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© 2003 American Society for Clinical Oncology Trastuzumab and Vinorelbine as First-Line Therapy for HER2-Overexpressing Metastatic Breast Cancer: Multicenter Phase II Trial With Clinical Outcomes, Analysis of Serum Tumor Markers as Predictive Factors, and Cardiac Surveillance Algorithm
From the Dana-Farber Cancer Institute, Brigham & Women’s Hospital, Harvard Medical School; Massachusetts General Hospital, Boston, MA; Duke University Medical Center, Durham, NC; South Carolina Oncology Associates, West Columbia, SC; Evanston Hospital, Evanston, IL; University Hospitals of Cleveland, Cleveland, OH; New Hampshire Oncology-Hematology, PA, Hooksett, NH; Capital District Hematology/Oncology, Latham, NY; Miriam and Rhode Island Hospitals, Providence, RI; Cancer Research Network, Plantation, FL. Address reprint requests to Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; email: hburstein{at}partners.org.
Purpose: Trastuzumab-based therapy improves survival for women with human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. We conducted a multicenter phase II study to evaluate the efficacy and safety of trastuzumab combined with vinorelbine, and to assess cardiac surveillance algorithms and tumor markers as prognostic tools.
Patients and Methods: Patients with HER2-positive (immunohistochemistry [IHC] 3+-positive or fluorescence in situ hybridization [FISH]-positive) metastatic breast cancer received first-line chemotherapy with trastuzumab and vinorelbine to determine response rate. Eligibility criteria were measurable disease and baseline ejection fraction Results: Fifty-four women from 17 participating centers were entered onto the study. The overall response rate was 68% (95% confidence interval, 54% to 80%). Response rates were not affected by method of HER2 status determination (FISH v IHC) or by prior adjuvant chemotherapy. Median time to treatment failure was 5.6 months; 38% of patients were progression free after 1 year. Concurrent therapy was quite feasible with maintained dose-intensity. Patients received both chemotherapy and trastuzumab on 90% of scheduled treatment dates. Two patients experienced cardiotoxicity in excess of grade 1; one patient experienced symptomatic heart failure. A surveillance algorithm of screening left ventricular ejection fraction (LVEF) at 16 weeks successfully identified women at risk for experiencing cardiotoxicity. Other acute and chronic side effects were tolerable. Lack of decline in HER2 ECD during cycle 1 predicted tumor progression. Conclusion: Trastuzumab and vinorelbine constitute effective and well-tolerated first-line treatment for HER2-positive metastatic breast cancer. Patients with normal LVEF can be observed with surveillance of LVEF at 16 weeks to identify those at risk for cardiotoxicity.
THERAPY FOR metastatic breast cancer is guided by biologic features of the tumor. Women with hormone-receptor–positive tumors are candidates for endocrine therapies, and women with human epidermal growth factor receptor 2 (HER2)–overexpressing tumors are candidates for trastuzumab, a humanized monoclonal antibody directed against the 185-kd HER2 protein.1 Compared with chemotherapy alone, chemotherapy with trastuzumab improves clinical outcomes, including response rate, time to progression, and overall survival for women with HER2-positive, metastatic breast cancer.2 However, trastuzumab therapy can be associated with cardiotoxicity. Subsequent retrospective analyses have indicated that concurrent exposure to anthracyclines and advanced age are predictors of trastuzumab-related cardiac dysfunction.3 Because of the improvement in survival, trastuzumab-based therapy has become a standard of care for women with HER2-positive advanced breast cancer. However, neither the optimal trastuzumab-based regimen nor the optimal duration of therapy with trastuzumab has been characterized. Preclinical data have indicated favorable interactions between trastuzumab and a variety of chemotherapeutic agents.4 Certain alkylators, taxanes, and combinations of taxanes and platinum salts, as well as vinorelbine, have reproducibly exhibited synergistic interactions with trastuzumab in laboratory analyses of growth of HER2-overexpressing breast tumor cell lines. For that reason, and because vinorelbine therapy is not associated with cardiotoxicity, alopecia, or significant gastrointestinal side effects, an initial phase II study of trastuzumab and vinorelbine was performed.5 In that single-center study, combination therapy with trastuzumab and vinorelbine yielded objective response in 75% of patients, including robust response rates in women with previous anthracycline and taxane treatment. This compared favorably to historic response rates with vinorelbine therapy, which have averaged between 16% and 40% for similar patients,6 and to monotherapy with trastuzumab, which has yielded response rates of 15% to 30%.7 There was no clinically apparent cardiotoxicity; two patients had asymptomatic declines in ejection fraction. Treatment with the combination regimen was delivered more than 93% of the time—an important consideration when trying to capture synergistic interactions between two agents. The initial study of trastuzumab and vinorelbine was a