ARTICLE

Results of Two Open-Label, Multicenter Phase II Studies of Docetaxel, Platinum Salts, and Trastuzumab in HER2-Positive Advanced Breast Cancer

Mark D. Pegram, Tadeusz Pienkowski, Donald W. Northfelt, Wolfgang Eiermann, Ravi Patel, Pierre Fumoleau, Eleonor Quan, John Crown, Deborah Toppmeyer, Michael Smylie, Alessandro Riva, Sandra Blitz, Michael F. Press, David Reese, Mary-Ann Lindsay, Dennis J. Slamon

Affiliations of authors: Oncology Research Network, David Geffen School of Medicine, and Division of Hematology/Oncology, University of California, Los Angeles (MDP, DWN. RP, EQ, DJS); Breast Cancer International Research Group, Edmonton, Alberta, Canada (TP, WE, PF, JC, DT, MS, AR, SB, DR, MAL); Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland (TP); University of Southern California Keck School of Medicine, Los Angeles, CA (MFP).

Correspondence to: Dennis J. Slamon, MD, PhD, University of California, Los Angeles, Peter Ueberroth Bldg., 3360B, 10945 Le Conte Ave., Los Angeles, CA 90095-7077 (e-mail: dslamon{at}mednet.ucla.edu)


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Preclinical data indicate that docetaxel, platinum salts, and the combination of both drugs are highly synergistic with the anti-HER2 antibody trastuzumab. The University of California at Los Angeles-Oncology Research Network (UCLA-ORN) and the Breast Cancer International Research Group (BCIRG) have conducted two phase II studies to evaluate docetaxel and trastuzumab in combination with either cisplatin or carboplatin for the treatment of women with advanced breast cancer that overexpresses HER2. Methods: Each study enrolled 62 patients with HER2-overexpressing tumors. Patients received a median of six cycles of docetaxel at 75 mg/m2 of body surface area and cisplatin (BCIRG 101 study) at 75 mg/m2 or carboplatin (UCLA-ORN study) at AUC = 6 mg/mL · min given on day 1 and then every 21 days. Trastuzumab was given on day 1, cycle 1 (4 mg/kg) and then continued weekly at 2 mg/kg for 1 year or until disease progression. Tumor measurements were obtained at baseline, after three cycles of chemotherapy, and then every 3 months. HER2 gene amplification was determined by fluorescence in situ hybridization. Results: Patient characteristics were comparable between trials with the exception that 15% of the patients in the UCLA-ORN study had received previous adjuvant taxane therapy. Both regimens were well tolerated, with manageable toxicities. Hematologic toxicities were more frequent in patients in the UCLA-ORN study than in patients in the BCIRG 101 study, whereas the reverse pattern was observed for non-hematologic toxicities. One patient in each study developed reversible congestive heart failure. Responses were observed in 49 of 62 patients in the BCIRG 101 study (overall response rate = 79%, 95% confidence interval [CI] = 66% to 89%) and in 34 of 59 evaluable patients in the UCLA-ORN study (overall response rate = 58%, 95% CI = 44% to 70%). Median times to progression were 9.9 months (95% CI = 8.3 to 13.1 months) and 12.7 months (95% CI = 8.6 to 15.5 months) for patients in the BCIRG 101 and UCLA-ORN studies, respectively. Overall response rates were higher and median time to progression was longer in the subset of patients whose tumors harbored HER2 gene amplification. Conclusion: Combinations of docetaxel, a platinum salt, and trastuzumab are feasible and active in patients with advanced breast cancers that overexpress HER2. The BCIRG is conducting ongoing randomized studies of the three-drug combination in both the metastatic and adjuvant settings.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The treatment of metastatic breast cancer continues to pose a substantial clinical challenge. Although the use of combination chemotherapy may improve survival in a small fraction of women, metastatic breast cancer is generally incurable (1,2), and new treatment approaches are needed. Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor 2 (HER2), is a novel agent introduced for the treatment of HER2-positive metastatic breast cancer (3). Women with primary breast cancers that contain HER2 gene amplification and/or overexpress HER2 protein have a poor prognosis that includes a greater risk of relapse and shortened survival compared with women whose cancers are negative for the alteration (49). Previously, a multinational, multi-institutional, randomized phase III trial demonstrated that, compared with chemotherapy alone, the use of trastuzumab in conjunction with standard chemotherapy (doxorubicin/cyclophosphamide [AC] or paclitaxel) increased both the response rate and overall survival in patients with HER2-positive metastatic disease (10). There was, however, an unacceptably high rate of cardiac dysfunction (27% incidence in 143 women), including congestive heart failure, in patients treated concurrently with doxorubicin and trastuzumab, which limits the utility of this particular combination in clinical practice (11).

Traditional approaches to the design of combination therapeutic regimens have involved adding a new drug to an already established regimen, assuming that there is no increased toxicity caused by integrating the new drug. This empiric approach does not take advantage of potential drug interactions that may be synergistic. Work done by us (1217) and others (18) indicates that there are statistically significant therapeutic interactions between trastuzumab and cytotoxic drugs other than those commonly used in current breast cancer treatment regimens. For example, in vitro and in vivo preclinical laboratory studies (1217) demonstrate that trastuzumab interacts synergistically with cisplatin, carboplatin, and docetaxel. By contrast, the cyto-toxic effects of paclitaxel or doxorubicin in combination with trastuzumab are additive (12). The synergistic effects of platinum salts and trastuzumab are the result of trastuzumab-induced attenuation of DNA repair that follows platinum-induced DNA damage (14) and suggest a complex molecular interaction between the HER2 signal transduction and DNA repair pathways (14,18). The underlying mechanism(s) of the synergy between docetaxel and trastuzumab is still under investigation, but preliminary data indicate that it may be the result of increased apoptosis (19).

