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NeoALTTO Trial Links Pathologic Complete Response to Clinical Outcomes

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Key Points

  • In this analysis, 3-year event-free survival was 86% in patients achieving a pathologic complete response vs 72% in those with no pathologic complete response, a 62% reduction in risk (P = .0003),
  • The pathologic complete response group had a 3-year overall survival of 94% vs 87% in patients without pathologic complete response. This result was most impressive in the hormone receptor–negative group.
  • The findings lend support to the concept that pathologic complete response might be an appropriate endpoint for drug approval by the FDA.

Final results of the phase III NeoALTTO trial have confirmed the value of pathologic complete response to dual HER2 blockade in the neoadjuvant setting. The achievement of pathologic complete response was associated with significantly improved event-free survival and overall survival in some women with HER2-positive tumors. The study was reported at the 2013 San Antonio Breast Cancer Symposium (Abstract S1-01) by Martine Piccart-Gebhart, MD, PhD, Chair of the Breast International Group in Brussels.

The benefit was restricted, however, to the subset of women with HER2-positive tumors who had hormone receptor–negative disease in the 30-week landmark analysis. “More and more, we believe that these are different diseases that require different treatment approaches,” Dr. Piccart-Gebhart said.

Study Details

The 86-institution NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial enrolled 455 patients with HER2-positive primary breast cancer with tumors > 2 cm. Patients were randomly assigned to lapatinib (Tykerb) (n = 154), trastuzumab (Herceptin) (n = 149), or dual HER2 blockade with the combination (n = 152). HER2-targeted therapy was given alone for 6 weeks, after which paclitaxel was added for a further 12 weeks, followed by surgery.

NeoALTTO is the first of the large trials of dual HER2 blockade for neoadjuvant therapy to report relatively long-term results. The primary endpoint of pathologic complete response in the breast was met, with rates of 51.3% of the combination arm vs 29.5% of the trastuzumab arm and 24.7% of the lapatinib arm.

“The question then becomes, does the incremental gain in pathologic complete response observed with dual HER2 blockade translate into improved event-free survival and overall survival?” Dr. Piccart-Gebhart said.

This was the subject of her report in San Antonio, which was the prespecified analysis performed 3 years after the last breast cancer surgery, with a median follow-up of almost 4 years. The event-free survival and overall survival by treatment arm was underpowered for statistical significance, and was intended to be descriptive only, she emphasized.

Achievement of Pathologic Complete Response Improves Clinical Outcomes

In the landmark analysis, where patients were assessed 30 weeks after randomization, 3-year event-free survival was 86% in patients achieving a pathologic complete response vs 72% in those with no pathologic complete response, a 62% reduction in risk that was highly significant (P = .0003), Dr. Piccart-Gebhart reported.

In the hormone receptor–negative subgroup, event-free survival was 85% in the pathologic complete response group and 65% in those without pathologic complete response (hazard ratio [HR] = 0.34, P = .001). In contrast, in the hormone receptor–positive subgroup, the difference was much less, with event-free survival of 87% in patients achieving pathologic complete response and 78% in those without (HR = 0.50, P = .13).

By treatment arm, patients receiving the combination of trastuzumab plus lapatinib had a 3-year event-free survival of 91% vs 73% in those without a pathologic complete response (HR = 0.32, P = .012).

The landmark analysis of 3-year overall survival found 94% of the pathologic complete response group alive vs 87% of those without pathologic complete response (HR = 0.35, P = .005). This result that was most impressive in the hormone receptor–negative group: 94% vs 80% (HR = 0.29, P = .003). Treatment with the combination led to a 3-year overall survival rate of 95% and  91%, respectively (HR = 0.35, P = .13).

While the benefit was clear in the hormone receptor–positive subgroup of HER2-positive patients, Dr. Piccart-Gebhart said a possible benefit in hormone receptor–negative patients should not be discounted. “It’s possible that with longer follow-up we will see a better treatment effect in this subgroup,” she suggested.

Implications for FDA Approval Process 

Dr. Piccart said the findings lend support to the concept that pathologic complete response might be an appropriate endpoint for drug approval, which is under consideration by the U.S. Food and Drug Administration (FDA).

“The FDA will give a definitive answer in June, and we will have the results of the adjuvant ALTTO trial by then,” she indicated. “This [trial] is powered to look at the impact of dual HER2 blockade on disease-free survival, and if this is improved—particularly in the hormone receptor-negative subgroup—then I think we have a very strong story, with NeoALTTO showing a trend and ALTTO confirming it. Then, yes, I agree that we could think of registering new drugs for these women [based on pathologic complete response].”

Jennifer Litton, MD, Associate Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, who moderated the press briefing where the results were first presented, agreed that the study supports pathologic complete response as a valid surrogate endpoint for drug development and faster approval. “Pathologic complete repsonse is standing out as a continuing strong surrogate endpoint,” she said.

The study was funded by GlaxoSmithKline. Dr. Piccart-Gebhart has received honoraria from Roche, and her institution has received research funding from GlaxoSmithKline.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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