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Gemcitabine and trastuzumab in metastatic breast cancer
Gemcitabine and Trastuzumab in Metastatic Breast Cancer Joyce O’Shaughnessy The background, rationale, and preliminary results of a phase II trial of gemcitabine plus trastuzumab in heavily pretreated metastatic breast cancer patients are presented. Gemcitabine and trastuzumab both exhibit single-agent activity in previously treated metastatic breast cancer. Preclinical studies of gemcitabine and trastuzumab in combination showed additive or synergistic antitumor effects in human breast cancer cell lines that overexpress HER2. A multicenter phase II trial was thus conducted to define the safety and efficacy of gemcitabine/trastuzumab in patients previously treated for metastatic breast cancer. Women with measurable metastatic breast cancer whose primary or secondary tumor overexpressed HER2 were eligible for inclusion. Gemcitabine 1,200 mg/m2 was administered on days 1 and 8 of a 21-day cycle. Trastuzumab was administered at a loading dose of 4 mg/kg initially, then at 2 mg/kg weekly thereafter. Preliminary analysis of 38 evaluable patients showed that gemcitabine/trastuzumab was well tolerated and had significant antitumor activity in this patient population. The study is now concluded, and final analysis of the data is nearing completion. Publication of the results is anticipated in 2003. Semin Oncol 30 (suppl 3):22-26. © 2003 Elsevier Inc. All rights reserved.
S
INCE 1989, a modest decrease in overall breast cancer mortality has occurred in the United States.1 Between 1950 and the late 1980s mortality was relatively stable. However, from 1989 to 1995, mortality decreased by 1.6% and improved further to 3.4% annually between 1995 and 1998.2 Despite these improvements in breast cancer survival, survival rates for women with metastatic breast cancer remain poor, on the order of 21% at 5 years (Fig 1). Approximately 7% of newly diagnosed women present with metastatic disease,3 and another 20% to 30% of women diagnosed with early-stage breast cancer will eventually develop metastatic disease.4
From the Baylor-Charles A. Sammons Cancer Center, Baylor University Medical Center, Texas Oncology PA, US Oncology, Dallas, TX. Dr. O’Shaughnessy has served as a consultant and member of the speakers’ bureau to Eli Lilly. Address reprint requests to Joyce O’Shaughnessy, MD, US Oncology, 3535 Worth St, Collins 5, Dallas, TX 75246. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3002-0307$30.00/0 doi:10.1053/sonc.2003.37272 22
Since the widespread adoption of chemotherapy for metastatic disease in the 1970s, clinicians have learned to accept that metastatic breast cancer remains an incurable disease. On average, chemotherapy improves survival by 9 to 10 months.5 Accordingly, the primary goal of treatment is palliation—prolonging life and improving quality of life. Currently, anthracyclines and taxanes are considered the most active agents for first-line treatment of metastatic disease. Salvage chemotherapy for metastatic breast cancer following anthracycline and taxane therapy, though not yet proven to improve overall survival, can palliate tumor-related symptoms in patients whose disease responds to therapy. A relatively new agent that has shown efficacy in a variety of solid tumors, including metastatic breast cancer, is gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN). Both gemcitabine and trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), the humanized antiHER2 monoclonal antibody, have shown singleagent activity in previously treated metastatic breast cancer. In preclinical studies, combined gemcitabine/trastuzumab treatment resulted in additive or synergistic antitumor effects in human breast cancer cell lines that overexpress the human epidermal growth factor receptor 2 (HER2) protein.6 The established activity of these agents, coupled with the relatively mild side-effect profiles of each drug, make the gemcitabine/trastuzumab combination an attractive treatment option for patients with pretreated metastatic breast cancer. Accordingly, a phase II study was initiated in 1999 to determine the safety and efficacy of gemcitabine plus trastuzumab in patients with HER2- positive metastatic breast cancer that had been previously treated with chemotherapy. This study is now completed and undergoing final analysis. The study rationale and preliminary results are briefly reviewed herein.7 GEMCITABINE
Gemcitabine (2⬘,2⬘-difluorodeoxycytidine) is a cytotoxic nucleoside analogue with a novel mechanism of action (Fig 2). Gemcitabine is metabolized intracellularly by nucleoside kinases to active Seminars in Oncology, Vol 30, No 2, Suppl 3 (April), 2003: pp 22-26
GEMCITABINE ⫹ TRASTUZUMAB IN BREAST CANCER
23
and capecitabine, is not associated with alopecia. The safety and efficacy of gemcitabine make it a reasonable choice for salvage therapy in the palliative treatment of metastatic breast cancer. TRASTUZUMAB
Fig 1. Five-year breast cancer survival rates by stage at diagnosis. Survival rates are based on follow-up of patients through 1997. American Cancer Society, Surveillance Research, 2001. (Data source: Nationa Cancer Institute Surveillance, Epidemiology, and End Results Program, 2001.)