Given these preclinical data, docetaxel and platinum salts (cisplatin or carboplatin) are logical candidates for combination therapy with trastuzumab (2026). Moreover, docetaxel may be the most active single agent against breast cancer, both as a monotherapy and in combination with other cytotoxic agents, and it does not have the cardiotoxicity associated with the anthracyclines (27). In one clinical trial, patients who received docetaxel had improved survival compared with patients who received mitomycin C plus vinblastine (28). Docetaxel has been also combined with cisplatin in the treatment of advanced breast cancer. In pilot studies (2932), response rates of 50%–61% were observed in patients who received this drug combination either as a first-line treatment or as a second-line treatment (i.e., in patients who had received prior chemotherapy), suggesting that this combination is active. These findings are consistent with observations demonstrating high response rates to other taxane–platinum salt combinations, such as paclitaxel plus carboplatin (33,34). Docetaxel plus carboplatin is a well-studied combination for other cancers such as ovarian and non–small-cell lung cancer (3540); doses, schedules, clinical safety, and efficacy have been characterized in randomized phase III clinical trials (39,41).

Taken together, these preclinical and clinical data suggest that the combination of docetaxel, platinum salt, and trastuzumab (TCH) may have the potential for clinically significant activity against breast cancers that overexpress HER2. As a direct result of the preclinical demonstration of synergy with TCH (42), we performed two nonrandomized phase II trials designed to evaluate this combination in women with HER2-positive advanced breast tumors.


    PATIENTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Study Design

Two separate phase II, nonrandomized, open-label, multicenter studies were conducted by the community-based University of California at Los Angeles Oncology Research Network (UCLA-ORN) and the Breast Cancer International Research Group (BCIRG) to test the feasibility and efficacy of the TCH combination. The UCLA-ORN trial, conducted in the United States, involved the combination of docetaxel, carboplatin, and trastuzumab as first- or second-line treatment for women with surgically unresectable stage IIIB or stage IV disease whose tumors had HER2 gene amplification or receptor protein overexpression. The BCIRG 101 trial, conducted in Europe and North America, involved the combination of docetaxel, cisplatin, and trastuzumab as first-line therapy for women with advanced or metastatic breast cancer whose tumors had HER2 gene amplification or receptor protein overexpression. Both studies were performed with the approval of independent ethics committees and in accordance with the World Medical Association Declaration of Helsinki.

The primary objectives of both protocols were to evaluate the objective response rate of patients with HER2-positive breast cancers treated with TCH therapy for advanced or metastatic breast cancer and to evaluate the safety of these regimens. The secondary objectives were to evaluate duration of response, time to disease progression, and overall survival. For the analysis of efficacy, two populations were defined: 1) all treated patients, including all patients who were enrolled in the study and received at least one cycle of treatment, and 2) evaluable patients, including all patients who received at least two cycles of treatment and at least one follow-up tumor assessment. Patients were accrued to the UCLA-ORN trial between December 6, 1999, and December 12, 2000. Patients in the BCIRG 101 study were enrolled between November 30, 1999, and November 2, 2000.

Patient Evaluation

Sixty-two patients were enrolled in each of the two TCH studies. The study population consisted of women aged 18 years or older with a primary histopathologic diagnosis of invasive breast cancer (surgically unresectable stage IIIB or stage IV). All patients had measurable disease, as documented by physical examination or radiographic findings. For patients to be included in the study, their tumors had to either overexpress the HER2 proto-oncogene as determined by using immunohistochemistry or have evidence of HER2 gene amplification as determined by using fluorescence in situ hybridization (FISH). Overexpression as determined by immunohistochemistry was defined as 2+ or 3+ staining using the HercepTest (Dako, Carpinteria, CA), and HER2 gene amplification as determined by FISH was defined as greater than 10 HER2 signals per cell uncorrected or greater than two signals per cell corrected for chromosome 17 polysomy using the PathVysion HER2/neu amplification kit (Vysis, Downers Grove, IL). A retrospective FISH analysis was performed in a central laboratory on 113 available tumor specimens identified after the clinical trial accrual was completed. Hormone receptor status was measured according to standard practices established at each participating institution. Additional inclusion criteria included Karnofsky performance status of 60% or greater (BCIRG) and Eastern Cooperative Oncology Group performance status of 0–2 (UCLA-ORN); absolute neutrophil count of at least 1500 cells/µL, platelet count of at least 100 000 cells/µL, hemoglobin level of at least 9 g/dL; bilirubin level within normal limits; aspartate aminotransferase of not greater than 2.5 times or not greater than 3.5 times the upper limit of normal for patients enrolled in the BCIRG 101 or UCLA-ORN trials, respectively, or not greater than 1.5 times the upper limit of normal if alkaline phosphatase levels were greater than 2.5 times the upper limit of normal for patients enrolled in either trial; alkaline phosphatase levels of not greater than 5 times the upper limit of normal; creatinine levels of not greater than 2.0 mg/dL (<=175 µmol), or a calculated creatinine clearance level of 60 mL/min or greater. All patients were required to have a normal left ventricular ejection fraction (LVEF) as determined by multi-gated acquisition scan or echocardiography. Women with childbearing potential had to have a negative pregnancy test and agree to use effective contraception. All patients assigned to receive cisplatin were required to have a normal baseline hearing test. All participants signed a written informed consent form approved by the Institutional Review Board.

