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Herceptin + Taxol/Carbo Improves Breast Cancer Control

Herceptin + Taxol/Carbo Improves Breast Cancer Control

SAN ANTONIO—Adding weekly paclitaxel (Taxol) and carboplatin (Paraplatin) to trastuzumab (Herceptin) improves disease control among women with advanced breast cancer, according to results of an ongoing phase II trial reported by Howard A. Burris III, MD, director of drug development, Sarah Cannon Cancer Center, Nashville.

The rationale for the study, Dr. Burris said, was the documented activity of trastuzumab and paclitaxel in randomized clinical trials, the established efficacy of a paclitaxel/carboplatin combination, and preclinical work suggesting a synergistic effect between trastuzumab, the taxanes, and the platinums.

The overall aim of the study was to develop a combination chemotherapy regimen that might avoid the cardiotox-icity seen when trastuzumab is combined with anthracyclines.

The researchers enrolled 52 patients with metastatic disease (mean age, 52). Eligibility requirements included 2+ or 3+ overexpression of HER-2-neu, normal organ function, no previous chemotherapy for metastatic disease, and no prior trastuzumab therapy or weekly taxane treatment.

Prior adjuvant chemotherapy was permitted if completed at least 3 months before the study began. Previous treatment with paclitaxel on a 3-week—but not weekly—schedule also was allowed.

Thirty of the women were hormone-receptor positive; 35 were HER-2-neu 3+ overexpressers; 28 had undergone prior adjuvant chemotherapy (20 with doxorubicin and 12 with 3-week paclitaxel), and one had received a stem cell transplant. Performance status was 0-1 for 50 patients and 2 for 2 patients.

All patients were placed on an 8-week induction regimen of trastuzumab, with a loading dose of 8 mg/kg followed by 4 mg/kg each week. At the end of 8 weeks, patients were evaluated and assigned to one of three regimens.

  • Patients who had achieved at least a minor response to the antibody (25% or greater reduction in their disease) continued on trastuzumab for another 8 weeks and then converted to a weekly regimen of lower-dose trastuzumab (2 mg/kg), paclitaxel (70 mg/m2), and carboplatin (AUC 2.0).

  • Patients whose disease remained stable during the 8-week trastuzumab induction (25% or less change in their disease) went straight to the lower-dose trastuzumab plus paclitaxel and carbo-platin regimen.

  • Patients whose breast cancer progressed during single-agent trastuzumab therapy were taken off the monoclonal antibody and placed on the weekly paclitaxel/carboplatin regimen.

Therapy was given in 8-week cycles—6 weeks on, followed by a 2-week rest period.

Response Rates

Among 46 patients who completed induction therapy and could be evaluated for response, single-agent trastuzumab produced 1 complete remission, 9 partial remissions, and 2 minor responses. Fourteen patients had stable disease, 14 progressed, and 6 were too early to evaluate. The overall response rate to trastuzumab alone was 25%, and two thirds of the patients experienced disease stabilization or better, Dr. Burris reported.

Among the 20 patients who ultimately received the three-drug regimen (including some patients who received 16 weeks of trastuzumab), there were 3 complete remissions, 6 partial remissions, 1 minor response, 1 stabilization, 5 progressions, and 4 patients who were too early to evaluate.

The overall response rate of this group (complete and partial remissions) was 56%, with nearly 70% of patients achieving stabilization or better.

Many of the 14 patients who progressed on the trastuzumab induction therapy benefited from paclitaxel/carboplatin therapy. "One complete remission and six partial remissions have been documented in this group, for a response rate—albeit small numbers—of 58%," Dr. Burris said. "Certainly this is encouraging activity for a group of patients believed to be refractory to Herceptin."

Well Tolerated

The regimens were very well tolerated overall, he said. Brief and reversible myelosuppression was the primary toxicity: Seven patients experienced grade 3 and one patient grade 4 neutropenia. Nonhematologic toxicities were minimal, with only a few patients reporting myalgia, fatigue, or diarrhea.

Cardiotoxicity data were available for 34 patients who had sequential evaluations on MUGA (multigated angiogram) or echocardiogram, Dr. Burris said.

Three of these patients had asymptomatic ejection fraction declines. One patient had a drop from 55% to 36% after 6 months. That patient was taken off trial, and her ejection fraction returned to 55%. Two patients experienced declines from 45% to 29% and 63% to 38% at 8 and 5 months, respectively. Both were treated medically and had no symptoms of congestive heart failure.

Concerning the overall activity of the regimens tested, Dr. Burris noted that the best overall response, whether with trastuzumab or the combination, was 63%, including four complete remissions. The median time to progression was 12 months.

Although longer follow-up is required on many patients, Dr. Burris noted, the actuarial progression-free survival at 1 year was 47%; overall survival was 78% at 1 year and 64% at 2 years.

The study results also suggest that the durability of response may be better in HER-2-neu 3+ overexpressers. "If you look at the 3+ vs the 2+ overexpressers, there is a trend for the 3+ overexpressers to do better with this regimen," he added. "Again, there are too few patients to reach statistical significance, but the curve is still nicely separated at the 12- to 18-month mark."

 
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