diphosphate and triphosphate nucleosides. A combination of two actions of the diphosphate and triphosphate nucleosides leads to cytotoxicity via inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, the enzyme responsible for the production of the deoxynucleotide triphosphates essential for DNA synthesis.8 Second, gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. When gemcitabine triphosphate is incorporated into DNA, the error in the DNA chain is masked. Thus, exonuclease enzymes are unable to remove the gemcitabine nucleotide and repair the growing DNA strands, resulting in masked DNA chain termination. The antitumor activity of gemcitabine is selfpotentiated, as the reduction in the intracellular concentration of deoxycytidine triphosphate (by action of gemcitabine diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA. It has been theorized that self-potentiation might be the mechanism by which gemcitabine achieves higher concentrations and persists longer in tumor cells, and exhibits greater activity against solid tumors than does cytosine arabinoside.9,10 In phase II studies, single-agent gemcitabine is associated with objective antitumor responses of 14% to 37% in patients previously treated with anthracyclines for metastatic breast cancer.10-13 In more heavily pretreated metastatic breast cancer following anthracycline and taxane treatment, objective response rates of 14.0% to 22.6% have been documented with gemcitabine.14,15 Further, gemcitabine is well tolerated and, like vinorelbine
Trastuzumab is a recombinant, DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the HER2 protein.16,17 Specifically, trastuzumab targets and inhibits the proliferation of human tumor cells that overexpress HER2. Approximately 25% to 30% of patients with breast cancer have tumors that overexpress HER2.18-20 The degree of HER2 present in tumor is expressed using a scale from 0 (negative) to 3⫹ (strongly positive). A strong relationship exists between the degree of HER2 expression and response to treatment with trastuzumab, with beneficial effects largely limited to patients with the highest level of HER2 overexpression (3⫹). Like gemcitabine, trastuzumab is well tolerated and is also an active agent for the treatment of HER2-positive metastatic breast cancer; objective response rates of 15% to 26% with trastuzumab as a single agent have been reported.21,22 A pivotal phase 3 study in 469 women with metastatic breast cancer showed that a trastuzumab/chemotherapy combination significantly prolonged time to disease progression and increased median overall survival compared with chemotherapy alone in women who had HER2-overexpressing tumors.23,24
Fig 2. Chemical structure of gemcitabine (2ⴕ, 2ⴕ-difluorodeoxycytidine).
