A phase 3 clinical trial pitted a nine-week treatment of adjuvant Herceptin against the regimen of a full year of treatment for patients with HER2-positive breast cancer. Results show that the standard treatment of one year is still optimal.
A phase 3 clinical trial (SOLD trial) tested the possibility that nine weeks of adjuvant Herceptin (trastuzumab) treatment for HER2-positive breast cancer could replace a full year of treatment. Results show that the standard treatment of one year is still optimal.
The trial demonstrated that disease-free survival (DFS) with nine weeks of adjuvant Herceptin was inferior to the standard 12 months when the two regimens were combined with chemotherapy in women with early stage HER2-positive breast cancer.
The five-year estimated DFS rate was 90.5 percent with one year of Herceptin versus 88 percent with nine weeks. The five-year estimated overall survival (OS) rates were 95.9 percent versus 94.7 percent, respectively. The estimated five-year rate of patients without distant recurrence (distant-free survival) was also higher with longer Herceptin at 94.2 percent compared with 93.2 percent, respectively.
“Chemotherapy plus one year of anti-HER2 therapy should remain the standard based on the SOLD results,” lead investigator Heikki Joensuu, MD, professor in the Department of Oncology at the Helsinki University Hospital and University of Helsinki in Finland, said at press conference during the 2017 San Antonio Breast Cancer Symposium.
Joensuu also noted that a subgroup analysis demonstrated a significant interaction between the dose of docetaxel administered concomitantly with Herceptin, with improved DFS observed in patients receiving a higher dose. Thus, it may be possible that for patients receiving 100 mg/m2 versus 80 mg/m2 of docetaxel, nine weeks of Herceptin is sufficient.
The SOLD trial, which was conducted at 65 centers in seven countries, accrued 2,176 patients with early-stage HER2-positive breast cancer between Jan 3, 2008, and December 16, 2014.
The nine-week arm included 1,085 patients and 1,089 patients were randomized to one year of Herceptin.
Patient characteristics were well balanced between the arms. The median age across both arms was 56, 33 percent of patients were premenopausal, 92 percent had ductal histological disease type, two-thirds of patients were ER-positive, and about 47 percent were PR-positive.
Sixty percent of patients across the trial were axillary node negative, about 30 percent had 1 to 3 positive nodes, and about 10 percent had more than 3 positive nodes. Breast tumor diameter was less than or equal to 10 mm in 13 percent of patients, 11 to 21 mm in 43 percent of patients, 21 to 50 mm in about 41 percent of patients, and more than 50 mm in 3 percent of patients.
In both arms, patients received 3 cycles of docetaxel (80 mg/m2or 100 mg/m2) and Herceptin, followed by 3 cycles of FEC chemotherapy (5-FU, epirubicin, and cyclophosphamide).
After this initial phase, patients in the nine-week arm received no additional treatment, while Herceptin was administered every three weeks for 14 cycles for patients in the 12-month arm. Guideline-appropriate radiation therapy and endocrine treatment was administered to ER-positive patients. The data collection cutoff date was December 31, 2016, and the median follow-up time was 5.2 years.
Commenting on predefined subgroup DFS analyses, Joensuu said, “In all subgroups we tested, the longer [Herceptin] arm tended to be better than the shorter one, but we detected an interaction between the docetaxel dose given to the patients and DFS.”
In the 80 mg/m2 docetaxel cohort, the estimated five-year DFS rate was 91.3 percent in the 12-month arm versus 86.8 percent in the nine-week arm. However, in patients who received 100 mg/m2 of docetaxel, the estimated five-year DFS rates were 92.2 percent in the shorter Herceptin arm versus 87.8 percent in the longer Herceptin arm.
“Docetaxel dosing with trastuzumab requires further study,” said Joensuu. He also hypothesized that there could be an immunological basis for the outcome discrepancy with the docetaxel dose variance.
“We know that docetaxel causes deep neutropenia, but it might also cause deep lymphopenia, not only in the bone marrow and the peripheral blood, but also in the tumor microenvironment. We know the lymphocytes residing in the tumor are mostly immunosuppressive—perhaps a larger dose of docetaxel would eradicate those immunosuppressive lymphocytes making it possible for trastuzumab to take action. It might be that the higher dose of docetaxel creates a time window for trastuzumab to act.”
Regarding safety, there was less cardiac toxicity with the shorter Herceptin regimen. In the nnie-week group there were 22 protocol-defined cardiac adverse events compared with 42 in patients receiving one year of Herceptin. Congestive heart failure occurred in 21 and 36 patients in the two arms, respectively.