The addition of lapatinib (Tykerb) to trastuzumab (Herceptin) to create dual HER2 blockade was no better than trastuzumab alone in the adjuvant treatment of patients with HER2 breast cancer in the global phase 3 ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, reported Martine J. Piccart-Gebhart, MD, PhD, Chair, Breast International Group, Brussels, Belgium, at a plenary session at ASCO 2014.
More than 8000 patients with early breast cancer were randomized after surgery to concurrent use of trastuzumab and lapatinib, to the sequential use of trastuzumab followed by lapatinib, or to trastuzumab alone for 1 year. A lapatinib-only arm was closed early because of futility. The majority (N = 4613) of patients received anti-HER2 agents after completing chemotherapy. Patients with hormone receptor–positive disease also received appropriate hormonal therapy.
At a median follow-up of 4.5 years, dual targeting, either concurrently or sequentially, was associated with slight numerical (but insignificant) reductions in progression versus trastuzumab alone.
“The ALTTO trial did not meet its end points,” Dr Piccart-Gebhart said. The disease-free survival rates at 4 years were 86% with trastuzumab, 88% with concurrent HER2-directed treatment, and 87% in the sequential arm. Similarly, the median overall survival rates were 94%, 95%, and 95%, respectively.
These results were unexpected, because the previous NeoALTTO trial, which evaluated the combination in the neoadjuvant setting, showed improved pathologic complete response rates with 2 agents versus 1 agent, which correlated with better clinical outcomes.
However, “the doubling in pathologic complete response observed with lapatinib plus trastuzumab in NeoALTTO did not translate into improved survival outcomes in ALTTO,” Dr Piccart-Gebhart said.
Furthermore, “lapatinib was also associated with significant increases in adverse events of special interest—diarrhea, skin rash or erythema, and hepatobiliary problems,” Dr Piccart-Gebhart added. Only 60% to 78% of patients in the lapatinib-containing arms received at least 85% of the protocol-specified dose. The rates of serious cardiotoxicity, however, were less than 1%, although 97% of women received anthracyclines.
ALTTO was the largest-ever adjuvant clinical trial in HER2-positive breast cancer, involving 8381 women from 946 centers in 44 countries.
George W. Sledge, Jr, MD, Chief, Division of Oncology, Stanford University Medical Center, CA, and past president of ASCO, called the findings “a serious disappointment, not only to investigators but for the entire field….The study’s failure tells us, at a simple level, that we won’t be using lapatinib in the adjuvant setting.”
Dr Sledge added that the fact that ALTTO did not corroborate findings from the NeoALTTO trial seriously calls into question the use of pathologic complete response rate as a surrogate end point for survival and as an end point that can be used in drug approvals, suggesting the need to “rethink our approach to the development of new drugs for early breast cancer.”
A Different Perspective
The one aspect of good news to come from ALTTO, according to coprincipal investigator Edith A. Perez, MD, Deputy Director at Large, Mayo Clinic Cancer Center, Jacksonville, FL, was that the 555 relapse events that occurred at 4.5 years were far less than the 850 events that were anticipated. “Another way of looking at this study is that the patients overall did pretty well—better than anticipated,” said Dr Perez.