24
JOYCE O’SHAUGHNESSY
Currently, trastuzumab is approved as singleagent treatment for previously treated metastatic breast cancer patients whose tumors overexpress HER2. Trastuzumab is also indicated in combination with paclitaxel for treatment of patients with metastatic breast cancer who have not received chemotherapy for their metastatic disease and whose tumors overexpress HER2. GEMCITABINE/TRASTUZUMAB IN METASTATIC BREAST CANCER
Preclinical data suggest that gemcitabine/trastuzumab has either additive or synergistic antitumor effects against human breast cancer cell lines that overexpress HER2. Table 1 compares gemcitabine to other agents known to have synergistic antitumor activity with trastuzumab.6 The combination index is a measure of antitumor additivity or synergism between agents, with a combination index less than 1 signifying synergistic antitumor activity. The combination index is 0.57 for gemcitabine and trastuzumab in cell culture against the strongly HER2-overexpressing SKBR3 human breast cancer cell line, which is similar to that described with vinorelbine and cisplatin, agents known to have marked synergistic antitumor activity in the clinical setting.6 To further investigate the potential of this combination, a multicenter phase II trial was conducted to define the safety and antitumor activity of gemcitabine and trastuzumab in patients with measurable metastatic breast cancer. PATIENTS AND METHODS
Patients for this study were accrued through the US Oncology network (Dallas, TX). Women with metastatic breast cancer having at least one bidimensionally measurable disease site were eligible for inclusion. Either the primary or secondary tu-
Table 1. Combination Index: Trastuzumab (8 to 10 mol/L) ⴙ Chemotherapy Cell Line H322 (Ad) A549 (Ad) SHP77 (SC) SKBR3 (Br)
Gemcitabine Cisplatin Paclitaxel Vinorelbine 0.21 0.09 ⬎ 2.0 0.57
0.29 0.06 ND 0.76
0.76 0.67 0.9 0.89
Adapted and reprinted with permission.6
0.89 0.88 ⬎ 2.0 0.61
mor had to overexpress HER2 (2⫹ or 3⫹) as demonstrated by immunohistochemical analysis conducted by a local laboratory. However, a central pathology review was conducted to ensure HER2 positivity and patient eligibility. A normal baseline left ventricular ejection fraction (LVEF) on cardiac multiple-gated acquisition scan was required, along with an Eastern Cooperative Oncology Group performance status ⱕ 2. Adequate hematologic, renal, and hepatic function was required. Up to three prior chemotherapy regimens were permitted, but prior treatment with trastuzumab or gemcitabine was not allowed. A life expectancy of at least 3 months was required. Patients were excluded if they had a history of clinically significant cardiac disease within the past 12 months. Women who were pregnant or lactating were ineligible. All patients provided written informed consent before entering the study. Treatment consisted of gemcitabine 1,200 mg/m2 administered intravenously over 30 minutes on days 1 and 8 of each 21-day cycle, provided the absolute neutrophil count was ⬎ 1,000/L. If the absolute neutrophil count was ⱕ 1000/L on day 8, gemcitabine was withheld (weekly trastuzumab was continued). Dose reductions to 1,000 mg/m2 were made in the event of grade 3/4 nonhematologic toxicity. Trastuzumab was administered as a standard loading dose of 4 mg/kg intravenously over 90 minutes, followed by a dose of 2 mg/kg administered over 30 minutes weekly. Both agents were continued until disease progression. PRELIMINARY RESULTS
Of 64 patients entered on this study, 38 were evaluable for response and toxicity at preliminary analysis.7 Median age for these initial 38 patients was 53 years. Twenty patients’ breast cancers (53%) were estrogen receptor/progesterone receptor-positive, and 22 (58%) had received prior hormonal therapy. Fifteen patients’ breast cancers (39%) were HER2 2⫹ positive and 23 (61%) were 3⫹ positive according to immunohistochemical analysis. Sites of visceral metastatic disease included lung in 24 patients (63%) and liver in 23 (61%). Other sites included bone in 17 patients (45%), brain in five patients (13%), and 21 patients (55%) had soft-tissue metastases. The median number of metastatic sites was two. The patients in this study were heavily pre-
GEMCITABINE ⫹ TRASTUZUMAB IN BREAST CANCER
25
