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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2218-2224 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.0994 Trastuzumab, Paclitaxel, Carboplatin, and Gemcitabine in Advanced Human Epidermal Growth Factor Receptor-2/neu–Positive Urothelial Carcinoma: Results of a Multicenter Phase II National Cancer Institute Trial
From the University of Michigan, Ann Arbor; Wayne State University, Karmanos Cancer Institute, Detroit, MI; Northwestern University, Feinberg School of Medicine, Chicago, IL; Columbia Presbyterian Medical Center; New York Presbyterian Hospital, New York; Roswell Park Cancer Institute, Buffalo, NY; University of California, Davis Cancer Center, Sacramento, CA; University of Pittsburgh, Pittsburgh, PA; University of Colorado Health Science Center, Aurora, CO; and the Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD Address reprint requests to Maha Hussain, MD, FACP, University of Michigan Comprehensive Cancer Center, 7314 CCGC, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0946; e-mail: mahahuss{at}umich.edu
Purpose We investigated the safety and efficacy (response rates, time to disease progression, survival) of trastuzumab, carboplatin, gemcitabine, and paclitaxel in advanced urothelial carcinoma patients and prospectively evaluated human epidermal growth factor receptor-2 (Her-2/neu) overexpression rates. Patients and Methods Advanced urothelial carcinoma patients were screened for Her-2/neu overexpression. Eligibility for therapy required human epidermal growth factor receptor-2 (Her-2/neu) overexpression by immunohistochemistry (IHC), gene amplification and/or elevated serum Her-2/neu, no prior chemotherapy for metastasis, and adequate organ function including a normal cardiac function. Treatment consisted of trastuzumab (T) 4 mg/kg loading dose followed by 2 mg/kg on days 1, 8, and 15; paclitaxel (P) 200 mg/m2 on day 1; carboplatin (C; area under the curve, 5) on day 1; and gemcitabine (G) 800 mg/m2 on days 1 and 8. The primary end point was cardiac toxicity. Results Fifty-seven (52.3%) of 109 registered patients were Her-2/neu positive, and 48.6% were positive by IHC. Her-2/neu–positive patients had more metastatic sites and visceral metastasis than did Her-2/neu negative patients. Forty-four of 57 Her-2/neu–positive patients were treated with TPCG. The median number of cycles was six (range, 1 to 12 cycles). The most common grade 3/4 toxicity was myelosuppression. Grade 3 sensory neuropathy occurred in 14% of patients, and 22.7% experienced grade 1 to 3 cardiac toxicity (grade 3, n = 2: one left ventricular dysfunction, one tachycardia). There were two therapy-related deaths. Thirty-one (70%) of 44 patients responded (five complete and 26 partial), and 25 (57%) of 44 were confirmed responses. Median time to progression and survival were 9.3 and 14.1 months, respectively. Conclusion We prospectively characterized Her-2/neu status in advanced urothelial carcinoma patients. TPCG is feasible; cardiac toxicity rates were higher than projected, but the majority were grade two or lower. Determining the true contribution of trastuzumab requires a randomized trial.