Patients were excluded from either trial if they had received previous trastuzumab therapy or were receiving concurrent hormonal treatment or immunotherapy. Patients were eligible for the BCIRG 101 trial if they had received previous adjuvant or neoadjuvant chemotherapy but were ineligible if they had received a platinum salt (cisplatin or carboplatin) or a taxane (paclitaxel or docetaxel). In the UCLA-ORN trial, patients were included if they had received previous adjuvant taxane treatment. Patients were included if they had received previous radiation therapy, providing that at least 4 weeks had elapsed since its completion and that the sites being treated were other than those used to assess response. Patients were also included if they were receiving concurrent therapy with bisphosphonates. Additional exclusion criteria included cumulative lifetime doxorubicin dose of greater than 360 mg/m2 of body surface area or epirubicin dose of greater than 600 mg/m2, presence of uncontrolled parenchymal brain metastases, peripheral neuropathy (grade 2 or higher), known hypersensitivity to polysorbate 80, serious intercurrent medical or psychiatric illness, a history of congestive heart failure, a history of another malignancy within the last 5 years that could affect the diagnosis or assessment of breast cancer, receipt of another investigational drug within 3 weeks of study entry, and male sex.

Tumor measurements were taken after every three cycles of chemotherapy (and then every 3 months after the end of chemotherapy) with the same imaging modalities used to determine the baseline extent of disease. Tumor response was classified according to World Health Organization (WHO) criteria (43). In the BCIRG 101 trial, patient responses were independently assessed by two radiologists. For the UCLA-ORN trial, response was assessed and reported by the investigators.

Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). A physical examination (including disease assessment), complete blood count, and blood chemistry assessment were performed at the start of each cycle of therapy.

Treatment Plan

All patients received 3-week cycles of TCH therapy. All treatments were administered intravenously. In the first cycle, a trastuzumab loading dose (4 mg/kg) was infused over 90 minutes on day 1; docetaxel at 75 mg/m2 was administered intra-venously over 1 hour on day 2, followed by cisplatin at 75 mg/m2 (BCIRG 101) or carboplatin equal to the area under the curve (AUC) of 6 mg/mL · min (UCLA-ORN) over 1 hour. For carboplatin, the AUC determination was made using the modified Calvert formula, in which the creatinine clearance (Cockroft–Gault determination) is substituted for the glomerular filtration rate (4447). Trastuzumab at 2 mg/kg was subsequently infused over 30 minutes on days 8 and 15. The rationale for this drug administration schedule is based on the observation that trastuzumab is more effective when administered before the cytotoxic chemotherapeutic agents in vivo than when administered after treatment with cytotoxic agents (48,49). In the remaining cycles, docetaxel and cisplatin or carboplatin (same doses as above) were administered on day 1 immediately following trastuzumab. Prophylactic steroid consisted of dexamethasone at 8 mg given orally the night before docetaxel infusion, the morning of the infusion, 1 hour before docetaxel, and twice daily for 36 hours thereafter. All patients treated with cisplatin (BCIRG 101) received intravenous hydration with at least 1 L of normal saline before and after receiving cisplatin. At the discretion of the treating physician, patients were given antiemetics, mannitol, and/or magnesium and potassium supplements, prophylactic antibiotics (e.g., ciprofloxaxin at 500 mg twice daily), and amifostine—a drug that minimizes the side effects of chemo-therapy. Exogenous growth factors were not routinely provided, except as noted below. Treatment continued for six cycles unless there was evidence of disease progression or unacceptable toxicity. At the discretion of the physician, TCH treatment could be extended beyond six cycles for patients with stable or responsive disease and no serious toxicity. Trastuzumab was continued weekly at 2 mg/kg for 1 year after chemotherapy ended or until progressive disease or unacceptable toxicity developed.

