Concurrent administration of trastuzumab, lapatinib, and paclitaxel appears to be safe from a cardiac standpoint, pilot data from the Mayo Clinic Cancer Research Consortium Trial RC0639 suggest.
“This was a pilot study to look at the cardiac safety and tolerability of giving paclitaxel concurrently with HER2-directed therapy with trastuzumab and lapatinib—the design of one arm of the worldwide ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial,” Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, said in reporting the data at the CTRC-AACR San Antonio Breast Cancer Symposium.
“Overall, we found the combination to be safe and tolerable from a cardiac standpoint, so we can be confident beginning this arm of ALTTO.”
The multicenter open-label ALTTO trial, whose total accrual goal is 8,000 patients, is employing two study designs:
* In Design 1, which is now closed to enrollment, all neoadjuvant and adjuvant chemotherapy is completed prior to administration of trastuzumab and/or lapatinib.
* In Design 2, whose cardiac safety is the subject of the current study, paclitaxel is given concurrently with trastuzumab and/or lapatinib after completion of anthracycline-based neoadjuvant and adjuvant chemotherapy.
From April 2007 to October 2008, a total of 109 evaluable patients initiated study treatment in the single-arm Phase II multicenter study. The median age was 51, with a range of 28 to 72 years.
All the women received 60 mg/m2 of doxorubicin (A) on Day 1 and 600 mg/m2 of cyclophosphamide (C) on Day 1, every two to three weeks for four cycles.
After completion of AC chemotherapy, the women received concurrent paclitaxel (80 mg/m2 weekly), trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly), and lapatinib (1,000 mg daily, which was amended to 750 mg in July 2008 due to a high rate of diarrhea) for a total of 12 weeks of treatment.
This was followed by trastuzumab (6 mg/kg on Day 1, every three weeks) and lapatinib (1,000 mg daily) for a total of 40 weeks of treatment.
The primary endpoint was severe symptomatic congestive heart failure (CHF), defined as New York Heart Association Class III or IV heart failure with a drop in left ventricular ejection fraction (LVEF) of at least 10 percentage points to below 50% as confirmed by a cardiologist. Secondary endpoints were cardiac death and Grade 3 or higher adverse events.
Over a median follow-up time of 17.9 months, no patient developed CHF or died from cardiac causes while on active treatment.
One patient, who refused further treatment after completing two cycles of paclitaxel, trastuzumab, and lapatinib, developed congestive heart failure 1.8 months after stopping treatment, with an LVEF of 45% and dyspnea on exertion.
Another patient, who discontinued treatment due to non-cardiac adverse events after completing two cycles of paclitaxel, trastuzumab, and lapatinib, died 2.9 months after discontinuation due to myocardial infarction.
“There was a statistically significant decrease in mean LVEF following initiation of paclitaxel, trastuzumab, and lapatinib; however, mean LVEF appears to partially recover in the post-treatment period,” Dr. Perez reported.
Specifically, the mean LVEF was 63.6% at baseline and 63.3% at the end of AC chemotherapy. By the end of paclitaxel, trastuzumab, and lapatinib treatment, it was 59.9%; and after Cycle 12, it was 59.3%.
At 18 months, the mean LVEF was 61.3%; at two years, it was 62.4%.
Grade 3 or higher non-hematologic adverse events with an incidence of greater than 5% included diarrhea in 42 (39%) patients, fatigue in 15 (14%), nausea in seven (6%) patients, vomiting in seven (6%) patients, acne in six (6%) patients, and hypokalemia in six (6%) patients.
Commenting on the poster presentation, Minetta C. Liu, MD, Associate Professor of Medicine in the Division of Hematology/Oncology at Lombardi Comprehensive Cancer Center, said, “Cardiac safety is always a big issue in breast cancer. These researchers wanted to demonstrate the cardiac safety of using two HER2-directed therapies together, and they did. The data support the ongoing ALTTO trial in which we are seeking to find out if we can [improve outcomes] by using two HER2-directed therapies,” she said, echoing Dr. Perez's comments.
© 2010 Lippincott Williams & Wilkins, Inc.