treated. Of 38 evaluable patients, 35 (92%) had received prior adjuvant therapy. Only one patient had received no prior chemotherapy for metastatic breast cancer. Eleven patients (29%) had received one prior regimen for metastatic disease, 20 (53%) received two prior regimens, and six (16%) received three prior regimens. The median number of prior regimens received was three. Eighty-nine percent of patients had been previously treated with doxorubicin, 58% with paclitaxel, and 47% with docetaxel. The median number of cycles received was 4.5. No complete responses were observed. Twelve of 38 patients experienced partial responses (32%). The median duration of response was 8.6 months. Stable disease was seen in 16 patients (42%). Median time to disease progression was 6.7 months at the preliminary analysis; median overall survival was 10.2 months. No unexpected toxicities were noted, nor was any clinically significant cardiac toxicity observed at the preliminary analysis. No clinically significant congestive heart failure occurred. Four patients experienced a ⱖ 15-point decrease in LVEF, two of whom had an LVEF less than 45% at some time during treatment. This led to no discontinuations in therapy. Table 2 shows the number of patients who experienced grade 3/4 hematologic and/or nonhematologic toxicities. Only three incidences of grade 4 toxicity were observed with the gemcitabine/trastuzumab combination; two patients developed transient grade 4 neutropenia,
Table 2. Incidence of Grade 3/4 Hematologic and Nonhematologic Toxicities No. of Patients
Asthenia Fever Dyspnea Neutropenia Abdominal or back pain Edema Dehydration Rash Alopecia Neuropathy Mucositis
Grade 3
Grade 4
2 3 3 7 4 1 0 0 0 0 0
0 1 0 2 0 0 0 0 0 0 0
one of whom also developed grade 4 fever. No grade 4 nonhematologic toxicities were observed. DISCUSSION
Preliminary analysis of this phase II study suggests that gemcitabine 1,200 mg/m2 administered on days 1 and 8 of a 21-day schedule is a reasonable dose in heavily pretreated patients with metastatic breast cancer. The combination of gemcitabine and trastuzumab administered as a 4 mg/kg loading dose, then 2 mg/kg weekly thereafter was well tolerated in this group of heavily pretreated patients. No unexpected toxicities were observed. Grade 4 neutropenia occurred in a minority of patients, and the decline in LVEF observed in four patients was not clinically significant. The preliminary analysis also suggests that this combination has significant antitumor activity in heavily pretreated patients with metastatic breast cancer whose disease is 2⫹ or 3⫹ HER2-positive according to immunohistochemical analysis. It is worth noting that this clinical trial could not be reproduced today, because trastuzumab is now administered much earlier in the course of metastatic disease for HER2 overexpressors. Therefore, the final results of this study will be primarily of historical interest but do justify continued studies of the gemcitabine/trastuzumab combination. CONCLUSION
Anthracyclines and taxanes are considered the most active agents for first-line treatment of women with metastatic breast cancer. Many patients are candidates for third- and fourth-line chemotherapy regimens to palliate symptoms and possibly prolong survival. The interim analysis of this phase II study of gemcitabine and trastuzumab suggests that the combination is safe and has significant antitumor activity in heavily pretreated patients with HER2-positive metastatic breast cancer who have not been previously treated with either agent. The final analysis of the safety and antitumor activity of this combination in all 64 patients treated in this phase II study is nearing completion. Publication of the complete results is anticipated to occur in 2003. REFERENCES 1. American Cancer Society: Breast Cancer Facts & Figures 2001-2002. Atlanta, GA, American Cancer Society, 2002
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2. Howe HL, Wingo PA, Thun MJ, et al: The annual report to the nation on the status of cancer (1973-1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 93: 824-842, 2001 3. American Cancer Society: 1999 Facts and Figures, Available at: http://www.cancer.org/statistics/cff99/data/data_leadingNew Cancer.html (accessed March 9, 1999) 4. Ellis MJ, Hayes DF, Lippman ME: Treatment of metastatic breast cancer, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of the Breast. