tumors, traditionally it has not been used for the treatment of breast cancer. Nonetheless, data from phase II studies have shown paclitaxel/carboplatin regimens are highly active in the metastatic setting, producing ORR of 55% to 62% administered every 3 weeks and 62% when administered as weekly therapy.21-23 This randomized, multicenter, phase III trial evaluated the clinical benefit and safety of the addition of carboplatin to trastuzumab and paclitaxel (TPC) versus trastuzumab and paclitaxel (TP) as first-line therapy for women with HER-2–overexpressing MBC. The primary study end point was ORR, with progression-free survival (PFS) and OS evaluated as secondary end points. The study was conducted by US Oncology in conjunction with the University of California, Los Angeles (Los Angeles, CA) and McGill University (Montreal, Quebec, Canada).
Eligibility Criteria Women with pathologically confirmed, uni- or bidimensionally measurable, HER-2–positive MBC were eligible. Patients were required to be  18 years of age, have an Eastern Cooperative Oncology Group performance status of 0 to 2, and provide written informed consent. Women of childbearing potential had to have a negative pregnancy test before entry and practice appropriate contraception while on study. Cancer tissue specimens were evaluated for HER-2 overexpression initially by immunohistochemistry (IHC; HercepTest; Dako Corp, Carpinteria, CA) performed centrally, with an IHC staining score of 2+ or 3+ required for enrollment. An amendment (after 60 patients enrolled) permitted initial HER-2 assessment to be performed locally using either the HercepTest or fluorescent in situ hybridization (FISH; PathVysion assay kit; Vysis Inc, Downers Grove, IL). Patients with samples scoring 3+ by IHC or positive by FISH were eligible, whereas those with a 2+ IHC score also had to have a positive result by FISH. For 2+ patients only, specimens were forwarded to the central reference laboratory for FISH evaluation.
Patients could not have received prior chemotherapy for MBC, although prior adjuvant or neoadjuvant chemotherapy was permitted provided a taxane had not been used and the patient’s cumulative doxorubicin exposure was
A pretreatment evaluation performed
Treatment Chemotherapy dose reductions were allowed in the event of serious hematologic, neurologic, or GI toxicity and were defined by the protocol. Hematopoietic growth factors were to be used only when clinically indicated and not prophylactically.
Evaluation of Response and Toxicity
Responses were assessed using standardized criteria.24 Complete response (CR) required the disappearance of all known disease for
Study Design and End Points All patients receiving at least two cycles of therapy and with at least one follow-up tumor assessment were assessable for response. Patients who discontinued before two cycles because of toxicity were assessable as those who had experienced treatment failure, whereas those who experienced progression before completing two cycles of treatment were classified as having progressive disease. Duration of response was defined as the interval of time between the date of onset of CR or PR and the date of progression or the date of last follow-up. PFS was defined as the interval between the date of first dose and the date of progression or death as a result of any cause. Patients without progression who received subsequent therapy were censored at the start date of the new treatment. Patients alive and without evidence of disease progression and not receiving new therapy were censored at the last date of contact. Survival was defined as the interval between the date of first dose and the date of death. The analysis was run on the intent-to-treat population, which included all registered patients. The efficacy analysis included only eligible patients, responses were calculated for all assessable patients, and all patients who received at least one dose of study drug were included in the analysis of toxicity. Kaplan-Meier methods were used to assess OS and PFS; log-rank tests were used to compare the differences between the treatment arms. The study protocol and informed consent were reviewed and approved by the appropriate institutional review boards.
Between November 1998 and May 2002, 196 women were enrolled across 83 study sites in the United States and Canada. Of these, 98 patients (66 IHC 3+, 32 IHC 2+) were randomly assigned to TPC and 98 patients (64 IHC 3+, 33 IHC 2+, one unknown [patient was ineligible and the data were not collected]) were randomly assigned to TP. Baseline patient characteristics were well balanced between study arms (Table 1) with no statistical differences noted. Patients were observed through March 2003.
