Kate Johnson

June 02, 2014

CHICAGO — Two HER2-targeted therapies are not better than 1 in the adjuvant setting for HER2-positive breast cancer, even though 2 are better in the neoadjuvant setting.

Adding lapatinib (Tykerb/Tyverb) to the standard trastuzumab (Herceptin) does not prolong survival and increases toxicity when used after surgery in women with HER2-positive early breast cancer, according to the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial.

The results, reported by Martine Piccart-Gebhart, MD, PhD, associate professor of oncology at Université Libre de Bruxelles and head of the Department of Medicine at the Jules Bordet Institute in Brussels, come as a surprise to experts who anticipated that ALTTO would confirm the positive results from NeoALTTO, which tested the combination before surgery.

"What does this failure tell us?" asked study discussant George Sledge, MD, from the Stanford University School of Medicine in California, here at the 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO), where the results were presented.

"At a simple level, we'll not be using lapatinib in the adjuvant setting. Not only does it not work, the combination is significantly more toxic than trastuzumab alone," he said.

"It's difficult to mount any enthusiasm for dual blockade in the adjuvant setting, at least with the combinations shown here. This is a serious disappointment, not just for investigators, but for the entire field," Dr. Sledge noted.

The ALTTO study is the largest adjuvant clinical trial conducted in HER2-positive breast cancer; it involved 8381 women with newly diagnosed early-stage disease.

All women underwent surgery and chemotherapy. They were then randomized to 1 of 4 treatment groups: trastuzumab alone, lapatinib alone, concurrent trastuzumab and lapatinib, or sequential trastuzumab and lapatinib.

HER2 treatment was administered after the completion of chemotherapy in 4613 women and concurrent with chemotherapy in 3768.

The lapatinib monotherapy group was closed early because of futility; results from that subgroup are not yet available.

After a median follow-up of 4.5 years, "this study failed to demonstrate that lapatinib added to the benefit of trastuzumab," said senior author Edith Perez, MD, deputy director at large at the Mayo Clinic Cancer Center in Jacksonville, Florida, during a press briefing.

"Patients did pretty well" in all 3 groups. However, disease-free survival was not significantly better with concurrent therapy than with trastuzumab monotherapy (88% vs 86%; hazard ratio [HR], 0.84), and not significantly better with sequential therapy than with trastuzumab monotherapy (87% vs 86%; HR, 0.96).

And overall survival was not significantly better with concurrent therapy than with trastuzumab monotherapy (95% vs 94%; HR, 0.80), or with sequential therapy than with trastuzumab monotherapy (95% vs 94%; HR, 0.91).

In a preplanned exploratory analysis, "a small signal in favor of lapatinib and trastuzumab appears to be driven by the hormone-receptor-negative cohort and by the sequential design," Dr. Piccart-Gebhart reported.

The increased toxicity in the lapatinib-treated patients was "as expected," and "generated fewer surprises than the efficacy analysis," she said.

Diarrhea was more common with concurrent therapy than with trastuzumab monotherapy (75% vs 20%), as were rash (55% vs 20%) and hepatobiliary problems (23% vs 16%). Diarrhea of grade 3 or higher was more common when lapatinib was involved in the treatment than when it was not (5% to 15% vs 1%). The incidence of febrile neutropenia was less than 1% in all the treatment groups.

"Cardiac safety was outstanding," noted Dr. Piccart-Gebhart.

This was a very important aspect of ALTTO, added Dr. Perez. "About 97% of the patients had received anthracycline-based therapy," she reported, "and we had less than a 1% incidence of cardiac events."

The cardiac data are "a very positive finding," said Claudine Isaacs, MD, professor of medicine and oncology and codirector of the breast cancer program at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. "This suggests that trastuzumab, when given as part of a regimen that includes anthracycline, is safer than we thought."

Profound Implications for Future Research

However, the failure of ALTTO to confirm results from the earlier NeoALTTO trial has "tremendous" and "profound" implications for future breast cancer drug research, noted ASCO president Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at the Memorial Sloan-Kettering Cancer Center in New York City.

"ALTTO represented a reasonable test of the hypothesis that improvements in the pathological complete response rate [seen in NeoALTTO] would be associated with improved disease-free survival. These hopes have now been dashed," said Dr. Sledge.

"An improvement in pathological complete response was the impetus for the recent FDA accelerated approval of pertuzumab, another monoclonal antibody that targets HER2 in the neoadjuvant setting," Dr. Isaacs explained. "The rate has been used as a surrogate for long-term outcome, and this calls into question whether that is a truth."

This trial "requires us to rethink our approach to the development of new drugs for early-stage breast cancer," said Dr. Sledge. "If ALTTO has taught us anything, it is that hopes and beliefs are no substitute for the hard work of well-conducted, definitive clinical trials."

Dr. Piccart-Gebhart reports financial relationships with PharmaMar, Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Symphogen, Synthon, and Verastem. Dr. Sledge reports financial relationships with Syndax Pharmaceuticals, Genentech/Roche, Seattle Genetics, and Symphogen. Dr. Perez has disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA4. Presented June 1, 2014.

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