The study design allowed drug doses to be modified for patients with severe hematologic and/or non-hematologic toxicity. In the UCLA-ORN TCH study, the first dose reduction (dose level –1) was to docetaxel 60 mg/m2 and carboplatin AUC = 5 mg/mL · min, and the second dose reduction (dose level –2) was to docetaxel 50 mg/m2 plus carboplatin AUC = 4. Further dose reductions of either chemotherapeutic agent were not allowed. Doses reduced because of toxicity were not re-escalated. In the UCLA-ORN trial, doses were reduced for both docetaxel and carboplatin for hematologic or non-hematologic toxicities, with the exception of diarrhea, for which dose modification of docetaxel alone was allowed. In the BCIRG 101 trial, either docetaxel or cisplatin doses were reduced stepwise as follows: the first dose reduction was to 60 mg/m2 for either agent (dose level –1), and the second dose reduction was to 50 mg/m2 (dose level –2). For patients who developed an episode of febrile neutropenia or a documented infection, prophylactic granulocyte colony-stimulating factor (G-CSF) was administered in subsequent cycles; if a second episode occurred, docetaxel was reduced one dose level. Docetaxel dose was also reduced for thrombocytopenia (50 000–99 000 cells/µL) and withheld for platelet counts of less than or equal to 50 000 cells/µL. Cisplatin dose reductions or delays in administration occurred in the case of renal toxicity. If creatinine levels increased to more than 2 mg/dL (>175 µmol/L), chemotherapy was withheld until the creatinine levels decreased to less than 2 mg/dL. Any delay in the administration of cisplatin or a calculated creatinine clearance of 31–49 mL/min led to the cisplatin dose being reduced by one dose level. Cisplatin was withheld if the calculated creatinine clearance was less than or equal to 30 mL/min. Chemotherapy was also withheld for grade 2 and 3 neuropathy and resumed at one dose level lower for both docetaxel and cisplatin after neuropathy resolved to grade 1 or below. No dose reductions were mandated for docetaxel-induced fluid retention; furosemide at 20 mg/day could be used to treat grade 1 or higher weight gain due to edema. Cisplatin was discontinued in patients who experienced a grade 3/4 hearing loss. In the event of a treatment delay, both chemotherapy drugs were withheld and subsequently administered after recovery from all toxicities to grade 1 or below. Treatment delays of greater than 2 weeks or 3 weeks were not permitted in BCIRG 101 or UCLA-ORN TCH trials, respectively. Dose delays or reductions of weekly trastuzumab were not performed for chemotherapy-associated toxicities in either study.

For symptomatic cardiac changes or decreases in LVEF to below the institutional lower limit of normal, trastuzumab was withheld until the condition resolved. If therapy for cardiac symptoms was required and the symptoms resolved, trastuzumab was continued after discussion with the patient concerning the risks and benefits of continued therapy. Patients who experienced an asymptomatic decrease of at least 15% in LVEF (but the LVEF remained above the lower limit of normal) were allowed to continue treatment with trastuzumab at the discretion of the investigator and/or patient but were monitored closely with serial cardiac ejection fraction testing. Chemotherapy (without trastuzumab) was allowed to continue in patients with cardiac dysfunction until at least 6 cycles were administered (assuming there was no other dose-limiting toxicity from chemotherapy).

For all other toxicities, treatment was discontinued until recovery to grade 1. After recovery, treatment was resumed in subsequent cycles at a dose level appropriate for avoiding toxicity.

Data and Statistical Analysis

Patients were considered evaluable for analysis of efficacy if they had received at least two cycles of treatment with at least one follow-up tumor assessment. Efficacy analyses were performed on all enrolled patients (intent-to-treat population) for the time to disease progression endpoint and on evaluable patients only for objective tumor response assessment. The duration of response for responding patients dated from the first documentation of objective response until the first documentation of progressive disease. The time to progression extended from the date of enrollment to the first occurrence of progression. Survival was calculated from the date of enrollment to the date of death from any cause. Duration of response, time to disease progression, and survival were analyzed using the Kaplan–Meier method (50).


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patient Characteristics

A total of 124 patients were enrolled on the UCLA-ORN TCH and BCIRG 101 trials (62 patients in each study, Table 1). The median age of the patients was 52 years (range = 29–76 years) for the BCIRG 101 trial and 54 years (range = 31–76 years) for the UCLA-ORN trial. The Eastern Cooperative Oncology Group performance status was 0 or 1 for more than 95% of patients enrolled in each of the trials. Cancers were positive for the estrogen receptor (ER) and/or progesterone (PR) in 53% and 65% of the patients enrolled in the BCIRG 101 and UCLA-ORN trials, respectively. All patients had documented HER2 protein overexpression by immunohistochemistry (2+ or 3+) or evidence of HER2 gene amplification by FISH. Eighty-six (69%) of 124 patients enrolled in these trials had an immunohistochemistry score of 3+ or were positive by FISH at the time of initial screening for study entry. Of 113 samples available for retrospective FISH testing, 76 (67%) were found to have HER2 gene amplification (Table 1). The median disease-free interval (i.e., the time from initial diagnosis to the appearance of first metastasis) was 28 months for patients in the BCIRG 101 trial and 25 months for patients in the UCLA-ORN trial. Approximately one-third of all patients had metastases to three or more organs at the time of study entry, and more than two-thirds of all patients had metastases to visceral organs. Almost half of all patients had bone metastases.


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Table 1. Patient and disease characteristics of those enrolled in open-label, phase II trials of docetaxel, platinum salts, and trastuzumab*

 
More than 50% of the patients had received prior adjuvant chemotherapy, including 34% in the BCIRG 101 trial and 45% in the UCLA-ORN trial who had received an anthracycline-containing adjuvant regimen. Of the patients enrolled in the UCLA-ORN trial, 15% had received adjuvant taxane therapy and 5% had received chemotherapy for treatment of metastases.