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 749-798 5. Cold S, Jensen NV, Brincker H, et al: The influence of chemotherapy on survival after recurrence in breast cancer: A population-based study of patients treated in the 1950s, 1960s, and 1970s. Eur J Cancer 29A:1146-1152, 1993 6. Bunn PA Jr, Helfrich B, Soriano AF, et al: Expression of HER2/neu in human lung cancer cell lines by immunochemistry and fluorescence in situ hybridization and its relationship to in vitro cytotoxicity by trastuzumab and chemotherapeutic agents. Clin Cancer Res 7:3239-3250, 2001 7. O’Shaughnessy J, Vukelja SJ, Marsland T, et al: Phase II trial of gemcitabine plus trastuzumab in metastatic breast cancer patients previously treated with chemotherapy: Preliminary results. Clin Breast Cancer 3:S17-S20, 2002 (suppl 1) 8. Huang P, Chubb S, Hertel LW, et al: Action of 2’,2’difluorodeoxycytidine on DNA synthesis. Cancer Res 51:61106117, 1991 9. Heinemann V, Hertel L, Grindey GB, et al: Cellular elimination of 2’,2’-difluorodeoxycytidine 5’-triphosphate (dFdCTP). Proc Am Assoc Cancer Res 29:504, 1988 (abstr) 10. Carmichael J, Possinger K, Phillip P, et al: Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 13:2731-2736, 1995 11. Blackstein M, Vogel CL, Ambinder R, et al: Gemcitabine as first-line therapy in patients with metastatic breast cancer: A phase II trial. Oncology 62:2-8, 2002 12. Possinger K, Kaufmann M, Coleman R, et al: Phase II study of gemcitabine as first-line chemotherapy in patients with advanced or metastatic breast cancer. Anticancer Drugs 10: 155-162, 1999 13. Spielmann M, Llombart-Cussac A, Kalla S, et al: Single-
JOYCE O’SHAUGHNESSY
agent gemcitabine is active in previously treated metastatic breast cancer. Oncology 60:303-307, 2001 14. Brodowicz T, Kostler WJ, Moslinger R, et al: Singleagent gemcitabine as second- and third-line treatment in metastatic breast cancer. Breast 9:338-342, 2000 15. Valerio M, Cicero G, Armata M, et al: Gemcitabine (G) in pretreated breast cancer (BC). Proc Am Soc Clin Oncol 20:51b, 2001 (abstr 1953) 16. Coussens L, Yang-Feng TL, Liao Y-C, et al: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132-1139, 1985 17. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 18. Press MF, Bernstein L, Thomas PA, et al: HER-2/neu gene amplification characterized by fluorescence in situ hybridization: Poor prognosis in node-negative breast carcinomas. J Clin Oncol 15:2894-2904, 1997 19. Stender M, Neuberg D, Wood W, et al: Correlation of circulating c-erb B-2 extracellular domain with clinical outcome in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 16:154a, 1997 (abstr) 20. Pegram MD, Pauletti G, Slamon DJ: HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52:65-77, 1998 21. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999 22. Vogel CL, Cobleigh M, Tripathy D, et al: First-line, single-agent Herceptin (trastuzumab) in metastatic breast cancer: A preliminary report. Eur J Cancer 37:25-29, 2001 23. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 344:783-792, 2001 24. Pegram MD, Lopez A, Konecny G, et al: Trastuzumab and chemotherapeutics: Drug interaction and synergies. Semin Oncol 27:21-25, 2000 (suppl 11)
S
INCE 1989, a modest decrease in overall breast cancer mortality has occurred in the United States.1 Between 1950 and the late 1980s mortality was relatively stable. However, from 1989 to 1995, mortality decreased by 1.6% and improved further to 3.4% annually between 1995 and 1998.2 Despite these improvements in breast cancer survival, survival rates for women with metastatic breast cancer remain poor, on the order of 21% at 5 years (Fig 1). Approximately 7% of newly diagnosed women present with metastatic disease,3 and another 20% to 30% of women diagnosed with early-stage breast cancer will eventually develop metastatic disease.4
From the Baylor-Charles A. Sammons Cancer Center, Baylor University Medical Center, Texas Oncology PA, US Oncology, Dallas, TX. Dr. O’Shaughnessy has served as a consultant and member of the speakers’ bureau to Eli Lilly. Address reprint requests to Joyce O’Shaughnessy, MD, US Oncology, 3535 Worth St, Collins 5, Dallas, TX 75246. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3002-0307$30.00/0 doi:10.1053/sonc.2003.37272 22
Since the widespread adoption of chemotherapy for metastatic disease in the 1970s, clinicians have learned to accept that metastatic breast cancer remains an incurable disease. On average, chemotherapy improves survival by 9 to 10 months.5 Accordingly, the primary goal of treatment is palliation—prolonging life and improving quality of life. Currently, anthracyclines and taxanes are considered the most active agents for first-line treatment of metastatic disease. Salvage chemotherapy for metastatic breast cancer following anthracycline and taxane therapy, though not yet proven to improve overall survival, can palliate tumor-related symptoms in patients whose disease responds to therapy. A relatively new agent that has shown efficacy in a variety of solid tumors, including metastatic breast cancer, is gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN). Both