The Oncologist, Vol. 6, Suppl 3, 22-25,
June 2001
© 2001 AlphaMed Press
Docetaxel and Herceptin: Foundation for Future Strategies
Mark D. Pegram
UCLA School of Medicine, Division of Hematology/Oncology, Los Angeles, California, USA
Correspondence:
Mark D. Pegram, M.D., UCLA School of Medicine, Division of Hematology/Oncology, 11-934 Factor Building, Mail Code 167817, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. Telephone: 310-206-9841; Fax: 310-825-6192.
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ABSTRACT
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Randomized controlled studies have demonstrated that both docetaxel and Herceptin are capable of increasing survival in patients with metastatic breast cancer. The two agents show synergy in vitro, and their use in combination is not likely to be associated with the problem of enhanced cardiotoxicity. In two trials of Herceptin plus docetaxel in patients with advanced breast cancer, preliminary data are available for 35 patients. These early results show that the combination is well-tolerated. No symptomatic cardiotoxicity has occurred. The preliminary response rates (RR) in these first- and second-line patients are 44% in one study and 63% in the other. In the subgroups of patients who were HER-2 3+ overexpressers, the RRs are currently 55% and 73%. In an attempt to maximize the efficacy of Herceptin, its use has also been studied in combination with docetaxel and a platinum salt, producing a preliminary RR of 78% in patients positive for HER-2 on the fluorescence in situ hybridization assay. These data are sufficiently promising to justify a study of the role of Herceptin in combination with adjuvant chemotherapy regimens containing docetaxel or docetaxel plus a platinum. The combination of Herceptin with adjuvant therapy containing docetaxel and a platinum may provide a helpful alternative to the potentially cardiotoxic Herceptin/anthracycline-containing regimens currently under investigation.
Key Words. Breast cancer • Docetaxel • Herceptin • HER-2 • Overexpression
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INTRODUCTION
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This paper reviews studies of the interaction of various cytotoxic agents with Herceptin and then provides an update on the ongoing clinical trial program investigating the combination of docetaxel with Herceptin in patients with metastatic breast cancer. Novel Herceptin combinations that do not involve anthracyclines and therefore avoid the risk of additive cardiotoxicity are discussed.
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HERCEPTIN INTERACTION WITH CYTOTOXIC DRUGS
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Previously, Chou and Talalay developed a computer model for studying the interaction between any two cytotoxic agents [1]. According to this model, a term called the combination index (CI) has a value of 1 when the two agents are additive in effect, a value of greater than 1 when they have antagonistic effects, and a value of less than 1 when there is synergistic interaction. Evidence of synergy between two agents on this model provides rationale for advancing clinical use of the drugs in combination, especially when synergy is specific for tumor cells and not normal cells.
A series of initial in vitro studies was conducted in which Herceptin was combined with conventional cytotoxic agents [2-5]. Use of the Chou and Talalay CI showed evidence of synergy when Herceptin was combined with the platinum agents cisplatin and carboplatin, and when it was given together with etoposide or thiotepa [2-6]. With doxorubicin, paclitaxel, methotrexate and vinblastine, Herceptin appeared to have an additive effect, while the combination of Herceptin with 5-fluorouracil was antagonistic [2-5]. Following this initial series of studies, investigation of the possible interaction of Herceptin was extended to include a series of newer drugs with activity in breast cancer. A surprising result of this investigation was that docetaxel showed synergy with Herceptin [3-5]. This contrasted with the additive effect that had been expected based on prior experience with paclitaxel. These studies have recently been extended using four different HER-2-overexpressing cell lines [7]. These data are summarized in Table 1
. With paclitaxel, the CI has confidence intervals that overlap 1.0 for each of the cell lines, indicating an additive effect. However, in the case of docetaxel, the values observed are significantly less than 1.0, indicating synergy.
The difference between the two taxanes is evident both for the SK-BR3 and BT-474 lines which highly overexpress HER-2 (and have 1.5-2 million copies of the HER-2 receptor per cell) and for the MDA-MB 361 and 453 lines, which overexpress HER-2 to a lesser degree.
