ALTTO Trial Findings Raise Questions on Approach to Drug Development in Early Breast Cancer

ALTTO Trial Findings Raise Questions on Approach to Drug Development in Early Breast Cancer

Long-awaited results from the large phase III ALTTO trial disprove the hypothesis that dual anti-HER2 therapy with lapatinib and trastuzumab in the adjuvant setting enhances clinical outcomes in patients with early-stage HER2-positive breast cancer (Abstract LBA4). Disease-free survival (DFS) at 4 years—the primary endpoint—was no better with the two HER2-targeted agents together than with trastuzumab alone.

Martine J. Piccart-Gebhart, MD, PhD, of the Jules Bordet Institute, Breast International Group, Belgium, presented the ALTTO findings during Sunday’s Plenary Session.

“This is a serious disappointment, not just for the investigators, but for the entire field,” remarked Discussant George W. Sledge, MD, of Stanford University. “It is difficult to mount any enthusiasm for combined blockade of HER2 in the adjuvant setting, at least with the combination used here.”

These findings come as quite a surprise considering that results of the NeoALTTO trial—the neoadjuvant counterpart to ALTTO—showed that combined use of lapatinib and trastuzumab doubled the pathologic complete response (pCR) rate compared with trastuzumab alone.

Breast cancer researchers have grown increasingly comfortable with the notion of conducting smaller neoadjuvant studies and using those findings to foretell outcomes in the adjuvant setting. However, the disparate findings from NeoALTTO and ALTTO now undermine confidence in translating treatment outcome from one setting to another.

The impetus for conducting the ALTTO trial was to improve outcomes following surgery among women with early-stage HER2-positive breast cancer. Although the current standard of adding trastuzumab to adjuvant chemotherapy successfully reduces the risk of relapse to approximately 20% at 10 years post-treatment, preclinical research suggested that loftier goals might be possible by hitting HER2-active tumors with a one-two punch of dual HER2 blockade by combining agents with different mechanisms of action.

To evaluate this possibility, 946 participating sites in 44 countries came together to carry out the largest adjuvant trial in the HER2-positive setting. “This was a stellar effort by a talented group of clinical researchers,” remarked Dr. Sledge.

Beginning in June 2007, 8,381 women with HER2-positive early-breast cancer joined the study and underwent random assignment to one of four treatment arms following surgery: trastuzumab alone (2,097 patients), lapatinib alone (2,100 patients), trastuzumab followed by lapatinib (2,091 patients), or trastuzumab plus lapatinib (2,093 patients). All regimens were given for 1 year and incorporated chemotherapy as a backbone, which could be delivered either prior to or concurrently with anti-HER2 therapy.

The first blow came early in August 2011, when the arm receiving lapatinib alone was closed at the request of the Independent Data Monitoring Committee because of futility.

Dr. Martine J. Piccart-Gebhart

The current results land additional blows. In a comparison of concurrently administered lapatinib and trastuzumab versus trastuzumab alone, the hazard ratio for DFS reached 0.84 (97.5% CI [0.70-1.02]) with a p-value of 0.048, which failed to meet the p ≤ 0.025 threshold for establishing statistical superiority. Similarly, sequential use of trastuzumab and lapatinib did not meet the noninferiority criteria compared with trastuzumab alone based on a hazard ratio for DFS of 0.96 (97.5% CI [0.80-1.15]) and a p-value of 0.610, which also fell below the value of 0.025 required for significance.

Analysis of the primary endpoint was triggered by time, set at a median of 4.5 years after the study start, rather than events, which reached only 555 of the preset target of 850. “As observed in many adjuvant breast cancer trials nowadays, the event rate was much lower than expected,” commented Dr. Piccart-Gebhart. This may be because of the large proportion of ALTTO patients with node-negative disease (40%) and with small tumors measuring less than 2 cm (46%).

Moreover, dual therapy with lapatinib and trastuzumab further loses luster when considering that diarrhea (75% vs. 20%), rash (55% vs. 20%), and hepatobiliary adverse events (23% vs. 16%) all occurred much more often with the anti-HER2 combination compared with trastuzumab alone.

Despite the marginal performance of lapatinib in ALTTO, Dr. Piccart-Gebhart notes that the results for trastuzumab in patients with early-stage HER2-positive breast cancer are heartening. First, patients who received trastuzumab alone achieved an impressive 4-year DFS rate of 86% and a 4-year overall survival rate of 94%. Second, although approximately 90% of patients received anthracycline-based chemotherapy, which has raised concerns regarding cardiotoxicity, congestive heart failure occurred in less than 1% across all arms.

The larger and more pressing implications of this trial pertain to the current approach to drug development in early breast cancer. As Dr. Sledge explained, 2 years ago the U.S. Food and Drug Administration outlined a path to accelerated approval for neoadjuvant breast cancer therapies, indicating that pCR represented a reasonable surrogate for adjuvant benefit. “It seemed logical to suggest that significant increases in pCR rates, in the context of randomized controlled trials, would predict the outcome of adjuvant trials. If this was indeed the case, we might get valuable new agents to patients years before the completion of our large, ponderous, cast-of-thousands adjuvant trials,” Dr. Sledge said.

ALTTO represented a reasonable test of this putative paradigm. However, the findings did not bear this out.

“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. Sledge concluded.