gemcitabine and trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), the humanized antiHER2 monoclonal antibody, have shown singleagent activity in previously treated metastatic breast cancer. In preclinical studies, combined gemcitabine/trastuzumab treatment resulted in additive or synergistic antitumor effects in human breast cancer cell lines that overexpress the human epidermal growth factor receptor 2 (HER2) protein.6 The established activity of these agents, coupled with the relatively mild side-effect profiles of each drug, make the gemcitabine/trastuzumab combination an attractive treatment option for patients with pretreated metastatic breast cancer. Accordingly, a phase II study was initiated in 1999 to determine the safety and efficacy of gemcitabine plus trastuzumab in patients with HER2- positive metastatic breast cancer that had been previously treated with chemotherapy. This study is now completed and undergoing final analysis. The study rationale and preliminary results are briefly reviewed herein.7 GEMCITABINE
Gemcitabine (2⬘,2⬘-difluorodeoxycytidine) is a cytotoxic nucleoside analogue with a novel mechanism of action (Fig 2). Gemcitabine is metabolized intracellularly by nucleoside kinases to active Seminars in Oncology, Vol 30, No 2, Suppl 3 (April), 2003: pp 22-26
GEMCITABINE ⫹ TRASTUZUMAB IN BREAST CANCER
23
and capecitabine, is not associated with alopecia. The safety and efficacy of gemcitabine make it a reasonable choice for salvage therapy in the palliative treatment of metastatic breast cancer. TRASTUZUMAB
Fig 1. Five-year breast cancer survival rates by stage at diagnosis. Survival rates are based on follow-up of patients through 1997. American Cancer Society, Surveillance Research, 2001. (Data source: Nationa Cancer Institute Surveillance, Epidemiology, and End Results Program, 2001.)
diphosphate and triphosphate nucleosides. A combination of two actions of the diphosphate and triphosphate nucleosides leads to cytotoxicity via inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, the enzyme responsible for the production of the deoxynucleotide triphosphates essential for DNA synthesis.8 Second, gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. When gemcitabine triphosphate is incorporated into DNA, the error in the DNA chain is masked. Thus, exonuclease enzymes are unable to remove the gemcitabine nucleotide and repair the growing DNA strands, resulting in masked DNA chain termination. The antitumor activity of gemcitabine is selfpotentiated, as the reduction in the intracellular concentration of deoxycytidine triphosphate (by action of gemcitabine diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA. It has been theorized that self-potentiation might be the mechanism by which gemcitabine achieves higher concentrations and persists longer in tumor cells, and exhibits greater activity against solid tumors than does cytosine arabinoside.9,10 In phase II studies, single-agent gemcitabine is associated with objective antitumor responses of 14% to 37% in patients previously treated with anthracyclines for metastatic breast cancer.10-13 In more heavily pretreated metastatic breast cancer following anthracycline and taxane treatment, objective response rates of 14.0% to 22.6% have been documented with gemcitabine.14,15 Further, gemcitabine is well tolerated and, like vinorelbine
Trastuzumab is a recombinant, DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the HER2 protein.16,17 Specifically, trastuzumab targets and inhibits the proliferation of human tumor cells that overexpress HER2. Approximately 25% to 30% of patients with breast cancer have tumors that overexpress HER2.18-20 The degree of HER2 present in tumor is expressed using a scale from 0 (negative) to 3⫹ (strongly positive). A strong relationship exists between the degree of HER2 expression and response to treatment with trastuzumab, with beneficial effects largely limited to patients with the highest level of HER2 overexpression (3⫹). Like gemcitabine, trastuzumab is well tolerated and is also an active agent for the treatment of HER2-positive metastatic breast cancer; objective response rates of 15% to 26% with trastuzumab as a single agent have been reported.21,22 A pivotal phase 3 study in 469 women with metastatic breast cancer showed that a trastuzumab/chemotherapy combination significantly prolonged time to disease progression and increased median overall survival compared with chemotherapy alone in women who had HER2-overexpressing tumors.23,24
Fig 2. Chemical structure of gemcitabine (2ⴕ, 2ⴕ-difluorodeoxycytidine).
