CHICAGO, IL— Adding lapatinib to adjuvant trastuzumab for early-stage HER2-positive breast cancer does not improve patients’ disease-free survival (DFS) rates, according to the first findings from the phase 3 ALTTO trial (BIG 2-06; NCCTG N063D) presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

The study “did not demonstrate the noninferiority” of the combination, concluded lead study author Martine Piccart-Gebhart, MD, PhD, the Jules Bordet Institute in Brussels, Belgium, and the Breast International Group. Earlier positive trial findings “did not translate into improved survival outcomes in ALTTO at 4.5 years follow-up.”

Both drugs target the HER2 pathway. Study coauthors and commenters agreed that the new findings came as a surprise, given earlier, promising data, including significantly improved pathologic complete response (pCR) rates in three of four randomized trials.

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The findings renew concerns that pCR might not be a reliable surrogate for event-free and overall survival, according to past ASCO president George Sledge, MD, of Stanford University Medical Center in Stanford, California.

Dr. Edith A. PerezEdith A. Perez, MD

“Early studies suggested [lapatinib] activity as a monotherapy but more importantly, in combination with trastuzumab,” noted Dr. Sledge. But in light of the ALTTO trial findings, that hope has been dashed, he said.

“We will not be adding lapatinib to trastuzumab in the adjuvant setting,” Dr. Sledge said. “It didn’t work. …It is significantly more toxic that trastuzumab alone.”“A key lesson of this trial is that we need robust clinical trials in specific disease settings to fully address and understand the value of new treatment regimens,” said study coauthor Edith Perez MD, of the Mayo Clinic Cancer Center in Jacksonville, Florida.

A total of 6,281 patients were randomly assigned to receive trastuzumab, concurrent trastuzumab plus lapatinib, or sequential trastuzumab → lapatinib for 1 year. At a median follow-up of 4.5 years, neither sequential nor concurrent lapatinib-plus-trastuzumab therapy did not significantly improve recurrence risk or overall survival, the authors reported.

The 4-year DFS rates were 86% for trastuzumab-only, 88% for concurrent combination therapy, and 87% for sequential dual-agent therapy; these were not significantly different, Dr. Piccart-Gebhart said (L+T vs. T hazard ratio [HR], 0.84; 97.5% CI: 0.70-1.02; T → L vs. T HR, 0.93; 97.5% CI: 0.76-1.13).

AEs included diarrhea, skin rash, and liver toxicity.

“These results illustrate the importance of conducting well-designed clinical trials,” said ASCO President Clifford A. Hudis, MD, FACP. “In this case, the increased in-breast response rate seen for this drug combination when used preoperatively did not predict improved disease-free survival. Other studies using different drugs could reach different conclusions, but for now this trial provides reassurance that trastuzumab is a safe and potent adjuvant treatment for HER2-positive breast cancer.”

Dr. Sledge suggested that inadequate therapeutic durations, the inability to select appropriate patients, and an inadequate understanding of tumor biology might each play a role in this and other recent disappointing study results for adjuvant use of targeted biologics.

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But he remains hopeful overall, pointing to current trials for pertuzumab (an anti-HER2 antibody), trastuzumab-DM1 fusion toxin, PI3K, Akt, HSP-90, and IGF-IR inhibitors, among others.

“I hope and I believe that at least one of these will prove fruitful,” he said. “But hopes and beliefs are no substitute for the hard work of well-designed clinical studies.”

The study was sponsored by GlaxoSmithKline.


  1. Piccart-Gebhart MJ, Holmes AP, Baselga J et al. Abstract LBA4. Presented at: 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2014; Chicago, IL.