Human epidermal growth factor receptors are involved in signal transduction pathways resulting in proliferation, cell survival, angiogenesis, and metastasis.1 The human epidermal growth factor receptor-2 (Her-2/neu, c-erbB2), has particular clinical relevance. It is overexpressed in approximately 30% of breast cancers,2 and is associated with a poor prognosis.2,3 Trastuzumab, a humanized monoclonal antibody that binds to Her-2/neu, was studied in women with metastatic breast cancer overexpressing Her-2/neu. As a single agent, trastuzumab results in a superior objective response rate/duration and median survival relative to salvage chemotherapy.4 As first-line treatment, trastuzumab yields a clinical benefit rate of 38%,5 and when combined with chemotherapy, trastuzumab improves the response rate/duration and overall survival.6 Trastuzumab with adjuvant chemotherapy improved disease-free7,8 and overall survival8 in women with Her-2/neu–overexpressing breast cancer. Her-2/neu expression in urothelial cancers (UCs) is variable, ranging from 8.5% to 81%.9-18 Some reported a correlation between Her-2/neu overexpression with a more aggressive clinical course.19,20 We reported an analysis on 80 bladder cancer cases treated by radical cystectomy. Samples were tested for Her-2/neu using immunohistochemistry (IHC) staining with polyclonal c-erbB-2 primary antibody (Dako Corp, Carpinteria, CA.). Twenty-eight percent of primary tumors were Her-2/neu positive (+2 or +3). Of the 80 cases, 60 had simultaneous or subsequent metastases. Her-2/neu overexpression (+2 or +3 by IHC) was present in 37% of primaries, 63% of lymph node metastases, and 86% of distant metastases. Forty-five percent of Her-2/neu negative primaries had Her-2/neu positive lymph node metastases, whereas 92% of positive primaries were associated with positive metastases. Her-2/neu overexpression was associated with metastasis, but was not prognostic for survival.16 Several taxane/platinum combinations are active in UC. We reported on carboplatin, gemcitabine, and paclitaxel in patients with advanced UC with an overall response of 68%, a complete response rate of 32%, and a median survival of 14.7 months.21 Synergistic effects have been reported with the addition of trastuzumab to paclitaxel22and carboplatin,23 and recent data suggest that carboplatin and paclitaxel combined with trastuzumab is superior to paclitaxel and trastuzumab alone in women with breast cancer.24 Given the prevalence of Her-2/neu overexpression in UC, the benefits of targeting Her-2/neu in breast cancer, and the synergistic interactions of trastuzumab with paclitaxel and carboplatin, we conducted a trial to investigate the safety and efficacy of trastuzumab, carboplatin, gemcitabine, and paclitaxel in patients with advanced UC. The rate of cardiotoxicity with this combination was our primary end point. The latter was based on safety concerns because data at time of study design on left ventricular (LV) dysfunction in early studies of trastuzumab in breast cancer was reported (for trastuzumab as a single agent, < 5% of women experienced cardiac dysfunction4,5; however, up to 27% of patients were reported to have LV dysfunction when trastuzumab was administered with doxorubicin and cyclophosphamide.6
Eligibility Eligible patients for this Cancer Therapy Evaluation Program (CTEP)–sponsored multi-institutional trial had to have a histologically or cytologically proven UC (either transitional or squamous cell histology) that was either metastatic or recurrent after local therapy and not curable by local therapy, measurable or assessable disease not previously irradiated, and no prior chemotherapy for advanced disease. Neoadjuvant or adjuvant chemotherapy at least 6 months before enrollment was permitted. Patients with prior radiation had to have completed therapy at least 4 weeks before enrollment and to have recovered from radiation-related myelosuppression. Tissue samples from the primary and/or metastatic site and a peripheral blood specimen were submitted for Her-2/neu determination. A Southwest Oncology Group performance status of 0 to 2, a life expectancy of greater than 12 weeks, serum creatinine of 2.0 mg/dL or lower, a total bilirubin of 1.5 mg/dL or lower, absolute granulocyte count (AGC) of at least 1,500/mm3, and a platelet count of 100,000/mm3 or greater were required. Patients with history of symptomatic coronary artery disease or a history of congestive heart failure were ineligible, and all patients had to have adequate cardiac function with an ejection fraction of at 50% on a MUGA (multiple-gate acquisition) scan or two-dimensional echocardiogram within 4 weeks of registration and no evidence of acute ischemic changes on a baseline ECG. Prestudy laboratory assessments to determine eligibility were completed within 14 days of registration, whereas x-rays, computed tomography scans, or physical examination used for tumor measurement were completed within 28 days. Patients with a history of prior malignancies were excluded, except for adequately treated nonmelanoma skin cancer, in situ carcinoma of any site, or other cancer for which patients were considered disease free. Patients who had unresolved bacterial infections, were pregnant or lactating, or were HIV positive were also excluded. All patients were informed of the investigational nature of the study and signed an informed consent in accordance with institutional and federal guidelines.
