Expert Point of View: George W. Sledge, Jr, MD

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George W. Sledge, Jr, MD

In his commentary on the ALTTO results, George W. Sledge, Jr, MD, Professor of Medicine and Director of the Division of Oncology at Stanford University, reminded attendees that the announcement of the first results for adjuvant trastuzumab, which occurred at the 2005 ASCO Annual Meeting, was “a defining moment in our field.” The 50% reduction in the annual odds of recurrence “remains one of the great success stories,” he said.

‘A Serious Disappointment’

“But a 50% improvement still meant that far too many women were relapsing and dying, and there was still real work to be done,” he continued. That work, he noted, was the exploration of a number of biology-based approaches, of which the combining of trastuzumab with kinase inhibition “at the time appeared to be the best bet.” This proposal was subsequently supported by preclinical and clinical evidence, leading to the development of the ALTTO trial.

“What mattered was whether dual HER2 blockade would move us further up the disease-free survival ladder, bringing us closer to a cure for HER2-positive breast cancer,” Dr. Sledge said.

“HER2 has reverted to the incrementalism we see so commonly in the adjuvant field,” Dr. Sledge offered. “This is not, alas, 2005. This is not a great leap forward. This is a serious disappointment, not just for the investigators but for the entire field.”

The negative findings “tell us at a simple level that we won’t be using lapatinib in the adjuvant setting,” he continued, predicting that further follow-up will not produce a statistically significant result. Furthermore, he added, “It’s difficult to mount any enthusiasm for dual blockade in the adjuvant setting, at least for the combination shown here.”

But he added that the findings have importance beyond the obvious. “You might be wondering why a negative adjuvant trial occupies a Plenary Session spot, a place usually reserved for practice-changing data. I suggest that the answer requires us to rethink our approach to the development of new drugs for early breast cancer,” he said.

“ALTTO represented a reasonable test of the hypothesis that improvements in pathologic complete response rates were associated with improved disease-free survival. These hopes have now been dashed. The null hypothesis won,” Dr. Sledge observed. The results of the adjuvant ­APHINITY trial in which pertuzumab plus trastuzumab are being tested will be of great interest, he added.

The Larger Question

Furthermore, Dr. Sledge suggested that ALTTO “invites a larger question,” specifically, whether drugs that prove themselves in the metastatic or neoadjuvant setting are similarly effective as adjuvant therapies. He noted that the ALTTO “failure” joins several others, including drugs targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) in colorectal cancer, and anti-VEGF drugs in breast cancer.

These approaches may have failed because they are the wrong drugs, are given for an inadequate duration, or are given to inappropriately selected patients, or perhaps because the biology of early vs metastatic cancer is poorly understood.

“Why have these approaches failed in the adjuvant setting, despite a plethora of preclinical evidence and numerous positive trials in the metastatic setting that show an overall survival advantage?” he asked. “These setbacks should prompt us to ask, are we facing a systemic crisis in the adjuvant failure of targeted therapies, or just having a string of bad luck?”

These failures must be elucidated in order to move forward and create new successes, he suggested. “But, move forward we shall, in HER2-positive breast cancer,” he said.

Many novel approaches are active areas of research. “I hope and I believe that at least one of these will prove fruitful,” he said, “and move us closer to the day when HER2-positive breast cancer will no longer be a public health problem.” ■

Disclosure: Dr. Sledge has received honoraria from Genentech for lecture and is a member of the science advisory board for Syndax.

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