Nick Mulcahy

December 11, 2013

SAN ANTONIO — A new study strengthens the evidence that pathological complete response (pCR) is a good surrogate marker of longer-term efficacy in the neoadjuvant drug treatment of breast cancer.

pCR, which is defined as the absence of invasive cancer in the breast and lymph nodes after treatment, can be measured within weeks of starting a drug. Thus, it can provide a very early indicator of efficacy.

However, here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS), investigators reported that short-term pCR results also correlate with longer-term event-free survival in the neoadjuvant setting.

At a meeting press conference today, Martine Piccart-Gebhart, MD, PhD, illustrated this using data from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial.

She explained that the combination of lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) provided significantly better 3-year event-free survival than either agent alone in women with early-stage HER2-postive disease.

Notably, this improvement correlated with pCR in the 455-patient trial, said Dr. Piccart-Gebhart, who is chair of the Breast International Group in Brussels.

At 3 years, there was a 62% reduction in the risk for an event, such as disease recurrence or a second primary tumor, among the 137 patients who had a pCR compared with the 274 patients who did not (hazard ratio [HR], 0.38; P = .0003).

The correlation between pCR and 3-year event-free survival is especially important because NeoALTTO is one of the first randomized trials to prospectively evaluate pCR in breast cancer, said Jennifer Litton, MD, from the University of Texas M.D. Anderson Cancer Center in Houston. She moderated the meeting press conference.

Multiple retrospective studies in the neoadjuvant setting have shown that pCR correlates with long-term outcomes, she explained. "We have been looking at it for decades," said Dr. Litton about pCR.

Thus, NeoALTTO extends the evidence that pCR is a "strong surrogate marker," she told Medscape Medical News.

"For me, that's the story of NeoALTTO: pCR shows benefit, and it's persisting [at 3 years]," Dr. Litton summarized.

She also explained that regulators have contributed to the emerging status of pCR. The US Food and Drug Administration (FDA) "has now looked at the totality of evidence and realized that pCR is an important surrogate end point."

This fall, the FDA approved pertuzumab (Perjeta, Genentech) for the neoadjuvant treatment of early HER2-positive breast cancer on the basis of pCR results. In other words, the drug was approved based on short-term efficacy findings using a surrogate marker. The drug, which received accelerated approval, will need to eventually show a longer-term survival benefit to keep its indication in this setting.

Approval on the basis of pCR results signaled a new day in drug approval in the United States.

"We have a whole new tool to get drugs to patients faster," said Dr. Litton.

Industry has also been understandably appreciative of the shift in FDA drug evaluation criteria in this setting.

"If we can shorten the time it takes to determine whether a breast cancer medicine works, that is clearly good news for patients," said Dietmar Berger, vice president of clinical hematology/oncology at Genentech, in a press statement earlier this year when the FDA was considering the use of pCR as a marker in breast cancer drug approval in the neoadjuvant setting. The agency has since issued a draft guidance on the use of the measure in trials in this setting.

Differing Opinions

In NeoALTTO, an international team of researchers led by Dr. Piccart-Gebhart randomized 455 women with HER2-positive primary breast cancer to lapatinib, trastuzumab, or a combination of the 2 for 6 weeks, followed by surgery, chemotherapy, and then 48 more weeks of the original neoadjuvant therapy.

At the 2010 SABCS, the investigators revealed that the combination of trastuzumab and lapatinib completely wiped out tumor cells in the breast, and thus achieved pCR, in 51.3% of women — about twice the rate of response seen with either drug alone. The difference was statistically significant (P =.001).

However, at that time, a number of experts said that pCR was not ready to be used as a surrogate marker.

pCR was "not ready for prime time" as a measure to be used for drug approval because it is not always correlated with improved disease-free and overall survival, said Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, at the 2010 meeting.

Another expert agreed with Dr. Winer at that time. "Complete pathological response is not a perfect surrogate for long-term survival," said Leif Ellisen, MD, PhD, from the Gillette Center for Breast Cancer at Harvard Medical School in Boston.

"It's predicted survival in some trials of breast cancer, but not in all," Dr. Ellisen said. "And the FDA has said that it will not allow pCR to be used as an end point."

How quickly things have changed.

The study was funded by GlaxoSmithKline. Dr. Piccart-Gebhart reports financial ties to Roche and GlaxoSmithKline.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-01. Presented December 11, 2013.

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