Sara M. Tolaney, MD, MPH
Trastuzumab (Herceptin) remains a standard of care in the neoadjuvant and adjuvant treatment settings for patients with HER2-positive breast cancer. Sara M. Tolaney, MD, is trying to determine whether combination regimens with additional HER2-directed therapies or alternative therapies could improve responses in this patient population without added toxicities.
Tolaney, associate director of clinical research, Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, explained the state of HER2-directed therapies for patients with HER2-positive breast cancer during the 16th Annual International Congress on the Future of Breast Cancer, hosted by Physicians’ Education Resource®
, LLC (PER®
In the multi-arm BCIRG-006 study assessing the benefit of adding anthracyclines to chemotherapy for early stage HER2-positive breast cancer, patients in both trastuzumab-containing arms performed significantly better than patients who were not treated with trastuzumab.1
Both trastuzumab-containing regimens showed an increased disease-free survival (DFS) rate compared with chemotherapy alone at 10.3 years follow-up. The DFS rate was 74.6% with doxorubicin (Adriamycin)/cyclophosphamide/docetaxel plus trastuzumab (AC-TH) and 73.0% with docetaxel/carboplatin plus trastuzumab (TCH). DFS was 67.9% for patients treated with doxorubicin/cyclophosphamide/docetaxel (AC-T) without added trastuzumab.
Tolaney pointed out that only 10 DFS events separated the 2 trastuzumab-containing regimens.
Treatment-related outcomes in patients with higher-risk lymph-node positive disease mimicked results of the overall population, and again, investigators observed no significant difference between the 2 trastuzumab-containing arms. The DFS was 69.6% with AC-TH compared with 68.4% with TCH. DFS with AC-T was 62.2%, and Tolaney suggested that this could indicate that there is still an advantage for anthracycline-based therapy, even in the higher-risk population.
However, trastuzumab is known to have cardiotoxicity risks. There was a 2% incidence of grade 3/4 congestive heart failure in the AC-TH arm in the BCIRG-006 trial, and a 0.4% incidence rate with TCH.
“One approach I have taken is to use TCH in patients with cardiac risk factors and AC-TH in most other patients,” she said.
Trastuzumab in Combination
“While outcomes for HER2-positive disease have dramatically improved with the addition of trastuzumab, approximately 15% of women with early stage HER2-positive disease still recur, so there is a need to do better,” Tolaney said.
Several combination regimens are being explored adding to trastuzumab in order to improve responses in these patients. One common approach is dual HER2-targeted therapy. Several studies have looked at the addition of lapatinib (Tykerb) to trastuzumab in the neoadjuvant setting. Patients treated with the combination have higher rates of pathologic complete response (pCR) compared with trastuzumab or lapatinib alone.
“These favorable pCR rates achieved with lapatinib and trastuzumab led many to think that dual inhibition may improve survival outcomes in the adjuvant setting,” she noted.
To test this hypothesis, the phase III ALTTO trial explored the combination of trastuzumab and lapatinib in the adjuvant setting in patients with early stage disease, yet no significant role was found when lapatinib was added in this setting.2
Patients were assigned to single-agent trastuzumab, single-agent lapatinib, lapatinib plus trastuzumab, or trastuzumab followed by lapatinib. At 6 years, the DFS rate with lapatinib and trastuzumab was 85%, compared with 84% for trastuzumab followed by lapatinib, and 82% in patients treated with trastuzumab alone.
Moreover, lapatinib monotherapy and the combination of lapatinib plus trastuzumab were associated with a much higher rate of adverse events (AEs). Nearly all (93%) of patients treated with the combination and 90% of those treated with lapatinib alone experienced treatment-related AEs compared with 64% among those treated with trastuzumab monotherapy.
Researchers have also actively explored pertuzumab (Perjeta) in combination with trastuzumab in breast cancer. In 2013, the FDA granted an accelerated approval to pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant setting for patients with HER2-positive breast cancer based on results of the NeoSphere and TRYPHAENA trials.
Results from APHINITY evaluating the role of pertuzumab in the adjuvant setting, were presented at the 2017 ASCO Annual Meeting. Adding pertuzumab to trastuzumab and chemotherapy resulted a slight improvement in 4-year invasive DFS rate compared with trastuzumab and chemotherapy alone, 92.3% versus 90.6% (HR, 0.81; P
= .045) The absolute benefit was 1.7%.3