Feasibility of Study Drug Administration

In total, 389 cycles of chemotherapy were administered in the BCIRG 101 trial and 385 cycles were administered in the UCLA-ORN trial (Table 2). The median number of chemotherapy cycles per patient in each trial was six (range = 2–13). Eighty-six percent (BCIRG 101) and 84% (UCLA-ORN) of patients received six or more courses of chemotherapy. Chemotherapy doses were reduced because of toxicity in 12% of the chemotherapy cycles in the BCIRG 101 trial and 20% of the cycles in the UCLA-ORN trial. In the UCLA-ORN trial, 42 patients received co-administration of G-CSF or granulocyte–macrophage colony-stimulating factor (GM-CSF), whereas in the BCIRG 101 trial, 10 patients received co-administration of G-CSF or GM-CSF to stimulate neutrophil recovery between cycles. Nine of 62 patients in the BCIRG 101 trial discontinued TCH therapy before completing six chemotherapy cycles: two patients had disease progression, three patients required surgery, one patient had congestive heart failure (cycle 4), two patients had grade 3 sensory neuropathy (both on cycle 5), and one patient withdrew voluntarily. Ten of 62 patients in the UCLA-ORN trial discontinued TCH therapy before completing six chemotherapy cycles: seven patients had disease progression, one patient had grade 3 diarrhea and edema (cycle 2), one patient had pancytopenia and electrolyte imbalance, and one patient withdrew voluntarily because of issues with medical insurance.


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Table 2. Study drug administration for patients enrolled in open-label phase II trials of docetaxel, platinum salts, and trastuzumab*

 
In the BCIRG 101 trial, there were 2503 trastuzumab infusions, of which 1160 occurred during chemotherapy. In the UCLA-ORN trial, there were 2520 trastuzumab infusions, of which 1242 occurred during chemotherapy (Table 2). The median number of trastuzumab infusions received while on chemotherapy was 18 (range = 4–57) for each trial, whereas the median number of trastuzumab infusions received after completion of chemotherapy was 25 (range = 1–75) in the BCIRG 101 trial and 24 (range = 1–87) in the UCLA-ORN trial (Table 2).

Safety and Tolerability

All patients were evaluable for tolerability and toxicity assessment. The TCH regimen was generally well tolerated with manageable toxicities. Clinically significant (grade 3 or 4) hematologic toxicity is shown in Table 3. Ten (16%) patients in the BCIRG 101 trial and 40 (65%) patients in the UCLA-ORN trial developed grade 4 neutropenia during at least one cycle of treatment. However, febrile neutropenia occurred in only eight (13%) patients in the BCIRG 101 trial and in 10 (16%) patients in the UCLA-ORN trial, with only two patients developing grade 3 or 4 infection in both studies combined. There were no deaths from sepsis. A minority of patients (9% and 6% in the BCIRG 101 and UCLA-ORN trials, respectively) developed grade 3 or 4 anemia. Only seven patients (11%) in the UCLA-ORN trial developed grade 3 or 4 thrombocytopenia.


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Table 3. Cumulative incidence of grade 3 or 4 hematologic and non-hematologic toxicities occurring among patients enrolled in open-label phase II trials (N = 62 for each) of docetaxel, platinum salts, and trastuzumab*

 
Acute non-hematologic side effects are shown in Table 3. The most frequent grade 3 or 4 toxicities for the BCIRG 101 and UCLA-ORN trials were nausea (18% and 11%, respectively), vomiting (11% and 8%, respectively), diarrhea (11% and 5%, respectively), and stomatitis (3% and 3%, respectively). In the BCIRG 101 trial, two patients (3%) developed grade 3 or 4 nephrotoxicity, and one patient (2%) experienced clinically significant ototoxicity. In the UCLA-ORN trial, none of the patients experienced nephrotoxicity or ototoxicity. Grade 3 or 4 asthenia occurred in 11 (18%) patients in each trial. Two patients (3%) in the BCIRG 101 trial developed grade 3 or 4 neuropathy, and one patient in each trial (2%) developed clinically significant peripheral edema.

The LVEFs were measured serially for all patients (Fig. 1). One patient (2%) in each trial developed symptomatic congestive heart failure requiring medical therapy (indicated by the bold lines in Fig. 1). Of note, neither of these patients had received prior anthracycline treatment. One patient in the BCIRG 101 trial developed congestive heart failure after four cycles of TCH therapy; however, the single patient in the UCLA-ORN trial with clinical congestive heart failure did not develop symptoms or a decline in LVEF until cycle 10 of TCH therapy. For each patient, the cardiac symptoms resolved, and LVEF returned to the normal range after discontinuing trastuzumab and receiving medical treatment for congestive heart failure. Eleven to 15% of all patients had asymptomatic declines in LVEF to below the institutional lower limits of normal (Table 4; Fig. 1). Moreover, when comparing the baseline LVEF with the last recorded LVEF assessment, we noted a slight but statistically significant decrease in both trials (4% decrease in mean LVEF in the BCIRG 101 trial [P<.001] and a 3% decrease in mean LVEF in the UCLA-ORN trial [P = .02]). It should be noted, however, that in many subjects the last recorded LVEF was at the time of disease progression and that LVEF was not assessed in a blinded fashion in either study.



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Fig. 1. Cardiac measurements (left ventricular ejection fraction [LVEF]) for all patients enrolled in the Breast Cancer International Research Group 101 protocol of docetaxel, cisplatin, and trastuzumab (A) and the University of California at Los Angeles-Oncology Research Network protocol of docetaxel, carboplatin, and trastuzumab (B) at all time points. Each line represents one patient. Bold lines indicate patients with symptomatic declines in LVEF. Box plot inserts illustrate baseline versus last observed LVEF measurements, where the center of the box denotes the median value; the top and bottom of the box denote the 75th and 25th percentiles, respectively; error bars denote the maximum and minimum values; and asterisk denotes values greater than 1.5 times the interquartile range.