Patients completed a median of six cycles of therapy on both the TPC and TP arms, with 72% of patients completing six cycles of TPC and 65% of patients completing six cycles of TP. There were no differences in median delivered doses of paclitaxel or trastuzumab between study arms. Dose modifications secondary to toxicities, primarily neutropenia, fatigue, and pain occurred in 48 patients (51%) receiving the TPC regimen and 31 patients (32%) receiving the TP regimen (P = .02).
Response
Improved response rates were most evident in the cohort of IHC 3+ patients, with an ORR of 57% with TPC (95% CI, 45% to 70%) versus 36% for TP (95% CI, 25% to 48%; P = .03). The ORRs in IHC 2+ patients (42% with TPC [95% CI, 25% to 59%] and 35% with TP [95% CI, 19% to 52%]) were not statistically different in this relatively small cohort. Median duration of response for all patients was 13.0 months (range, 1.6 to 46.3 months) in the TPC arm compared with 11 months (range, 1.4 to 47.1 months) in the TP arm. Median PFS was significantly longer in patients receiving TPC compared with TP: 10.7 (range, < 1 to 50.4 months) v 7.1 months (range, < 1 to 55.3 months; P = .03), respectively (HR = 0.66; 95% CI, 0.59 to 0.73; Fig 1). Median PFS was also significantly longer in IHC 3+ patients receiving TPC compared with TP: 13.8 (range, < 1 to 50.4 months) v 7.6 months (range, < 1 to 55.3 months; P = .005), respectively (HR = 0.55; 95% CI, 0.48 to 0.62; Fig 2).
For TPC, the clinical benefit rate (CBR; CR + PR + stable disease 6 months) was 55%; for TP, the CBR was 40% (P = .06). For IHC3+ TPC patients, the CBR was 61%, whereas in TP patients, it was 40% (P = .03). At last follow-up, half of the patients in each arm had died, primarily from disease progression. There were no significant differences in cause or number of deaths between study arms. The 4-year OS rates were 38% with TPC versus 31% with TP. There was a trend toward improved survival with TPC; the median OS time was 35.7 (range, < 1 to 56.8 months) v 32.2 months (range, < 1 to 55.3 months) with TP (HR = 0.9; 95% CI, 0.88 to 0.92), but this difference was not statistically significant (Fig 3). In IHC 3+ patients, there was a greater difference in median survival times: 41.5 months (range, < 1 to 51.8 months) with TPC and 30.6 months (range, < 1 to 55.3 months) with TP (HR = 0.74; 95% CI, 0.46 to 0.64), but again the difference was not significant (Fig 4). The estimated 4-year survival rates in this cohort were 39% v 29%, respectively.
At the time this trial was designed and initiated, IHC was the only approved assay method to evaluate HER-2 status in routine clinical specimens to select patients for trastuzumab therapy. During the course of the study, evaluation of HER2 gene amplification by FISH was also approved, leading to inclusion of this method for determination of initial patient eligibility. An attempt was made to evaluate retrospectively all specimens using FISH and compare these findings with clinical outcomes; however, FISH results were only available for approximately 70% of the patients. Although we noted trends toward improved clinical response and PFS with TPC compared with TP, in the subset of FISH-positive patients, the incomplete data set and the retrospective nature of the evaluation prevent any more conclusive statement.