relatively small, single-institution trial; it included patients with extensive prior therapy, as well as patients with tumors that were HER2 2+-positive and 3+-positive as determined by immunohistochemistry (IHC). Because of evolving changes in treatment, we sought to characterize the clinical value of such a regimen as first-line treatment, particularly among women with tumors that were strongly HER2-positive (ie, either 3+-positive by IHC or having evidence of gene amplification when measured by fluorescence in situ hybridization [FISH]); retrospective analyses have indicated that such patients are most likely to benefit from trastuzumab-based treatment.8 We sought to extend the safety and efficacy experience in a multicenter trial to more accurately gauge the value of the regimen and to assess a practical algorithm for cardiac function surveillance in women receiving trastuzumab-based therapy. In addition, we wanted to evaluate the utility of serologic testing for HER2 extracellular domain (HER2 ECD) in the serum of patients receiving trastuzumab-based therapy. HER2 ECD is a prognostic factor that has been extensively evaluated among patients with advanced breast cancer but not in patients receiving trastuzumab.9 A multicenter, phase II study of trastuzumab and vinorelbine was developed to examine these clinical questions.
Eligibility Eligible patients had stage IV breast cancer, with measurable disease according to the Response Evaluation Criteria in Solid Tumors Group criteria, and no active CNS metastases. Patients with asymptomatic brain metastases were eligible if they had finished local therapy more than 3 months before enrollment. Patients were required to be 18 years of age or older, with Eastern Cooperative Oncology Group performance status 0 to 2 and life expectancy greater than 3 months. Patients could not have received prior chemotherapy for metastatic breast cancer or prior vinorelbine. Prior adjuvant treatment with trastuzumab was permitted for patients who were 1 year from the conclusion of that therapy. Adjuvant chemotherapy was permitted, provided that the cumulative doxorubicin dosage did not exceed 360 mg/m2 and that patients were at least 3 weeks from the conclusion of treatments. Prior hormone therapy for early-stage or metastatic breast cancer was permitted. Patients had to have concluded prior radiation therapy at least 14 days before enrollment. Any previous hormonal or other biologic therapy was discontinued at the time of study entry.
Eligibility criteria were absolute neutrophil count more than 1,500/µL, platelet count more than 100,000/µL, bilirubin less than 2 mg/dL, AST Patients were required to have tumors with documented overexpression of HER2, either 3+-positive by IHC or with gene amplification by FISH, according to routine pathology and laboratory methods at each participating center. All patients provided written informed consent before entering onto the study. The protocol was reviewed and approved by the institutional review boards at all participating centers. The study was conducted in accordance with guidelines established by the United States Department of Health and Human Services. Patients were entered onto the study between October 2000 and October 2001.
Treatment Plan
Vinorelbine was given weekly on the same days as trastuzumab, after trastuzumab administration. The dose of vinorelbine was 25 mg/m2, administered through a free-flowing IV line as a 6- to 10-minute IV infusion, followed by 125 mL of saline solution. Patients were assessed with weekly complete blood count with differential, and liver function tests every 4 weeks. The protocol called for the vinorelbine dose to be adjusted each week on the day of therapy, on the basis of hematologic toxicity, as shown in Table 1
Patients had LVEF measured at baseline and at week 16 on study (ie, after two cycles of therapy). Patients experiencing absolute declines in LVEF of greater than 20% had cardiac surveillance with LVF determination every 8 weeks. Patients were taken off study if they experienced grade 3 cardiac toxicity (symptomatic congestive heart failure) or if they developed LVEF less than 40%. Those patients with no cardiac symptoms, LVEF  40% at week 16, and no LVEF decline of more than 20% were not required to have ongoing surveillance. Investigators could re-evaluate LVEF as clinical circumstances warranted.
HER2 ECD
Study Analysis
The primary end point of this study was overall response (CR% plus PR%) on the basis of all eligible patients who received at least one dose of protocol therapy. The accrual goal was 52 eligible patients; a total of 55 patients were entered onto the study, to ensure that 52 patients would be eligible. The study design was based on the assumption that if at least 27 of these patients (52%) were to have a response, the combination of trastuzumab and vinorelbine would be deemed useful for additional development in phase III trials; if 26 or fewer ( All patients who met inclusion criteria and exclusion criteria and enrolled onto the study were included in the analysis, to determine response rate. Eligible patients removed from treatment because of toxicity, withdrawal of consent, or death as a result of any cause were counted in the denominator for computing the proportion of responses.