24
JOYCE O’SHAUGHNESSY
Currently, trastuzumab is approved as singleagent treatment for previously treated metastatic breast cancer patients whose tumors overexpress HER2. Trastuzumab is also indicated in combination with paclitaxel for treatment of patients with metastatic breast cancer who have not received chemotherapy for their metastatic disease and whose tumors overexpress HER2. GEMCITABINE/TRASTUZUMAB IN METASTATIC BREAST CANCER
Preclinical data suggest that gemcitabine/trastuzumab has either additive or synergistic antitumor effects against human breast cancer cell lines that overexpress HER2. Table 1 compares gemcitabine to other agents known to have synergistic antitumor activity with trastuzumab.6 The combination index is a measure of antitumor additivity or synergism between agents, with a combination index less than 1 signifying synergistic antitumor activity. The combination index is 0.57 for gemcitabine and trastuzumab in cell culture against the strongly HER2-overexpressing SKBR3 human breast cancer cell line, which is similar to that described with vinorelbine and cisplatin, agents known to have marked synergistic antitumor activity in the clinical setting.6 To further investigate the potential of this combination, a multicenter phase II trial was conducted to define the safety and antitumor activity of gemcitabine and trastuzumab in patients with measurable metastatic breast cancer. PATIENTS AND METHODS
Patients for this study were accrued through the US Oncology network (Dallas, TX). Women with metastatic breast cancer having at least one bidimensionally measurable disease site were eligible for inclusion. Either the primary or secondary tu-
Table 1. Combination Index: Trastuzumab (8 to 10 mol/L) ⴙ Chemotherapy Cell Line H322 (Ad) A549 (Ad) SHP77 (SC) SKBR3 (Br)
Gemcitabine Cisplatin Paclitaxel Vinorelbine 0.21 0.09 ⬎ 2.0 0.57
0.29 0.06 ND 0.76
0.76 0.67 0.9 0.89
Adapted and reprinted with permission.6
0.89 0.88 ⬎ 2.0 0.61
mor had to overexpress HER2 (2⫹ or 3⫹) as demonstrated by immunohistochemical analysis conducted by a local laboratory. However, a central pathology review was conducted to ensure HER2 positivity and patient eligibility. A normal baseline left ventricular ejection fraction (LVEF) on cardiac multiple-gated acquisition scan was required, along with an Eastern Cooperative Oncology Group performance status ⱕ 2. Adequate hematologic, renal, and hepatic function was required. Up to three prior chemotherapy regimens were permitted, but prior treatment with trastuzumab or gemcitabine was not allowed. A life expectancy of at least 3 months was required. Patients were excluded if they had a history of clinically significant cardiac disease within the past 12 months. Women who were pregnant or lactating were ineligible. All patients provided written informed consent before entering the study. Treatment consisted of gemcitabine 1,200 mg/m2 administered intravenously over 30 minutes on days 1 and 8 of each 21-day cycle, provided the absolute neutrophil count was ⬎ 1,000/L. If the absolute neutrophil count was ⱕ 1000/L on day 8, gemcitabine was withheld (weekly trastuzumab was continued). Dose reductions to 1,000 mg/m2 were made in the event of grade 3/4 nonhematologic toxicity. Trastuzumab was administered as a standard loading dose of 4 mg/kg intravenously over 90 minutes, followed by a dose of 2 mg/kg administered over 30 minutes weekly. Both agents were continued until disease progression. PRELIMINARY RESULTS
Of 64 patients entered on this study, 38 were evaluable for response and toxicity at preliminary analysis.7 Median age for these initial 38 patients was 53 years. Twenty patients’ breast cancers (53%) were estrogen receptor/progesterone receptor-positive, and 22 (58%) had received prior hormonal therapy. Fifteen patients’ breast cancers (39%) were HER2 2⫹ positive and 23 (61%) were 3⫹ positive according to immunohistochemical analysis. Sites of visceral metastatic disease included lung in 24 patients (63%) and liver in 23 (61%). Other sites included bone in 17 patients (45%), brain in five patients (13%), and 21 patients (55%) had soft-tissue metastases. The median number of metastatic sites was two. The patients in this study were heavily pre-