 

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Table 4. Cumulative incidence of cardiac toxicity among patients enrolled in open-label, phase II trials of docetaxel, platinum salts, and trastuzumab

 
Efficacy

All 62 patients in the BCIRG 101 trial were assessed for clinical response (Table 5). Three patients achieved an objective complete response and 46 achieved a partial response, for an overall objective response rate (intent-to-treat population) of 79% (95% confidence interval [CI] = 66% to 89%). FISH analysis was performed retrospectively to identify the patient subset with HER2 gene amplification. In subset analysis, there were no statistically significant differences in the response rates between patients with FISH-positive and FISH-negative tumors. Responses were observed in 27 of 35 patients (77%, 95% CI = 59% to 90%) whose tumors were FISH positive compared with 16 of 19 patients (84%; 95% CI = 60% to 96%) whose tumors were FISH negative. Twelve patients (19%) had stable disease as their best response. The median duration of response was 7.5 months (95% CI = 5.8 to 11.3 months), and the median time to progression for the intent-to-treat population was 9.9 months (95% CI = 8.3 to 13.1 months) (Fig. 2, A). The median time to progression was 12.7 months (95% CI = 8.9 to 14.2 months) for patients whose tumors were FISH-positive and 7.9 months (95% CI = 5.8 to 13.2 months) for patients whose tumors were FISH-negative (Fig. 2, B). With a median follow-up of 16 months, the median overall survival has not yet been reached.


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Table 5. Clinical objective responses to treatment among patients enrolled in open-label, phase II trials (N = 62 for each) of docetaxel, platinum salts, and trastuzumab*

 


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Fig. 2. Kaplan–Meier curves for time to progression for patients enrolled in the Breast Cancer International Research Group 101 protocol of docetaxel, cisplatin, and trastuzumab. A) Kaplan–Meier curves showing time to progression for all 62 patients (intent-to-treat population). Median time to progression was 9.9 months (95% confidence interval [CI] = 8.3 to 13.1 months). Broken lines represent 95% CIs. B) Time to progression among 54 patients for whom human epidermal growth factor receptor 2 (HER2) gene amplification status (determined by fluorescence in situ hybridization) was available. Median time to progression was 12.7 months (95% CI = 8.9 to 14.2 months) for patients with tumors that were positive for HER2 gene amplification (solid line) and 7.9 months (95% CI = 5.8 to 13.2 months) for patients with tumors that were negative for HER2 gene amplification (broken line).

 
In the UCLA-ORN trial, 59 patients were evaluable for clinical response (Table 5). Of the three patients who were not evaluable for response, two patients had withdrawn from the study before the first tumor assessment because of problems with toxicity, and one patient left the study because of insurance issues. An objective complete response was achieved in 12 patients (20%), and a partial response was achieved in 22 patients (37%), for an overall response rate of 58% (95% CI = 44% to 70%). Objective clinical responses were achieved in 25 of 40 (63%, 95% CI = 46% to 77%) evaluable patients whose tumors were FISH positive and in 7 of 17 (41%, 95% CI = 19% to 67%) evaluable patients whose tumors were FISH negative. Among the subset of patients with FISH-positive tumors who received first-line therapy, 24 of 37 (65%, 95% CI = 47% to 79%) achieved an objective response, suggesting statistically nonsignificant evidence of higher responses in patients with HER2 gene amplification. Two patients with a clinical complete response underwent mastectomy. Of these two patients, one had a pathologic complete response (i.e., no residual invasive disease), and the other had residual disease with histologic findings of cell necrosis, consistent with a response to TCH. The median time to progression in the intent-to-treat population was 12.7 months (95% CI = 8.6 to 15.5 months) (Fig. 3, A). The median time to progression was 15.6 months, (95% CI = 9.1 to 17.3 months) for patients whose tumors were FISH positive and 7.4 months (95% CI = 6.7 to 12.0 months) for patients whose tumors were FISH negative (Fig. 3, B). The median time to progression was 17.4 months (95% CI = 9.1 months –[upper confidence bound not estimable]) for patients whose tumors were FISH positive and who received first-line therapy for metastatic breast cancer and 7.4 months (95% CI = 6.7 to 12.0 months) for patients whose tumors were FISH negative. With a median follow-up of 20 months (range = 1–30 months), the median overall survival has not yet been reached for this cohort.



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Fig. 3. Kaplan–Meier curves showing time to progression for patients enrolled in the University of California at Los Angeles-Oncology Research Network protocol of docetaxel, carboplatin, and trastuzumab. A) Kaplan–Meier curves showing time to progression for all 62 patients (intent-to-treat population). Median time to progression was 12.7 months (95% confidence interval [CI] = 8.6 to 15.5 months). Broken lines represent 95% CIs. B) Time to progression among 59 patients for whom human epidermal growth factor receptor 2 (HER2) gene amplification status (determined by fluorescence in situ hybridization) was available. Median time to progression was 15.6 months (95% CI = 9.1 to 17.3 months) for patients with tumors that were positive for HER2 gene amplification (solid line) and 7.4 months (95% CI = 6.7 to 12.0 months) for patients with tumors that were negative for HER2 gene amplification (broken line). Patients with tumors that were positive for HER2 gene amplification and who received therapy as a first-line treatment had a median time to progression of 17.4 months.