Toxicity
In this phase III randomized trial, the addition of carboplatin to paclitaxel and trastuzumab resulted in significant improvements in response and PFS in women with HER-2–overexpressing MBC. The beneficial combination of rhuMAb HER-2 antibody with platinum compounds (ie, cisplatin) has been disclosed previously.19 The current TP regimen was the same as that used in the pivotal clinical trial evaluating the benefit of adding trastuzumab to chemotherapy. As reported by Slamon et al,11 the ORR with trastuzumab and paclitaxel was 41% v 17% for paclitaxel alone, with median times to disease progression of 6.9 and 3 months, respectively. In our study, the clinical outcomes in the TP arm (ORR, 36%; median PFS, 7.1 months) were quite comparable to those of Slamon et al. The addition of carboplatin further improved clinical benefit, producing an ORR of 52% and median PFS of 10.7 months. A limitation of this trial is that it is underpowered for analysis of survival. Improved outcomes were most apparent in patients with IHC 3+ overexpression, with significant improvements in both ORR and PFS with TPC compared with TP. IHC 3+ patients are FISH positive more often than 2+ patients. Lower responses and reduced PFS were seen in the 2+ patients, as expected. This study was not powered to run this subset analysis. Retrospective evaluation of clinical benefit according to FISH status was limited by specimen availability. Although there were trends suggesting improved benefit with the TPC compared with TP in FISH-positive patients, data limitations do not permit firm conclusions. Data from the pivotal trials of trastuzumab have suggested that clinical benefit is seen predominantly in patients with HER-2 3+ overexpression, and this study is in accordance.10-12 More recently, studies have suggested that HER2 gene amplification status is a better indicator of potential benefit from trastuzumab therapy.25,26 It is also possible to speculate that synergistic activity between trastuzumab and platinum may be more pronounced in HER-2 3+ patient subset. Therapy was well tolerated in both study arms. There was an increased incidence of grade 4 neutropenia and grade 3 thrombocytopenia with the TPC regimen, although this was consistent with what would be expected with the addition of carboplatin. The hematologic toxicities seen were generally uncomplicated, and nonhematologic toxicities were most commonly mild to moderate in severity. The use of trastuzumab in combination with a taxane and a platinum agent for the treatment of HER-2–positive MBC currently is of great interest, evidenced by a number of current investigations. The North Central Cancer Treatment Group has recently reported preliminary results of a randomized phase II study comparing administration of trastuzumab, paclitaxel, and carboplatin weekly versus every 3 weeks in women with HER-2–positive MBC.27 The ORR produced by the weekly regimen was 81% (TTP, 13.8 months; OS, 3.2 years) compared with 65% (TTP, 9.9 months; OS, 2.3 years) with the therapy administered every 3 weeks. The combination of trastuzumab with docetaxel and either cisplatin or carboplatin, in women with MBC that overexpresses HER-2, has been evaluated in two phase II studies conducted by The University of California at Los Angeles-Oncology Research Network and the Breast Cancer International Research Group.28 Data from these studies indicated that both platinum analogs are active; the cisplatin combination produced a 79% ORR (77% in FISH-positive disease) and the carboplatin-containing regimen produced an ORR of 58% (63% in FISH-positive disease). These studies provided foundation for the initiation of Breast Cancer International Research Group study 007, a large randomized trial comparing trastuzumab and docetaxel versus trastuzumab, docetaxel, and carboplatin in women with HER-2–positive MBC. The results of our study indicate that the addition of carboplatin to trastuzumab and paclitaxel significantly improves response and median PFS in HER-2–positive MBC. These results will help define the optimal use of trastuzumab with taxanes and platinum agents in the treatment of women with HER-2–positive MBC.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank Kristi Boehm, Christine Gutheil, and Clinical Insights Inc for their editorial assistance, and DakoCytomation for providing the HercepTest and financial support of the central laboratory analysis at IMPATH (now Genzyme Oncology).