Clinical Efficacy A total of 55 patients from 17 participating centers in the United States entered onto the study. One patient was ineligible, did not receive protocol-based therapy, and was not included in the study analysis; the data analyses reflect the experience of the other 54 patients. The demographic characteristics of the study patients are shown in Table 2  . Patients had a median of three sites of tumor burden; the vast majority of patients (81%) had visceral sites (eg, lung, liver) of metastatic disease. Eighty percent of patients were eligible by virtue of HER2 status determined by IHC; 20% were eligible by virtue of by FISH. Roughly half of the patients had tumors that were estrogen receptor (ER)-positive and HER2-positive, and nearly two thirds had received adjuvant chemotherapy.
Objective response, either CR or PR, was seen in 37 of 54 patients (overall response rate 68%; 95% CI, 54% to 80%; Table 3 ). Four patients had CRs, 33 had PRs, and an additional nine patients had stable disease for 6 months or longer. Response rates were analyzed among clinical subsets of patients, defined by HER2 status, hormone-receptor status, and prior adjuvant chemotherapy treatment (Table 4). There were no statistically significant differences in response rate between patients who entered onto the study with IHC 3+-positive or FISH-positive tumors, or between hormone-receptor–positive tumors versus hormone-receptor–negative tumors, or between patients who had received adjuvant chemotherapy and those who had not.
At the time of study analysis, four patients remained on treatment, and 50 patients had come off study. Of those 50 patients, 31 had experienced tumor progression, including five who had isolated progression in the CNS. Among the remaining 19 patients withdrawn from study before overt tumor progression, seven patients withdrew after achieving optimal chemotherapy response and continued receiving trastuzumab monotherapy. An additional seven patients withdrew consent for physician or patient preference. Five patients went off study for excessive toxicity. Figure 1 shows the time to treatment failure; patients electing to go off study for personal preference or optimal tumor response are censored. Patients were on study for a median of 5.6 months (range, 0.46 to 16+ months). A substantial fraction of patients (38%) remained free of progression through 12 months of treatment.
Dosing and Toxicity Protocol therapy called for ongoing weekly trastuzumab treatment without dose modification and administration regardless of vinorelbine dosing on days of treatment. In contrast, vinorelbine dose in this study was adjusted week to week, on the basis of laboratory parameters, as shown in Table 1  . A total of 1,634 treatment weeks were recorded on study. Vinorelbine was given at full dose (25 mg/m2) in 1,226 (75%) treatment weeks, and a reduced dose (15 mg/m2) was given in 243 (14.9%) treatment weeks. Thus, in 90% of the treatment weeks, concurrent administration of chemotherapy and trastuzumab could be accomplished. Vinorelbine was omitted in 165 treatment weeks (10%) for the following reasons: neutropenia, 67 weeks (4%); patient-scheduling arrangements (eg, travel), 55 weeks (3.4%), coordination of surgical procedures (eg, installation of indwelling catheters), 10 weeks (0.6%); minor upper respiratory or cardiovascular symptoms, 7 weeks (0.4%); patient preference, 11 weeks(0.7%); other reasons, 15 weeks (0.9%).
To assess the effect of cumulative and prolonged chemotherapy treatment, we analyzed the administration of chemotherapy for each week over time. Figure 2
The incidence and severity of acute toxicity associated with combined trastuzumab-vinorelbine therapy was quite low. All treatment-related toxicities that occurred in more than 10% of patients on study are shown in Table 5 . There were two patients with febrile neutropenia; both recovered without sequelae. The nonhematologic toxicity profile shown was also quite favorable, with few grade 3 or 4 toxicity events. One patient had grade 3 cardiotoxicity (see Cardiac Surveillance and Cardiotoxicity). Three patients had thromboembolic events; two patients had upper extremity deep-vein thromboses associated with indwelling venous catheters, and one patient had a pulmonary embolism. Modest degrees of fatigue, injection-site reactions, and peripheral neuropathy were observed, which were not treatment limiting. Fewer than one third of patients had any degree of alopecia, and gastrointestinal symptoms were also mild, with less than 10% of patients having grade 2 constipation and no patients having grade 3 or 4 gastrointestinal toxicities. Side effects related to chronic chemotherapy exposure, such as fluid retention, nail changes, phlebitis, or hand-foot syndrome, were rarely encountered, if at all.
