After surgery, adjuvant therapy with trastuzumab alone works just as well as trastuzumab combined with lapatinib for women with early-stage HER2-positive breast cancer. Study authors Martine J. Piccart-Gebhart, MD, PhD, professor of oncology at the Université Libre de Bruxelles in Belgium, Edith Perez, MD, of the Mayo Clinic Cancer Center in Jacksonville, Florida, and colleagues found no difference in 4-year disease free survival (DFS) between the two treatment arms.
These results (abstract LBA4), from the large phase III ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study were presented at a press briefing at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30–June 3, in Chicago.
“This is the first adjuvant study reported [on the combination of lapatinib plus trastuzumab that] unfortunately did not corroborate the hypothesis that an improvement in neoadjuvant pathologic complete responses [pCRs] correlates with longer term disease-free survival [DFS],” said Perez.
The combination therapy was associated with a numerically lower risk of recurrence of invasive breast cancer, development of a second primary cancer, and death compared with those who received trastuzumab only during the 4.5-year median follow-up, but the results were not statistically significant, with DFS rates of 86% in the trastuzumab arm, 88% in concurrent therapy arm, and 87% in the sequential therapy arm.
Lapatinib is an approved oral HER2 and epidermal growth factor receptor (EGFR) inhibitor used in combination with capecitabine for women with metastatic HER2-positive breast cancer following chemotherapy, and in combination with letrozole for post-menopausal women with HER2-positive disease.
Trastuzumab is the post-surgical standard of care for women with HER2-positive disease. Still, approximately 20% of these patients develop more advanced cancer within 10 years. A smaller study, NeoALTTO, had previously shown that the addition of lapatinib to trastuzumab provided a benefit to patients when given prior to surgery.
The ALTTO trial is the largest ever HER2-positive breast cancer adjuvant trial with 8,381 patients with newly diagnosed early-stage disease recruited from 44 different countries. Women had surgery and were then randomized to receive trastuzumab alone, trastuzumab followed by lapatinib (sequential therapy), or the combination of the two drugs (concurrent therapy) for 12 months. More than half of the patients had first received adjuvant chemotherapy, and the rest were also given chemotherapy along with the clinical trial therapy. Those patients who also had hormone-positive disease also received hormonal therapies.
Adding lapatinib to trastuzumab resulted in a greater rate of side effects, such as skin rash, liver problems, and diarrhea.
While heart-related side effects have been tied to the use of doxorubicin and other anthracycline chemotherapy agents, in this study, the rate of serious effects on the heart was low: less than 1% congestive heart failure even though 95% of women received an anthracycline regimen. These results reflect the safety of the chemotherapy regimen used in this study, as well as the good medical care patients received, Perez told Cancer Network.
The study authors are now analyzing blood and tissue samples from this trial to try to understand the characteristics of patients who relapse after adjuvant therapy compared with those who do not. Patient follow-up is planned for 10 more years.
“This is an important breast cancer trial, demonstrating the feasibility of cooperation amongst researchers and patients throughout the world, ” said Perez. “The patients on the trial did better than we had anticipated, and the safety of the current standard is better than [what may have been] perceived.”
“The ‘negatives’ of the trial are also very important,” Perez noted. “Lapatinib does not add to the benefit of trastuzumab, pCR improvement did not correlate with DFS or OS benefit in this longer follow-up time assessed in the adjuvant setting. Thus, we truly need to re-evaluate reliance on pCR as a way to evaluate new agents in early-stage HER2-positive breast cancer.”