Supported by grants from Bristol-Myers Squibb Co, Princeton, NJ, and Genentech Inc, South San Francisco, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. 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 235:177-182, 1987 2. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 3. Owens MA, Horten BC, DaSilva MM: Correlation of HER-2/neu immunohistochemistry with fluorescence in situ hybridization in 3568 breast cancers. Breast Cancer Res Treat 76:S68, 2002 (abstr 236) 4. Press MF, Sauter G, Bernstein L, et al: Comparison of HER-2/neu status determined by fluorescence in situ hybridization (FISH) in the BCIRG central laboratories with HER-2/neu status determined by immunohistochemistry or FISH in outside laboratories. Breast Cancer Res Treat 76:S69, 2002 (abstr 238) 5. Kallioniemi OP, Holli K, Visakorpi T, et al: Association of c-erbB-2 protein over-expression with a high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 49:650-655, 1991[Medline] 6. Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance of c-erbB-2 expression in breast cancer. J Clin Oncol 10:1049-1056, 1992[Abstract] 7. Andrulis IL, Bull SB, Blackstein ME, et al: Neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. J Clin Oncol 16:1340-1349, 1998 8. Press MF, Pike MC, Chazin VR, et al: Her-2/neu expression in node-negative breast cancer: Direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res 53:4960-4970, 1993 9. Press MF, Bernstein L, Thomas PA, et al: HER-2/neu amplification characterized by fluorescence in situ hybridization: Poor prognosis in node-negative breast carcinomas. J Clin Oncol 15:2894-2904, 1997[Abstract] 10. 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 17:2639-2648, 1999 11. 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 344:783-792, 2001 12. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab (Herceptin) as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002 13. Seidman A, Hudis C, Pierri K, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221, 2002 14. Pegram MD, Finn RS, Arzoo K, et al: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537-547, 1997[CrossRef][Medline] 15. Pegram M, Hsu S, Lewis G, et al: Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18:2241-2251, 1999[CrossRef][Medline] 16. Pegram MD, Lopez A, Konecny G, et al: Trastuzumab and chemotherapeutics: Drug interactions and synergies. Semin Oncol 27:21-25, 2000 (suppl 11)[Medline] 17. Slamon D, Pegram M: Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28:13-19, 2001 (suppl 3)[Medline] 18. Konecny G, Pegram MD, Beryt M, et al: Therapeutic advantage of chemotherapy drugs in combination with herceptin against human breast cancer cell with HER-2/neu overexpression. Breast Cancer Res Treat 57:114, 1999 (abstr 467) 19. Pietras RJ, Pegram MD, Finn RS, et al: Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17:2235-2249, 1998[CrossRef][Medline] 20. Pegram MD, Lipton A, Hayes DF, et al: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185 HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659-2671, 1998[Abstract] 21. Perez EA, Hillman DW, Stella PJ, et al: A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer 88:124-131, 2000[CrossRef][Medline] 22. Fountzilas G, Dimopoulos AM, Papadimitriou C, et al: First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): A phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 9:1031-1034, 1998 23. Loesch D, Robert N, Asmar L, et al: Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol 20:3857-3864, 2002 24. Hayward JL, Ruens RD, Carbone PP, et al: Assessment of response to therapy in advanced breast cancer: A project of the programme on clinical oncology of the International Union against Cancer, Geneva, Switzerland. Eur J Cancer 14:1291-1292, 1978[Medline] 25. Mass RD, Press M, Anderson S, et al: Improved survival benefit from herceptin (trastuzumab) in patients selected by fluorescence in situ hybridization (FISH). Proc Am Soc Clin Oncol 20:22a, 2001 (abstr 85) 26. Vogel CL, Cobleigh M, Tripathy D, et al: Superior outcomes with herceptin (trastuzumab) in fluorescence in situ hybridization (FISH)-selected patients. Proc Am Soc Clin Oncol 20:22a, 2001 (abstr 86) 27. Perez EA, Suman VJ, Rowland KM, et al: Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every 3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 6:425-432, 2005[Medline] 28. Pegram MD, Pienkowski T, Northfelt DW, et al: Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-postive advanced breast cancer. J Natl Cancer Inst 96:759-769, 2004 Submitted September 12, 2005; accepted March 16, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
360 mg/m2. Concurrent immunotherapy or hormonal therapy was not allowed. Patients with brain metastasis not responding to treatment were excluded. At least 4 weeks must have elapsed between last surgery or radiation therapy with full recovery, and indicator lesions had to be outside prior radiation fields. Patients with a history of congestive heart failure, prior malignancy within the last 5 years that might affect breast cancer diagnosis or assessment, or any other medical or psychiatric condition that could compromise study participation were excluded. 