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RATIONALE FOR THE DOCETAXEL/HERCEPTIN COMBINATION
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Docetaxel is arguably the most active single agent in metastatic breast cancer [8]. It has proven superiority to monotherapy with doxorubicin and has shown a survival advantage compared with a standard combination chemotherapy regimen when used in patients who have failed anthracycline-containing chemotherapy [9, 10]. Herceptin has also demonstrated a significant survival benefit in metastatic breast cancer [11, 12].
In the pivotal clinical trial of Herceptin, patients treated with doxorubicin plus cyclophosphamide plus Herceptin had a 28% risk of developing congestive heart failure [11]. Although largely subclinical, there were cases of overt heart failure in these patients, suggesting that doxorubicin plus Herceptin is a problematic combination. Docetaxel has not been associated with cardiotoxicity and may therefore prove a more appropriate partner for Herceptin [13]. Finally, the preclinical models (reviewed above) used to assess the interaction between taxanes and Herceptin have shown additive effects in the case of paclitaxel but synergy with docetaxel [3-5].
Such considerations amply justified investigation of the combination of Herceptin with docetaxel in patients with advanced breast cancer.
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DOCETAXEL AND HERCEPTIN AS FIRST- OR SECOND-LINE THERAPY FOR WOMEN WITH HER-2-OVEREXPRESSING METASTATIC BREAST CANCER
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In the study by Burris et al., docetaxel is being given at a dose of 75 mg/m2 q 3 weeks together with weekly i.v. Herceptin at the standard dose of 2 mg/kg [5, 14]. The initial 21 patients whose data are available for analysis had a median age of 54 years (range 36-72 years). Fourteen of these women had the highest level of HER-2 overexpression (3+), while the remaining women had a level of 2+. HER-2 overexpression correlates with absence of estrogen receptor expression, and 11 of these women were ER–. The patients included in this study had had extensive prior therapy: 12 had had radiation therapy, 15 hormonal therapy and 16 chemotherapy (which in three cases had been high-dose and supported by stem cell transplantation). Nine of the 21 patients had been exposed to anthracyclines.
A total of 108 courses of combined docetaxel and Herceptin have been administered and 8 of 21 are still receiving the combination. The number of cycles given has ranged from one to nine (median 6). Twelve patients have received six or more cycles. After receiving six or more cycles of the combination, five patients continued to receive Herceptin alone until progression.
Toxicity
Grade 3 myelosuppression has been the primary toxicity, although only 1 of 21 patients has been hospitalized for febrile neutropenia. Five patients received G-CSF during treatment. Grade 2 dermatitis was seen in two patients, and grade 3 dermatitis in one patient resulted in treatment withdrawal. No significant cardiotoxicity has been observed, i.e., there were no patients in whom the left ventricular ejection fraction (LVEF) dropped by 20% or more to a value of less than 50% or in whom the LVEF was below 40%. There were no cases of symptomatic congestive heart failure.
Activity
Preliminary data available for the first 16 patients show one complete (CR) and six partial responses (PR), giving an overall response rate (RR) of 44%. Six of the seven responses occurred in patients who were 3+ HER-2, giving a 55% RR in this subgroup (compared with 20% in those who were 2+ HER-2). The median time to progression is greater than 6 months. Although median follow-up is still short, 18 of the 21 patients treated remain alive.
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A PHASE II TRIAL OF WEEKLY DOCETAXEL PLUS HERCEPTIN IN ADVANCED BREAST CANCER
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In a second study, an initial 25 patients are being treated with weekly 35 mg/m2 docetaxel for 6 of 8 weeks plus weekly Herceptin at 2 mg/kg [15]. Preliminary data are available on 69 cycles delivered to 21 patients, with the median number of cycles delivered being three (range 1-7) and the median follow-up 9 months.
The median age of the patients whose data are available is 53 years (range 35-73 years). Fifteen of the 21 (71%) are HER-2 3+. The median number of disease sites is two, and these are predominantly visceral.
Response data are available for 19 patients. There were two CR and 10 PR, giving an overall RR of 63%. In the HER-2 3+ subgroup, the RR was 73%. Median response duration has not yet been reached.