Cardiac Surveillance and Cardiotoxicity Eligible patients began the study with LVEF 50% or greater and were screened with a single reanalysis of LVEF at week 16 on study. One patient developed grade 3 cardiotoxicity during the second 8-week cycle of therapy, with symptoms of heart failure and LVEF of 41%, decreased from 62% at baseline. Her symptoms resolved with appropriate medical therapy. A second patient had asymptomatic grade 2 cardiotoxicity with LVEF that declined to 40% after 7 months on study (Table 5 ).
The median LVEF at baseline was 64% (Fig 4
Serum Testing of HER2 ECD Levels of HER2 ECD were determined at baseline and serially throughout treatment. Levels at baseline and at the end of cycle 1 were available for 43 patients. Figure 5A shows the absolute change in serum HER2 ECD levels through one cycle of trastuzumab-vinorelbine therapy. Most patients had a decline in serum levels, including patients with clinical response (either CR or PR; blue lines) or stable disease (green line) at the end of cycle 1. We performed exploratory analyses of the predictive value of HER2 ECD, and examined both baseline levels and changes with one cycle of treatment. Neither the baseline level of HER2 ECD nor a decrease in HER2 ECD with therapy predicted clinical response after one cycle of treatment. However, a lack of decline in HER2 ECD was a predictor for tumor progression after cycle 1, as shown in the ROC curve (Fig 5B).
This multicenter phase II trial of combination therapy with trastuzumab and vinorelbine as first-line treatment for HER2-positive metastatic breast cancer demonstrated high rates of clinical activity achieved with limited acute toxicity. More than two thirds of patients had objective response, and nearly 40% of patients were without disease progression at 1 year. Prior adjuvant chemotherapy did not affect response rates. Because laboratory data indicate synergy between vinorelbine and trastuzumab, it was important to assess the long-term feasibility of concurrent treatment. Patients received combined therapy in 90% of treatment weeks, and dose-intensity was well maintained through extended periods of treatment. Cardiac toxicity, a side effect of particular concern in trastuzumab treatment, was acceptably low; only one patient developed symptomatic heart failure. A cardiac-screening algorithm was used that reassessed LVEF after 16 weeks of therapy. Among patients receiving ongoing protocol-based treatment, the finding of LVEF  50% at 16 weeks appeared to identify patients at risk for grade 2 or greater cardiotoxicity. Among patients with LVEF greater than 50%, subsequent grade 2 or greater cardiotoxicity was not encountered. There was a low incidence of peripheral neuropathy, perhaps in part because patients had not previously received neurotoxic chemotherapy for advanced breast cancer. Other phase II trials have demonstrated response rates on the order of 60% to 80% for combinations of trastuzumab with taxanes,13–15 vinorelbine,5,16 or triplets of trastuzumab with taxanes and platinum salts.17 Preliminary analysis of a randomized trial of trastuzumab with paclitaxel versus trastuzumab in combination with paclitaxel and carboplatin indicates improvement in time to progression with the triplet combination.18 Other trials that have compared polychemotherapy to monotherapy for metastatic breast cancer have frequently shown improvements in progression-free survival, but not overall survival, with the use of multiagent regimens.19 Comparisons among these several trials are fraught with difficulty, owing to different definitions of HER2 overexpression and varying degrees of prior therapy. Given these limitations, the results of treatment with trastuzumab and vinorelbine are generally comparable in terms of response rate and time to progression with other reports of single-agent chemotherapy with trastuzumab. Almost 40% of patients had disease that was either responsive or stable through 1-year of treatment. A substantial fraction of patients elected to end study treatment before experiencing disease progression in favor of trastuzumab monotherapy or trastuzumab with hormonal therapy; this result is a testimony to the palliative efficacy of the regimen. However, neither the clinical benefit of ongoing trastuzumab therapy in such circumstances nor the impact of discontinuation of chemotherapy is known. The cardiac-surveillance strategy developed for this trial represents the first such prospective algorithm for women receiving trastuzumab. On the basis of this experience, we believe patients with normal baseline cardiac function can have a single re-examination of LVEF after 16 weeks of trastuzumab-vinorelbine treatment. Those patients without cardiac symptoms or without substantial declines in LVEF may be observed thereafter, without frequent cardiac surveillance. Patients who had tumors that were HER2-positive were eligible for this trial by virtue of documented