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The concept of receptor-enhanced chemosensitivity, resulting from an anti–growth factor receptor antibody and cytotoxic drug combination, was developed more than a decade ago. In a series of in vitro and in vivo studies, Sela et al. (51) found that the combination of an anti-epidermal growth factor receptor (EGFR/HER1) antibody and cisplatin had substantially more activity than either agent alone in EGFR-overexpressing tumor xenografts. Moreover, the concomitant administration of anti-EGFR antibody and cisplatin had greater antitumor efficacy than an antibody conjugate consisting of cisplatin covalently coupled to the anti-EGFR antibody (51). In analogous experiments using an anti-HER2 antibody in combination with cisplatin, similar results indicating true pharmacologic synergy were noted in HER2-overexpressing breast and ovarian cancer cells and xenografts (12,14,52). These observations suggest that tumor cells deriving a proliferative advantage from activation or overexpression of the HER2 receptor tyrosine kinase may be particularly susceptible to combination treatment with anti-receptor agents and specific chemotherapeutics (12,14).

To explore the potential clinical benefits of synergistic interaction between trastuzumab and specific cytotoxic agents, we evaluated the clinical efficacy of the TCH regimen in the treatment of women with HER2-overexpressing advanced breast cancer. This three-drug combination was chosen because, like cisplatin (and unlike other drugs, including paclitaxel), docetaxel demonstrates synergistic cytotoxicity with trastuzumab (17). Moreover, docetaxel treatment is not associated with an increased risk of cardiotoxicity either as a single agent or in combination with anthracyclines (17,53). The current trials (BCIRG 101 and UCLA-ORN TCH) were developed on the basis of an increased understanding of the underlying molecular biology of the HER2 receptor tyrosine kinase and its interaction with DNA repair activity and preclinical experimental determination of the optimum efficacy of drug interactions between trastuzumab and a variety of cytotoxic drugs (12,14,18,48).

The overall response rates observed in the current trials appear promising, especially when compared with previous results with trastuzumab-containing combination chemotherapy regimens (10). In the pivotal, registrational, randomized phase III trial of patients with HER2-overexpressing metastatic breast cancer, trastuzumab with chemotherapy (paclitaxel or AC) yielded an overall response rate of 50% (10). Although that study and the present trials cannot be compared directly, the patients in the current studies appear to have had similar extent of disease, performance status, and history of prior adjuvant chemotherapy (although it should be noted that approximately 20% of patients treated with paclitaxel–trastuzumab in the randomized trial had received prior high-dose chemotherapy with stem cell support). The response rates in the current studies compare favorably with those of both treated populations in the registrational trial (10); those receiving AC with trastuzumab had a 58% response rate, and those receiving paclitaxel with trastuzumab had a 41% response rate (10). Additional preliminary results from recently conducted phase II trials using trastuzumab in conjunction with weekly docetaxel, paclitaxel, vinorelbine, gemcitabine, and liposomal doxorubicin report response rates of {approx}30%–87% (21,5460). Results from the two trials presented herein compare favorably with these reports. The median times to progression in the trials reported in this article are the longest yet reported for a trastuzumab-based combination regimen, and they compare favorably with the time to progression of 7.9 months reported in the randomized trial (10). Taken together, these data suggest that TCH may be one of the most active trastuzumab-based combination regimens for HER2-positive breast cancers, and phase III trials using the TCH regimen in the metastatic, neoadjuvant, and adjuvant settings are currently underway (6168).

One observation that emerged from the earlier randomized trial was that patients whose tumors exhibited HER2 gene amplification as determined by FISH analysis had the greatest likelihood of responding to trastuzumab (10,69). In the current trials, we found a similar result in the UCLA-ORN trial for which the overall response rate for FISH-positive patients was 63% versus 41% for FISH-negative patients. However, in the BCIRG 101 trial, no difference in response rates was noted among women whose tumors were FISH-positive (response rate = 77%) or FISH-negative (response rate = 84%). However, the number of patients in each group was small, preventing a meaningful statistical comparison. The high response rate, even among patients whose tumors were negative for HER2 amplification by FISH, suggests that the combination of docetaxel and cisplatin is highly active in breast cancer, irrespective of HER2 status. In contrast to the response data, however, in these trials, the median time to progression in patients with FISH-positive tumors who received first-line treatment was substantially longer than that of patients with FISH-negative tumors (12.7 months versus 7.9 months, respectively, for patients in the BCIRG 101 trial, and 17.4 months versus 7.4 months, respectively, for patients in the UCLA-ORN trial), a result that compares favorably to what was observed in the earlier randomized study (10).

Patient tolerance for both TCH regimens was satisfactory. Only 5% of patients discontinued therapy because of unacceptable toxicity, a rate that would likely occur with docetaxel and platinum salt combinations alone. Indeed, the adverse events observed in these trials were generally those anticipated from a docetaxel and platinum salt combination, suggesting that the addition of trastuzumab did not increase toxicity (10,13,2932,3540). Importantly, only one patient on each trial developed symptomatic congestive heart failure, an incidence substantially below that encountered in the registrational trial in patients receiving AC with trastuzumab. These data confirm the lack of a clinically significant interaction between docetaxel and trastuzumab (in terms of cardiotoxicity) reported in other studies (2124,90).