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MAXIMIZING THE EFFICACY OF HERCEPTIN COMBINATIONS: TRIPLE THERAPY
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It is reasonable to suggest that the clinical benefits of Herceptin will be most clearly evident when it is used in combination with cytotoxic drugs that are highly active in breast cancer, noncardiotoxic, and shown to have synergistic effects with each other and the new agent.
Using the Chou and Talalay computer model, the three-drug combination of docetaxel with platinum salts and Herceptin (TCH) has been shown to be highly synergistic across the entire cytotoxic dose range.
In a trial being conducted by the UCLA Oncology Research Network, docetaxel is being given at a dose of 75 mg/m2 together with carboplatin to an area under the concentration time curve (AUC) of 6 mg/ml x min q 3 weeks accompanied by weekly Herceptin (Fig. 1). In a comparable BCIRG pilot study, docetaxel 75 mg/m2 is being administered together with cisplatin 75 mg/m2, again with the standard weekly Herceptin dose (Fig. 1).
In the UCLA program, 30 of the 43 patients enrolled are evaluable for safety and 18 for response. In total, there have been 134 cycles of TCH administered, and 433 administrations of weekly Herceptin. While neutropenia has occurred in 22 of 30 patients, only four have had febrile neutropenia and there have been no cases of clinically overt infection. Since there is HER-2 expression in the kidney, there might be potential for renal toxicity. It is therefore encouraging that no cases of renal toxicity have been seen. Two of 30 patients (one of whom had been exposed to anthracyclines) have shown asymptomatic decreases in LVEF: in one patient, the initial value of 77% fell to 61%; in the second case, LVEF fell from 59% to 43%. Four patients experienced grade I/II neurologic toxicity, but there was only one case of grade III asthenia.
There have been three CR and five PR among 18 evaluable patients. Two of the three CR and four of the five PR occurred among the nine patients who were positive on the HER-2 fluorescence in situ hybridization (FISH) assay (an RR in this subgroup of 78%).
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DISCUSSION
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Both the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Intergroup cooperative organizations in the United States are conducting trials in which adjuvant Herceptin is added to paclitaxel-containing adjuvant chemotherapy regimens in the experimental arm, following four cycles of an anthracycline-based regimen.
Data from the pilot studies reviewed above are sufficiently promising for an adjuvant study to have been designed to assess the role of Herceptin in combination with alternative docetaxel-containing adjuvant chemotherapy regimens. In the BCIRG 006 trial, 3,000 HER-2-positive women who are node-positive or high-risk node-negative will be randomized to one of three arms (Fig. 2). In the first, four cycles of AC are followed by four cycles of docetaxel 100 mg/m2. In the second arm of the study, four cycles of AC are followed by four cycles of docetaxel accompanied by weekly i.v. Herceptin, with the Herceptin administration maintained for 1 year. In the third arm of the study, patients receive six cycles of the novel combination of docetaxel plus platinum salts (at a dose of 75 mg/m2 for cisplatin or to an AUC of 6 mg/ml x min for carboplatin) accompanied by i.v. administration of Herceptin starting with the first dose of chemotherapy and maintained for 1 year.
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Figure 2. BCIRG 006 adjuvant breast cancer trial in node-positive and high-risk node-negative patients: treatment schedule.
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The third arm of the study should avoid any problems of cardiotoxicity that may be associated with other adjuvant regimens to which Herceptin is added. In BCIRG 006, patients assigned to the second arm of the study (in which Herceptin plus docetaxel follows four cycles of AC) will be carefully monitored, and recruitment to this arm of the study will be halted if any indications of cardiotoxicity emerge. The rest of the trial, however, will proceed. This is one advantage of the BCIRG study design over those of the NSABP and Intergroup. A further consideration is that HER-2-positive patients in the BCIRG trial have a two-in-three chance of being randomized to adjuvant therapy containing Herceptin. Finally, patient eligibility for this trial will be based on the FISH assay—the most accurate test available for detection of the HER-2 alteration.
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REFERENCES
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Received February 6, 2001;
accepted for publication March 5, 2001.
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Abstract
Introduction