GEMCITABINE ⫹ TRASTUZUMAB IN BREAST CANCER
25
treated. Of 38 evaluable patients, 35 (92%) had received prior adjuvant therapy. Only one patient had received no prior chemotherapy for metastatic breast cancer. Eleven patients (29%) had received one prior regimen for metastatic disease, 20 (53%) received two prior regimens, and six (16%) received three prior regimens. The median number of prior regimens received was three. Eighty-nine percent of patients had been previously treated with doxorubicin, 58% with paclitaxel, and 47% with docetaxel. The median number of cycles received was 4.5. No complete responses were observed. Twelve of 38 patients experienced partial responses (32%). The median duration of response was 8.6 months. Stable disease was seen in 16 patients (42%). Median time to disease progression was 6.7 months at the preliminary analysis; median overall survival was 10.2 months. No unexpected toxicities were noted, nor was any clinically significant cardiac toxicity observed at the preliminary analysis. No clinically significant congestive heart failure occurred. Four patients experienced a ⱖ 15-point decrease in LVEF, two of whom had an LVEF less than 45% at some time during treatment. This led to no discontinuations in therapy. Table 2 shows the number of patients who experienced grade 3/4 hematologic and/or nonhematologic toxicities. Only three incidences of grade 4 toxicity were observed with the gemcitabine/trastuzumab combination; two patients developed transient grade 4 neutropenia,
Table 2. Incidence of Grade 3/4 Hematologic and Nonhematologic Toxicities No. of Patients
Asthenia Fever Dyspnea Neutropenia Abdominal or back pain Edema Dehydration Rash Alopecia Neuropathy Mucositis
Grade 3
Grade 4
2 3 3 7 4 1 0 0 0 0 0
0 1 0 2 0 0 0 0 0 0 0
one of whom also developed grade 4 fever. No grade 4 nonhematologic toxicities were observed. DISCUSSION
Preliminary analysis of this phase II study suggests that gemcitabine 1,200 mg/m2 administered on days 1 and 8 of a 21-day schedule is a reasonable dose in heavily pretreated patients with metastatic breast cancer. The combination of gemcitabine and trastuzumab administered as a 4 mg/kg loading dose, then 2 mg/kg weekly thereafter was well tolerated in this group of heavily pretreated patients. No unexpected toxicities were observed. Grade 4 neutropenia occurred in a minority of patients, and the decline in LVEF observed in four patients was not clinically significant. The preliminary analysis also suggests that this combination has significant antitumor activity in heavily pretreated patients with metastatic breast cancer whose disease is 2⫹ or 3⫹ HER2-positive according to immunohistochemical analysis. It is worth noting that this clinical trial could not be reproduced today, because trastuzumab is now administered much earlier in the course of metastatic disease for HER2 overexpressors. Therefore, the final results of this study will be primarily of historical interest but do justify continued studies of the gemcitabine/trastuzumab combination. CONCLUSION
Anthracyclines and taxanes are considered the most active agents for first-line treatment of women with metastatic breast cancer. Many patients are candidates for third- and fourth-line chemotherapy regimens to palliate symptoms and possibly prolong survival. The interim analysis of this phase II study of gemcitabine and trastuzumab suggests that the combination is safe and has significant antitumor activity in heavily pretreated patients with HER2-positive metastatic breast cancer who have not been previously treated with either agent. The final analysis of the safety and antitumor activity of this combination in all 64 patients treated in this phase II study is nearing completion. Publication of the complete results is anticipated to occur in 2003. REFERENCES 1. American Cancer Society: Breast Cancer Facts & Figures 2001-2002. Atlanta, GA, American Cancer Society, 2002
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