gene amplification (ie, FISH-positive) or marked surface expression by IHC 3+-positive because we recognize that trastuzumab efficacy appears limited to those patients with clear HER2 overexpression.8 In our trial, equal response rates were noted among patients eligible by virtue of IHC 3+-positive (n = 44) and FISH-positive (n = 10) tests, indicating that either test as performed by participating centers is appropriate for selecting patients for trastuzumab-based therapy. The optimal testing method for selecting patients for trastuzumab-based therapy remains uncertain. Predictive markers for response to trastuzumab-based treatment—aside from tumor HER2 status—are not well characterized. Previous research has indicated that high HER2 ECD levels were associated with greater likelihood of tumor response among 30 patients receiving trastuzumab-docetaxel treatment and that changes in HER2 ECD correlated with tumor response.14 We prospectively evaluated the utility of serum HER2 ECD as a predictor of response during cycle 1 of trastuzumab-vinorelbine therapy. We did not find that baseline HER2 ECD was a predictor of response or that change in HER2 ECD predicted response. This lack of association was due principally to declines in HER2 ECD, even among patients with stable disease. This indicates that trastuzumab therapy may be associated with clearance of HER2 ECD, as measured by immunoassay. In contrast, lack of decline in HER2 ECD was a predictor for tumor progression after cycle 1 of therapy. At present, we do not believe that measurement of HER2 ECD is sufficiently reliable for determining response to trastuzumab-based therapy, although additional studies that involve larger numbers of patients for longer periods of time are warranted. The optimal trastuzumab-based chemotherapy regimen is not known. Our data support the use of trastuzumab and vinorelbine as a safe, well-tolerated, and effective first-line treatment for women with HER2-positive metastatic breast cancer. The regimen is currently being compared to taxane-based trastuzumab regimens in the metastatic setting and is under evaluation as preoperative therapy for women with HER2-positive stage II or III breast cancer.
Supported in part by research grants-in-aid from GlaxoSmithKlein and Genentech. Reagent test kits were supplied by Oncogene Science.
1. McKeage K, Perry CM. Trastuzumab. Drugs 62:209–243, 2002[CrossRef][Medline]
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3. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215–1221, 2002 4. Pegram MD, Lopez A, Konecny G, et al: Trastuzumab and chemotherapeutics: Drug interactions and synergies. Semin Oncol 27:21–25, 2000 (6 suppl 11)[Medline]
5. Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19:2722–2730, 2001 6. Domenech GH, Vogel CL: A review of vinorelbine in the treatment of breast cancer. Clin Breast Cancer 2:113–128, 2001[Medline]
7. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726, 2002 8. 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) 9. Nunes RA, Harris LN: The HER2 extracellular domain as a prognostic and predictive factor in breast cancer. Clin Breast Cancer 3:125–135, 2002[Medline] 10. Anderson TI, Paus E, Nesland JM, et al: Detection of c-erbB-2 related protein in sera from breast cancer patients: Relationship to ERBB2 gene amplification and c-erbB-2 protein overexpression in tumour. Acta Oncol 34:499–504, 1995[Medline] 11. Hanley JA, McNeil BJ: The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143:26–36, 1982
12. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216, 2000
13. Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19:2587–2595, 2001
14. Fountzila G, Tsavdaridid D, Kalogera-Fountzila A, et al: Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer: A Hellenic Cooperative Oncology Group phase II study. Ann Oncol 12:1545–1551, 2001
15. Esteva FJ, Valero V, Booser D, et al: Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20:1800–1808, 2002
16. Jahanzeb M, Mortimer J, Yunus F, et al: Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer. Oncologist 7:410–417, 2002 17. Nabholtz MJ, Pienkowski T, Nothfelt D, et al: Results of two open label multicentre phase II pilot studies with Herceptin in combination with docetaxel and platinum salts (cis or carboplatin) as therapy for advanced breast cancer in women with tumors over-expressing the HER2-neu protooncogene. Eur J Cancer 37:190, 2001 (abstr 695, suppl 6) 18. Robert N, Leyland-Jones B, Asmar L, et al: Phase III comparative study of trastuzumab and paclitaxel with and without carboplatin in patients with HER-2/neu positive advanced breast cancer. Breast Cancer Res Treat 76:S37, 2002 (abstr 35, suppl 1)[CrossRef] 19. Burstein HJ, Bunnell CA, Winer EP: New cytotoxic agents and schedules for advanced breast cancer. Semin Oncol 28:344–358, 2001[CrossRef][Medline] Submitted February 5, 2003; accepted May 15, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