Her-2/neu Testing To be eligible for therapy, patients had to fulfill the eligibility criteria and have Her-2/neu overexpression by at least one of the following criteria: 2+ or 3+ by IHC of either primary or metastatic tissue, gene amplification based on a positive FISH score of more than 2 (Her-2/neu/Cep17) from the primary or metastatic tissue, or elevated serum Her-2/neu -ECD of more than 16 ng/mL.
Treatment Plan
Response Definition and Monitoring Standard solid tumor criteria were used. Details are outlined in the Appendix (online only).
End Points and Statistical Design Because details regarding rates of cardiac toxicities were not available at time of study design, sample calculations were based on the assumption that the regimen is acceptable if the cardiac toxicity rate was 2% or less and unacceptable if the rate was 10% or higher. A sample size of 40 assessable patients was estimated to provide 82% power to distinguish this difference, assuming a one-tailed test and a 5% type I error. The response rate of the regimen was estimated with an SE no greater than 7.9% and response rates were reported with 95% CIs. Confirmed responses required a maintained status for at least 4 weeks. If scans were not repeated to confirm the status then the response was coded as unconfirmed. Survival, progression times, and response duration were estimated using the Kaplan-Meier method, with the median and 95% CIs reported.
From October 2000 to March 2005, 109 patients were screened for Her-2/neu status at nine participating institutions. Table 2 outlines patients characteristics.
Her-2/neu Status Table 3 details the Her-2/neu expression by assay type. Fifty-seven (52%) of the 109 patients were Her-2/neu positive by at least one method. The majority (49% of total) were considered positive by IHC. Her-2/neu–positive IHC was recorded for 29 primary and 27 metastatic tissue samples. Eleven primary tumor samples and four metastatic tumor samples were FISH positive. Median values for FISH analysis of the primary and metastatic specimens were 1.32 (range, 0.90 to 3.83) and 1.12 (range, 0.79 to 3.33), respectively. Twelve (11.0%) of 109 screened patients did not have serum provided; however, all of the 44 Her-2–positive treated patients had serum available. The median value for serum Her-2/neu-ECD was 11.9 (range, 6.5 to 102.0).
Her-2/neu–positive patients had a trend for more liver/bone metastases, significantly higher median number of metastatic sites (two sites v one site; P = .014) and a higher incidence of two or more metastatic sites (51% v 31%; P = .051) compared with Her-2/neu–negative patients (Table 4).
Patients Receiving Protocol Therapy Of the 57 Her-2/neu–positive patients, 44 were eligible for protocol therapy. Their characteristics are outlined in Table 5. Thirteen Her-2/neu–positive patients did not receive protocol-specified therapy for several reasons including ineligibility because of not fulfilling other eligibility criteria, early death, and patient or physician decision.
The median number of treatment cycles was six (range, one to 12 cycles). All patients are currently off protocol therapy. Reasons for removal from protocol were as follows: 11 patients (25%) for progression, 10 patients (23%) for toxicities, physician decision in nine (20%), treatment completed in seven (16%), patient request in five (11%), and death in two patients (5%).
Toxicities
Response All 44 treated patients are included in the response analysis; five had a complete response (CR; 11%; four of five confirmed), 26 (59%) had a partial response (PR; 21 of 26 confirmed), five (11%) had stable disease (SD), and five (11%) had no response assessment. The overall response rate was 70% (95% CI, 55% to 83%; 57% confirmed response rate). Two patients with a clinical PR had a pathologic CR. Objective responses were seen in 14 (67%) of 21 Her-2/neu 2+ patients, 15 of 20 (75%) patients who were Her-2/neu 3+, nine (82%) of 11 FISH-positive patients and 22 (67%) of 33 FISH-negative patients.
