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Sunday, March 09, 2014
ONLINE FIRST: NeoALTTO Trial: Pathological Complete Response Shown to Translate to Increased Overall Survival in HER2-Positive Breast Cancer

BY ED SUSMAN

 

Women diagnosed with breast cancer who are able to achieve a pathological complete response (pCR) to treatment with HER2-receptor antagonists appear to have significantly longer overall and event-free survival, according to a study reported at the San Antonio Breast Cancer Symposium.

 

Presenting the results of the Phase III Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial, Martine Piccart-Gebhart, MD, PhD, Chair of the Breast International Group (BIG) and Professor of Oncology and Director of Medicine at Jules Bordet Institute in Brussels, Belgium, explained that she and her colleagues had previously reported that the combination therapy resulted in twice as many patients having a pCR.

 

And now in the updated report, achievement of a pCR showed benefits in event-free survival. Of the 137 patients who achieved pathological complete responses, there were 19 relapses during the four years of follow-up – a four-year event-free survival rate of 86 percent.

 

But for the 274 patients who did not achieve a pCR, there were 79 events, or a 72 percent event-free survival rate at four years. The difference, she reported, was highly significant (P=0.0003), and translated to a 63 percent reduction in the risk of having an event.

 

The study assessed whether use of two anti-HER2 drugs would induce higher rates of pCR in women with HER2-positive breast cancer that were two centimeters or larger compared with use of single HER2-receptor blockade with trastuzumab or lapatinib.

 

For the 427 women who underwent surgery, events were defined as primary breast cancer recurrence, second primary cancers, or death. For the 28 who chose not to have surgery, an event was defined as regional or distant disease progression during neo-adjuvant treatment or death.

 

Much of the difference in outcome related to women who were diagnosed with HER2-positive/hormone receptor (HR)-negative breast cancer, Piccart-Gebhart said. In these women, those who achieved a pathological complete response had an 85 percent event-free survival rate at four years compared with 65 percent for patients who did not achieve a pCR. 

 

About 87 percent of patients with HER2-positive/HR-positive breast cancer who achieved a pCR had a four-year event-free survival compared with 78 percent of women who did not have a complete response.

 

“The results provide further evidence that HER2-positive/HR-negative and HER2-positive/HR-positive breast cancer subgroups are two different diseases,” Piccart-Gebhart said.

 

In the original report of the study three years ago, the researchers observed that about 61 percent of women with HR-negative breast cancer were able to achieve a pathological complete response with dual HER2-receptor blockade; overall 50 percent more women achieved a pCR with dual blockade.

 

“Our new analysis shows that the improved pathologic complete response rates seen in the hormone receptor negative/HER2-positive subgroup seem to translate into better long-term outcomes for patients,” she said.

 

“I believe that these results if confirmed in the large ALTTO [Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization] adjuvant trial will impact the process of drug development in the field of early HER2-positive breast cancer.”

 

Those results in the trial that enrolled 8,300 women are expected later this year, she said.

 

‘Very Valid Surrogate Endpoint’

Speaking at a news conference that featured the NeoALTTO study, the moderator, Jennifer Litton, Associate Professor of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, said, “What Dr. Piccart-Gebhart has shown is that pathological complete response continues to be a very valid surrogate endpoint and continues to be valid for the development of new drugs so that we can get them to patients quicker, with smaller numbers of patients involved and less cost.

 

“For me, pathological complete response standing out as a strong clinical endpoint is the continued importance of this study,” 

 

Piccart-Gebhart said that when she and her colleagues analyzed the results, a similar pattern was observed with overall survival. The women who achieved a pCR had a 94 percent overall survival rate at four years compared with 87 percent for the patients who did not achieve a pCR, a relative risk reduction in death of 65 percent. 

 

There was little difference in overall survival among the HR-positive breast cancer patients – 96 versus 93 percent for those who did not achieve a pCR, but there was a major difference among the women with HR-negative breast cancer. Women who had a pCR also had a 94 percent overall survival rate at four years compared with 80 percent for the women with HR-negative disease who were unable to achieve a pCR.

 

Patients who achieved a pathological complete response had significantly better event-free survival and overall survival compared with patients who did not achieve a complete response irrespective of the treatment arm,” she said.

 

Overall survival by treatment arm showed a 22 percent relative risk reduction in death for those women treated in the dual HER2-blockade arm – a 95 percent survival rate over four years, compared with 93 percent for patients treated with lapatinib and 90 percent for those on trastuzumab. The difference, though, failed to achieve statistical significance, she said.

 

Piccart-Gebhart said the NeoALTTO trial was powered to detect pCR differences between the treatment arms, but underpowered to detect moderate differences in event-free and overall survival between the treatment arms. Another follow-up analysis will be performed in two and a half years, she added.

 

No adverse events were observed that were inconsistent with the known safety profile of lapatinib and/or trastuzumab, she said.

 

The study, managed under the overall umbrella of the Breast International Group, was supported by funds from GlaxoSmithKline; and Piccart-Gebhart disclosed that she has received honoraria from Roche and that her institution has received research funding from GlaxoSmithKline.

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