Additional phase II and III trials are currently evaluating the trastuzumab–docetaxel combination, and the BCIRG is conducting a randomized trial comparing TCH with trastuzumab–docetaxel (TH) in patients with HER2-amplified (FISH-positive) metastatic breast cancer (71). The results of these additional studies should further elucidate the possible benefit of platinum salts in combination with trastuzumab and docetaxel and shed further light on the clinical predictive value of synergistic interactions observed in a preclinical setting. Recently, a randomized phase III trial comparing paclitaxel plus trastuzumab versus paclitaxel plus carboplatin plus trastuzumab in HER2-overexpressing advanced breast cancer has been reported (72). Statistically significantly higher response rates (52% versus 32%; P = .04) and longer time to progression (11.2 months versus 6.9 months; P = .007) were observed in the paclitaxel plus carboplatin plus trastuzumab arm compared with the paclitaxel plus trastuzumab arm, demonstrating that integration of the synergistic platinum salt–trastuzumab combination with taxanes results in superior clinical efficacy.

The efficacy and safety of TCH, as demonstrated in the UCLA-ORN and BCIRG studies, provide rationale for evaluating such regimens in the adjuvant setting. The BCIRG has initiated a randomized trial comparing TCH (carboplatin) to AC followed by docetaxel and trastuzumab (AC->TH), or AC followed by docetaxel (AC->T) in 3150 women with lymph node–positive or high-risk lymph node–negative disease. Carboplatin is being used exclusively in this adjuvant trial on the basis of the toxicity profiles gleaned in the two present trials and the comparable efficacy of the two agents. In contrast to other adjuvant trastuzumab studies (7375), all patients in the BCIRG adjuvant trastuzumab study must have FISH-positive tumors (as measured in centralized reference laboratories). Patients receiving trastuzumab and docetaxel after AC will be carefully monitored for cardiac function, and this arm of the trial could be discontinued if any significant increased incidence of cardiac toxicity emerges.

In conclusion, TCH appears to be highly active in the treatment of advanced breast cancers that overexpress HER2. More importantly, the median times to progression emerging from the current phase II trials are among the longest times reported to date for a patient population with HER2-positive metastatic breast cancer. The toxicity of the regimen is manageable and is consistent with that observed in other clinical settings for the combination of docetaxel plus platinum salts. Finally, there is a low incidence of clinically significant cardiac dysfunction with the TCH regimen and, as with other trastuzumab-based regimens, the cardiac dysfunction appears to be reversible with appropriate clinical management (11). Ongoing randomized trials will ultimately determine the role of this nonempirically developed (TCH) regimen in both the advanced and adjuvant settings and will determine whether the use of TCH will alter the natural history of HER2-positive breast cancer (49).


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
M. D. Pegram is a consultant for Genentech, maker of Herceptin; Aventis Pharmaceuticals, maker of docetaxel; and Bristol-Meyers Squibb, maker of carboplatin. T. Pienkowski currently conducts research sponsored by Aventis Pharmaceuticals and Hoffman-La Roche. P. Fumoleau is a consultant for Hoffman-La Roche, France, Aventis Pharmaceuticals, Pierre Fabre Oncology, Orthobiotechnology, and Novartis, France. J. Crown has received research support and speaker honoraria from Aventis Pharmaceuticals, Bristol-Meyers Squibb, Genentech, and Hoffman-La Roche. A. Riva holds stock in Aventis Pharmaceuticals, conducts clinical research sponsored by Aventis Pharmaceuticals and Genentech, and is a member of the speakers’ bureau for Aventis Pharmaceuticals. M. F. Press is a member of the speakers’ bureau for Aventis Pharmaceuticals. D. J. Slamon is a member of speakers’ bureau for Genentech and Aventis Pharmaceuticals.

Supported by a grant from Aventis Pharmaceuticals. The BCIRG 101 study was also supported by Hoffman-La Roche.

We acknowledge the following individuals for their contribution to this work: UCLA-ORN investigators: John Glaspy, Erin Ellis, Sebastian George (deceased), Nora Ku, Beth Overmoyer, Jerome L. Rubin, James D. Sanchez, Susan Tannenbaum, Joan Trey, Deborah J. Villa, Rafat Ansari, John Barstis, Alexander Black, Donald H. Berdeaux, Thomas P. Bradley, G. Thomas Budd, Gabriel Carabulea, Sheldon J Davidson, Phillip Gold, Frederic C. Kass, Michael Milder, Madan Mukopadhyay, Giribala Patel, Shamel Sanani, Carl L. Singerman, Grant Swanson, John Tate, N. Simon Tchekmedyian, Mary Territo, D. Vicario, Arnold Wax, David Weng, and Thomas Woliver. BCIRG investigators: Paul Klimo, Miguel Martin Jimenez, Gunter Von Minckwitz, Catherine Prady, Moise Namer, Shailendra Verma, Emilio Alba Conejo, Henri Roche, Shou-Ching Tang, Silvana Spadafora, Barbara Walley, and Louise Yelle. UCLA-ORN and BCIRG Network staff: Lisa Yonemoto, Nathalie Chorn, Lenora Gordon, Lilliana Mariscal, Nancy Ryba, Camille Loret, Jim Mortimer, Nathalie Noel, and Jerome Zobel.

We thank Bart Vanhauwere, Jacqueline Hilger, and Christina Yeon for their thoughtful review of the manuscript.


    REFERENCES
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 Patients and Methods
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Manuscript received August 12, 2003; revised March 16, 2004; accepted March 22, 2004.


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