Survival
Her-2/neu overexpression in UC ranges from 8.5% to 81%.9-18 This variability could be attributed to tumor heterogeneity, sampling, and methods used. Indeed, several groups have reported heterogeneous Her-2/neu expression within tumors,25,26 and we observed differences in overexpression between primary tumors compared with metastases.16 Our objectives were to determine prospectively the feasibility of Her-2/neu targeted therapy in UC on the basis of overall safety profile and clinically practical rates of target prevalence, and to generate preliminary efficacy data on combination therapy. The results of this study reaffirmed our prior observations. With Her-2/neu overexpression of more than 50%, it is feasible to consider designing definitive trials to prospectively address the role of anti–Her-2/neu therapy. Unlike breast cancer, overexpression without gene amplification is more common in UC,15,27-30 and is of unclear prognostic significance.9-18 We evaluated Her-2/neu expression prospectively by IHC, FISH, and serum analysis. Overall 52% of patients had Her-2/neu overexpression by at least one of these methods. The majority of Her-2/neu–positive patients (93%) were detected by IHC, and a minority (26%) were positive by FISH or serology (23%). The best method to detect Her-2/neu overexpression in UC cancer is not known. Because the greatest clinical benefit is observed in patients with the highest levels of HER-2/neu expression, trastuzumab trials in breast cancer often require eligible patients to have either 3+ overexpression by IHC or 2+ expression by IHC with positive FISH results. However, initial studies permitted patients with either 2+ or 3+ expression by IHC, as we did in this trial4-6 Reports suggest that gene amplification is not a common mechanism by which Her-2/neu overexpression occurs in bladder cancer.15,27-30 Similarly, in non–small-cell lung cancer, another tumor type in which trastuzumab has been investigated, only 2% of cases were shown to have Her-2/neu gene amplification despite higher rates of overexpression by IHC.31 Although our sample size is not large, FISH may not be a valid test to determine Her-2/neu overexpression in UC. In addition to IHC and FISH, we included serum analysis for the Her-2/neu-ECD in the screening of patients to better assess its role and because if it correlated with tissue findings, then it would be more convenient for screening. Others have shown that women with breast cancer have significantly higher Her-2/neu-ECD levels than do normal controls,32 that up to 40% of women with metastasis have elevated Her-2/neu-ECD levels,33 and that levels appear to be partly dependent on tumor burden.34,35 The utility of a pretreatment elevated Her-2/neu-ECD level is not clear because reports are conflicting as to whether higher values imply a poorer response rate to various chemotherapeutic regimens. Nonetheless, several reports suggest that elevated levels are associated with a higher response rate to trastuzumab-based therapy.36 Similarly, Her-2/neu-ECD levels have also been studied in lung cancer with mixed results.37 Although elevated serum Her-2/neu levels have been suggested to be an indicator of a significantly poorer prognosis,38 results of screening for overexpression of Her-2/neu in at least one study evaluating trastuzumab in non–small-cell lung cancer questions the utility of detecting ECD. Only 6% of patients had an elevated Her-2/neu-ECD level, and IHC results were not predictive of serum findings.31 Admittedly, the utility of assessing Her-2/neu-ECD and correlating with tissue Her-2/neu status remains investigational. Therefore, with only 23% of patients (13 of 57) in our study having elevated Her-2/neu-ECD levels, caution should be taken in drawing conclusions on its significance. Incorporating trastuzumab with chemotherapy was driven by the rate of Her-2/neu overexpression, clinical impact in breast cancer and the recognized positive interactions of this agent with chemotherapeutic agents known to be active in UC including paclitaxel and carboplatin.22-24 Despite a poor-risk population, a