Test of dual HER2 drugs finds trastuzumab alone remains gold standard

Volume 3, Issue 3, 2014


A combination of lapatinib, trastuzumab and chemotherapy doesn't improve patient outcome.

Photograph of Edith A. Perez, M.D., deputy director at large, Mayo Clinic Cancer Center

Edith A. Perez, M.D.

In the largest clinical trial testing the effectiveness of one vs. two drugs to treat HER2-positive breast cancer, lapatinib did not add benefit to the standard trastuzumab adjuvant therapy.

Researchers reported these results at the 2014 American Society of Clinical Oncology Annual Meeting.

Results of the phase III clinical trial, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) study, demonstrated that adding lapatinib (Tykerb) to trastuzumab (Herceptin) and chemotherapy did not improve patient outcome — defined as disease-free survival or overall survival — and that use of lapatinib significantly increased toxicity.

"These findings suggest that standard adjuvant (post-surgery) treatment for early-stage HER2-positive breast cancer should remain trastuzumab in combination with chemotherapy," said Edith A. Perez, M.D., deputy director at large of the Mayo Clinic Cancer Center and director of the Breast Cancer Translational Genomics Program at Mayo Clinic's campus in Florida.

"The ALTTO trial did not confirm the working hypothesis that adding lapatinib to trastuzumab, either concurrently or sequentially, would improve patient outcome, which was the primary endpoint," Dr. Perez said. "These results were surprising and very important, as we had hypothesized and hoped that dual blockade of HER2 using two anti-HER2 agents would provide more benefit compared to single anti-HER2 therapy."

In addition, these findings didn't confirm the benefit of using both anti-HER2 therapies before cancer surgery (neoadjuvant therapy), a prediction based on the Neo ALTTO clinical trial, which compared the efficacy of neoadjuvant lapatinib plus paclitaxel vs. trastuzumab plus paclitaxel vs. concomitant lapatinib and trastuzumab plus paclitaxel for HER2-positive breast cancer.

Dr. Perez and Martine Piccart, M.D., Ph.D., professor of oncology at the Université Libre de Bruxelles, Belgium, are co-chairs of ALTTO. Dr. Piccart presented results of Neo ALTTO at the 2013 San Antonio Breast Cancer Symposium.

The ALTTO results suggest that improved pathological complete response (pCR) in neoadjuvant clinical trials of patients with HER2-positive breast cancer may not be predictive of improved long-term outcome of specific treatment in the adjuvant setting.

When therapy is given before surgery, pathologists can examine excised breast tissue for evidence of pathological complete response — complete absence of cancer. Researchers and physicians have wondered, however, if pathological complete response after neoadjuvant treatment is indeed linked to better outcomes for early-stage HER2-positive breast cancer.

"The pCR measure from neoadjuvant clinical trials is increasingly being used as a surrogate marker of outcome in adjuvant studies," Dr. Perez said. "The results of ALTTO suggest that pCR is not a factor that reliably predicts the long-term benefit when comparing two treatments.

"These ALTTO adjuvant results call into question the entire way breast cancer care and research have been leaning in the last few years — which is to rely on pCR from neoadjuvant studies as surrogates of long-term outcome," Dr. Perez said. "We believe these results will be difficult for the field to absorb but will ultimately guide our clinical research."