BioOncology Watch Timely Information for Practicing Physicians
april 2001 Metastatic Breast Cancer Trastuzumab combined with chemotherapy. Synergistic or additive antitumor effects have been observed in preclinical studies in which trastuzumab was combined with cytotoxic chemotherapy agents to treat cancers that overexpressed HER2. In a phase III study reported by Dennis Slamon and colleagues, patients with breast cancer who had not previously received chemotherapy for metastatic disease were randomized to receive standard chemotherapy and trastuzumab (n=235) or standard chemotherapy alone (n=234). Standard chemotherapy consisted of intravenous (iv) doxorubicin 60 mg/m^2 (or epirubicin 75 mg/m^2) and cyclophosphamide 600 mg/m^2 every 3 weeks for patients who had not previously received adjuvant therapy with an anthracycline, and for those who had previously received adjuvant therapy with an anthracycline, iv paclitaxel 175 mg/m^2 every 3 weeks. Trastuzumab was administered intravenously in a loading dose of 4 mg/kg followed by an iv dose of 2 mg/kg weekly. After a median follow-up of 30 months, patients who received trastuzumab had a higher objective tumor response rate (50% vs 32%; P<0.001), a longer median time to disease progression (7.4 vs 4.6 months; P<0.001), a longer median survival time (25.1 vs 20.3 months; P =0.046), and a 20% reduction in the risk of death. However, the incidence of cardiotoxicity was higher among patients treated with trastuzumab: 27% in the anthracycline/cyclophosphamide/trastuzumab group; 8% in the anthracycline/cyclophosphamide group; 13% in the paclitaxel/trastuzumab group; and 1% in the paclitaxel group. These data demonstrated that the addition of trastuzumab to first-line chemotherapy for metastatic breast cancer that overexpressed HER2 provided increased clinical benefit, but with a high incidence of cardiotoxicity. (Slamon DJ, et al. N Engl J Med 2001;344:783-792) Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor (VEGF) Phase I studies. VEGF, a potent neovascularization agent, is associated with enhanced tumor activity. VEGF activity is mediated by 2 receptors, flt-1 and KDR, found on vascular endothelial cells. Recombinant humanized (rhu) monoclonal antibody (MAb) VEGF (Genentech, Inc.) blocks the binding of VEGF to its receptors, and preclinical studies demonstrated an inhibition of tumor growth in a dose-dependent manner. M.S. Gordon et al conducted a phase I study of rhuMAbVEGF administered as a 90-minute iv infusion on days 0, 28, 35, and 42 to patients with metastatic cancer that had failed prior therapy (n=25). Doses of rhuMAbVEGF were escalated from 0.1 to 10.0 mg/kg, and no grade 3 or 4 adverse events were attributed to the study drug. Adverse events observed included asthenia, headache, and nausea. There were also 3 episodes of tumor-related bleeding. Stable disease was achieved in 12 patients but no objective responses were seen. Subsequently, K. Margolin et al conducted a phase Ib trial in patients with advanced solid tumors in which iv rhuMAbVEGF (3 mg/kg) was given weekly for 8 weeks in combination with 2 cycles of the following iv chemotherapy regimens: doxorubicin 50 mg/m^2 every 4 weeks (n=4); carboplatin (AUC of 6) and paclitaxel 175 mg/m^2 every 4 weeks (n=4); 5-fluorouracil 500 mg/m^2 and leucovorin 20 mg/m^2 weekly for 6 weeks every 8 weeks (n=4). No significant toxicities were associated with rhuMAbVEGF and no patients developed antibodies to rhuMAbVEGF. Antitumor responses were observed in 3 patients. These studies demonstrate that rhuMAbVEGF is well tolerated and can be safely combined with standard chemotherapy regimens. (Gordon MS, et al. J Clin Oncol 2001;19:843-850 and Margolin K, et al. J Clin Oncol 2001;19:851-856) Graft-Versus-Host Disease (GVHD) Prophylaxis CD6+ donor marrow T-cell depletion (TCD). TCD has not become an accepted method of GVHD prophylaxis because it has been associated with higher rates of disease relapse, graft rejection, and lymphoproliferative disease. Robert Soiffer and coworkers investigated the use of the T12 antibody (an IgM monoclonal antibody), which recognizes CD6+ T cells (but does not react with thymocytes, natural killer cells, B cells, monocytes, or hematopoietic precursors), to accomplish donor marrow TCD. Early clinical trials of CD6+ donor marrow TCD for patients undergoing HLA-mismatched related bone marrow transplantation (BMT) showed that the addition of total lymphoid irradiation (TLI) to conditioning with cyclophosphamide (Cy) and total body irradiation (TBI) was necessary to eliminate residual host T cells that caused a high rate of graft rejection by destroying donor hematopoietic elements. In the present trial, CD6+ donor marrow TCD was the sole intervention for GVHD prophylaxis for patients with hematopoietic malignancies undergoing allogeneic BMT from HLA-mismatched unrelated donors after conditioning with TLI/Cy/TBI. Of the first 48 patients enrolled in this study, all have demonstrated neutrophil engraftment (achieved at a median of 12 days [range, 9 to 23 days]), there have been no cases of late graft failure, and only 5 relapses have occurred. Grade 2-4 acute GVHD developed in 42% of patients and the mortality at day 100 was 19%. Multivariate analysis showed that patients less than 50 years of age have done especially well with an estimated 2-year survival of 58% (P=0.002). These data indicate that CD6+ TCD results in a favorable incidence of GVHD, while not interfering with marrow engraftment, in patients undergoing unrelated BMT who are at high risk for developing GVHD. Further study, particularly in younger patients, is warranted. (Soiffer RJ, et al. J Clin Oncol 2001;19:1152-1159) B-Cell Lymphoma Homodimers of Rituxan. Studies of monoclonal antibodies (mAb) that react with malignant B cells have previously shown that homodimers of IgG inhibit tumor cell growth more effectively than IgG monomers. Consistent with these findings, Maria-Ana Ghetie and coworkers recently observed that IgG and F(ab')2 homodimers of Rituxan (IDEC Pharmaceuticals, Genentech, Inc.), a chimeric anti-CD20 mAb approved for the treatment of low-grade/follicular B-cell lymphoma, more effectively inhibited the growth of B-lymphoma cell lines than monomers of Rituxan. The homodimers, but not the monomers, of Rituxan were also found to induce both apoptosis and necrosis in several of the B-cell lymphoma lines. Furthermore, only the homodimeric forms of Rituxan were able to reverse chemotherapy resistance in CD20+ B-lymphoma cells and demonstrate synergistic effects in combination with an anti-CD22 immunotoxin. These experiments indicate that homodimers of Rituxan may be more efficacious than the monomeric Rituxan currently in use. In vivo studies of the antitumor activity of Rituxan homodimers in B-cell lymphoma are warranted. (Ghetie M-A, Bright H, Vitetta ES. Blood 2001;97:1392-1398)
Return to Archive Produced by Market Development Group through an educational grant from Genentech, Inc. and IDEC Pharmaceuticals. Comments and inquiries can be e-mailed to webmaster@biooncologywatch.org