high response rate of 70% was observed. However, the impact of trastuzumab in the context of a single-arm phase II trial is difficult to determine. Of interest is that responses were seen in 75% of IHC 3+ and 67% of IHC 2+ patients, whereas 82% of FISH-positive patients and 67% of FISH-negative patients responded to treatment. Although the trends suggest a possible relationship between extent of overexpression and response, this study was not designed to address this question. A median of six courses were delivered, and the toxicity profile with the addition of trastuzumab to chemotherapy is predominantly reflective of the chemotherapy adverse effects. Myelosuppression was the primary toxicity. Two patients (5%) died secondary to infection. In our prior study of the triplet combination, hematologic toxicity was also observed; grade 3 and 4 neutropenia occurred in 35.4% and 40% of patients, respectively, but the febrile neutropenia rate of 1.4% was lower than that observed in this study, and with no treatment-related deaths.21 The addition of trastuzumab to chemotherapy may result in higher rates of neutropenia or neutropenic fever. Metastatic breast cancer patients randomly assigned to docetaxel + trastuzumab had higher rates of grade 3 or 4 neutropenia (32% v 22%) and neutropenic fever/neutropenic sepsis (23% v 17%) compared with docetaxel alone.39 In the metastatic setting, 2% of women who received trastuzumab as first-line therapy developed cardiac dysfunction, defined as congestive heart failure, cardiomyopathy, or a decrease in ejection fraction of greater than 10%.5 Similarly, 4.7% who received it as salvage therapy experienced this complication. The majority of these events were symptomatic.4 In the pivotal phase III metastatic breast cancer trial, 27% of women who received trastuzumab with doxorubicin and cyclophosphamide and 13% of women treated with trastuzumab and paclitaxel experienced cardiac dysfunction. Both asymptomatic and symptomatic cardiac dysfunction were identified, but the incidence of New York Heart Association NYHA class III or IV cardiac dysfunction was greatest among patients who received trastuzumab with doxorubicin and cyclophosphamide.6 A subsequent multivariate analysis identified concomitant or prior anthracycline use as an independent risk factor for cardiac toxicity with trastuzumab, along with age greater than 50 years and a history of NYHA class II dyspnea on study entry.40 In this study, 10 (22.7%) of 44 patients experienced grade 1 to 3 cardiac toxicity, but only two (4.5%) had grade 3 toxicity: one LV dysfunction and one sinus tachycardia. Notably, there were no grade 4 or 5 cardiac toxicities. Although the overall rate of cardiac toxicity was higher than that set by protocol for an acceptable level of toxicity, it is important to note that the percentage of symptomatic LV dysfunction was low. The response rate of 70%, median response duration of 7 months, median time to progression of 9.3 months, and a median survival of 14 months compare favorably to results with gemcitabine/carboplatin (GC). In the initial study comparing GC with methotrexate, vinblastine, doxorubicin, cisplatin, an overall response rate of 49% was reported.41 Updated analysis showed a median progression-free survival of 7.7 months and a median survival of 14.0 months42; however, 29.5% of patients were nonmetastatic, more than 50% had no visceral metastases, and prior chemotherapy was not permitted.41 In our study, all treated patients had metastases, 32.6% previously received adjuvant or neoadjuvant chemotherapy, and 55% had visceral metastases. UC has a high rate of Her-2/neu overexpression, best detected by IHC. Trastuzumab and chemotherapy is feasible and very active. Although the absolute rate of all grades of cardiac toxicity was higher than projected, the rate of high-grade toxicity, particularly LV dysfunction, was low, and in the context of the setting is felt to be clinically acceptable and consistent with that observed in breast cancer trials.43,44 Determining the true contribution of trastuzumab requires a randomized trial.
