Negative ALTTO Results Reverberate for Lapatinib, Novel Clinical Trials

Anita T. Shaffer @Shaffer1
Published: Sunday, Jun 01, 2014

Dr. Edith A. Perez

Edith A. Perez, MD

A dual HER2-blockade strategy that added lapatinib to trastuzumab for the adjuvant treatment of women with early breast cancer failed to demonstrate a significant improvement in disease-free survival (DFS) over the standard therapy with trastuzumab alone, according to findings from a major clinical trial released Sunday.1

The combination faltered in the phase III ALTTO trial despite positive signals in an earlier study that suggested pathologic complete response (pCR) to the dual agents when used as neoadjuvant therapy could serve as a surrogate marker for long-term treatment impact.  

As a result, the findings may deal a blow to an emerging movement to establish pCR as a clinical trial endpoint in earlier disease settings not only in breast cancer but also in other malignancies, experts said.

The ALTTO trial, which enrolled more than 8000 women in 44 countries, is the largest adjuvant clinical trial ever conducted in women with HER2-positive breast cancer and the findings were eagerly anticipated in the oncology community.

Released at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, the findings indicated that treatment with lapatinib plus trastuzumab, either sequentially or concurrently, was associated with a high rate of DFS but that combining the drugs did not produce a statistically significant advantage over trastuzumab alone.

At a median follow-up of 4.5 years, the DFS rates were 86% for patients who received trastuzumab alone; 88% for participants treated with trastuzumab and lapatinib concurrently; and 87% for patients who received trastuzumab followed by lapatinib. All patients also received chemotherapy.

The results proved to be a disappointment to researchers pursuing a new approach for reducing the risk of relapse for women treated after surgery with trastuzumab and chemotherapy. Approximately 20% of patients relapse within 10 years, and usually develop metastatic disease, according to ASCO.

Findings from the NeoALTTO study,2 released in December 2013, showed that patients who achieved a pCR after receiving the two drugs as neoadjuvant therapy displayed a significantly higher rate of 3-year event-free survival, raising hopes that ALTTO would confirm those results.

However, senior study author Edith A. Perez, MD, said during the press briefing that ALTTO did not corroborate the theory that pCR could be used as a surrogate marker in a smaller trial, making large trials such as ALTTO unnecessary. The findings are “important for the breast cancer field overall,” said Perez, who is deputy director at large at the Mayo Clinic Cancer Center in Jacksonville, Florida.

“From a practical point of view, this is the kind of study that, if positive, would have changed practice tomorrow morning because these drugs are available and the adjuvant setting is one where there is a tremendous drive to reduce recurrence and prevent early death,” said Clifford A. Hudis, MD, president of ASCO, who served as moderator during the press briefing.

He said that the results also have “tremendous potential implications” for getting drugs to patients preoperatively based on pCR rates studied in smaller-scale clinical trials.

Clifford A. Hudis, MD

Clifford A. Hudis, MD

“This is going to cause a lot of high-level scientific discussion in terms of drug development,” said Hudis, who is chief of Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center in New York City. “This is a really important study. It’s important because it has profound long-term implications right now in terms of drug development.”

Impetus for Launching ALTTO

Launched in January 2007, the ALTTO trial took international research cooperation to a new level, according to the National Cancer Institute (NCI).3 The global initiative was coordinated by two large academic research networks, the North American Breast Cancer Groups (NABCG), based in the United States, and the Breast International Group (BIG) in Brussels, Belgium. The NCI and GlaxoSmithKline, which markets lapatinib in the United States as Tykerb, sponsored the trial.

Researchers were seeking to determine whether combining the two drugs, which targeted HER2 in different ways, would prove more beneficial than trastuzumab alone and whether lapatinib would deliver similar benefits to trastuzumab in the adjuvant setting.

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