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. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Ulka Vaishampayan, Genentech Research Funds: Maha H.A. Hussain, Genentech; Ulka Vaishampayan, Genentech; Gurkamal S. Chatta, Genentech; Donald L. Trump, Genentech; David C. Smith, Genentech Testimony: N/A Other: N/A
Conception and design: Maha H.A. Hussain Provision of study materials or patients: Maha H.A. Hussain, Gary R. MacVicar, Daniel P. Petrylak, Ulka Vaishampayan, Primo N. Lara, Gurkamal S. Chatta, David M. Nanus, L. Michael Glode, Donald L. Trump, Helen Chen, David C. Smith Collection and assembly of data: Rodney L. Dunn, Maha H.A. Hussain Data analysis and interpretation: Rodney L. Dunn, Maha H.A. Hussain Manuscript writing: Maha H.A. Hussain Final approval of manuscript: Maha H.A. Hussain, Gary R. MacVicar, Daniel P. Petrylak, Rodney L. Dunn, Ulka Vaishampayan, Primo N. Lara, Gurkamal S. Chatta, David M. Nanus, L. Michael Glode, Donald L. Trump, Helen Chen, David C. Smith
Toxicity Monitoring and Dose Modifications Patients were assessed every 3 weeks with a history, toxicity evaluation, and physical examination. A CBC and differential were obtained weekly to monitor for hematologic toxicity. Serum creatinine, total bilirubin, alkaline phosphatase, and transaminases were obtained every 3 weeks. The Common Toxicity Criteria version 2.0 for toxicity and adverse event reporting was used. Paclitaxel and carboplatin doses were reduced to –1 dose level for grade 4 neutropenia (< 500/mm3) or grade 3 or greater thrombocytopenia (< 50,000/mm3). If a similar toxicity reoccurred, then doses were reduced to –2 dose level. Paclitaxel and carboplatin doses were modified for peripheral neuropathy. No change was made for grade 0 to 1 toxicity, but a grade 2 peripheral neuropathy resulted in paclitaxel and carboplatin dose reduction to –1 dose level. If grade 3 or higher toxicity was observed, then paclitaxel and carboplatin were held but gemcitabine and trastuzumab were continued until recovery of neurotoxicity to grade 1 or lower. Therapy was resumed at –1 dose level for paclitaxel and carboplatin. If same-grade neuropathy recurred, then therapy was withheld again until recovery to grade 1 or lower and restarted at –2 dose level. If no improvement was seen after withholding therapy, then patients were removed from protocol. Patients were also removed from study if they experienced grade 4 neuropathy. Left ventricular ejection fraction (LVEF) was monitored with a MUGA scan or a two-dimension echocardiogram every 12 weeks and as clinically indicated. Patients were required to have the same test performed at the same institution. In the event that LVEF was reduced within 10% or less of the institution's lower limit of normal (ILLN), trastuzumab was continued with careful monitoring. A repeat study was performed 4 weeks later, and if the study showed the LVEF to be no more than 10% below the ILLN, then trastuzumab was continued. If grade 1 LVEF toxicity was observed, then trastuzumab was withheld, and chemotherapy was continued. A repeat study was performed 4 weeks later, and if the LVEF was no more than 10% below the ILLN, then trastuzumab was resumed. If the LVEF was more than 10% below the ILLN, then trastuzumab was permanently discontinued, but chemotherapy was continued. In the event of a grade 2 cardiac toxicity, trastuzumab was discontinued, and grade 3 or 4 toxicity resulted in removal from study. For other toxicities, excluding alopecia, nausea, and vomiting, therapy was withheld for grade 3 or 4 toxicities until recovery to grade 1 or less, and subsequent doses were reduced to –1 dose level. If toxicity reoccurred, then an additional dose reduction to the –2 level was required. No more than two dose level reductions were allowed. Patients requiring dose reductions beyond the –2 dose level were removed from protocol.
Response Definition and Monitoring Patients achieving a CR after three cycles received an additional three cycles to complete their course of therapy. Patients achieving a PR or SD continued treatment until achieving a CR or progression of disease, or unacceptable toxicity. In compliance with the response criteria, the best response was reported based on assessment of all sites of disease. For example, if a patient had bone-only metastatic disease, then they were coded as either having progressive disease, SD, or CR based on whether the bone scan demonstrated progression versus no change versus complete resolution. There was no PR category for patients with bone-only metastases. For patients with bone and soft tissue disease, the best response assessment was also based on assessing all sites of disease, and best response was coded taking into account that the bone scan has to show SD at a minimum. Therefore, unless the bone scan normalized, a patient with complete resolution of soft tissue disease would have a best response assessment category of a PR.
We thank Derek Raghavan, MD, PhD, for his contributions to this trial and University of Michigan Center for Advancement of Clinical Research for help with data management.
Supported by Cancer Therapy Evaluation Program, Cancer Center Core Grant 5P30CA046592-17, John & Suzanne Munn Endowed Research Fund, and Genentech. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
