High Pathologic Complete Response Rates Observed With Neoadjuvant Ado-Trastuzumab Emtansine

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Nadia Harbeck, MD, PhD

Early tumor response predicts for pathologic complete response and can already be detected after 3 weeks.

—Nadia Harbeck, MD, PhD

Neoadjuvant treatment with a chemotherapy-free, anti-HER2 regimen yielded high rates of pathologic complete response in patients with HER2-positive, hormone receptor-positive early breast cancer in the phase II WSG-ADAPT HER2+/HR+ (ADAPT) trial presented at the 2015 San Antonio Breast Cancer Symposium.1

“Therapy de-escalation in this population is possible,” said lead investigator Nadia Harbeck, MD, PhD, Head of the Breast Center, Oncological Therapy and Clinical Trials Unit, University of Munich, Germany. The ADAPT trial also showed that early tumor response, measured by a drop in Ki67 or low cellularity, was predictive of pathologic complete response.

“In HER2-positive early breast cancer, the current standard treatment—chemotherapy plus anti-HER2 therapy—is independent of hormone receptor status. HER2-positive, hormone receptor–positive (ie, “triple-positive”) patients are a distinct entity among the HER2-positive subset,” according to Dr. Harbeck.

Within the HER2 subset of patients, the impact of pathologic complete response rates after neoadjuvant chemotherapy plus anti-HER2 therapy differs according to hormone receptor status, she pointed out.

“Therefore, endocrine plus anti-HER2 therapy, without systemic chemotherapy, may be an effective neoadjuvant strategy,” she said. “So far, we have no efficacy data on single-agent T-DM1 in this setting, nor for the combination of T-DM1 plus endocrine therapy.”

Thus, the ADAPT trial evaluated this strategy and aimed to identify early responders, said Dr. Harbeck, who presented the findings on behalf of the West German Study Group.

Trial Details

The ADAPT trial is a large umbrella trial that has enrolled 5,000 patients with various breast cancer phenotypes. Patients were randomized to 12 weeks of ado-trastuzumab emtansine (T-DM1, Kadcyla), ado-trastuzumab emtansine plus endocrine therapy (tamoxifen or an aromatase inhibitor), or trastuzumab (Herceptin) plus endocrine therapy (the control arm). This regimen was followed by surgery and 1 year of adjuvant trastuzumab.

The primary endpoint was pathologic complete response (ypN, ypT0) between each of the ado-trastuzu­mab emtansine arms in comparison with the trastuzumab plus endocrine therapy arm.

For this analysis, 463 women were screened, and 354 completed treatment. Their median baseline Ki67 level was approximately 40%. Investigators aimed to identify an early-response biomarker (eg, drop in Ki-67 or low celluarity.

High Response Rates

“More than 40% of ado-trastuzumab emtansine–treated patients achieved a pathologic complete response (in the breast and lymph nodes) after 12 weeks of therapy that did not include systemic chemotherapy,” Dr. Harbeck reported.

Rates of pathologic complete response were 41% for ado-trastuzumab emtansine alone, 41.5% for ado-trastuzumab emtansine plus endocrine therapy, and only 15.1% for trastuzumab plus endocrine therapy. The differences between both ado-trastuzumab emtansine arms and the control arm were highly significant (P < .001).

“Adding endocrine therapy to T-DM1 does not increase pathologic complete response rates,” she stated.

The effect of ado-trastuzumab emtansine was independent of menopausal status, although pathologic complete response rates were higher among postmenopausal women than premenopausal women in all arms.

Early Response Is Predictive

Early tumor response was significantly associated with more than double the odds of achieving a pathologic complete response. Early response was defined by low cellularity (< 500 tumor cells) or Ki67 drop ≥ 30% in the biopsy taken at week 3.

“Early tumor response predicts for pathologic complete response and can already be detected after 3 weeks,” Dr. Harbeck noted. The rate of pathologic complete response for early responders, vs nonresponders, was 35.7% and 19.8% in the overall population; 39.3% vs 25.0% in the single-agent ado-trastuzumab emtansine arm; 47.4% vs 24.0% in the ado-trastuzumab emtansine plus endocrine therapy arm; and 17.7% and 12.5% in the tratsuzumab/endocrine therapy arm, respectively, she reported.

Ado-trastuzumab emtansine was associated with low toxicity, and no new safety signals emerged.

Dr. Harbeck said that based on ADAPT’s findings, future trials should separately investigate therapeutic concepts for HER2-positive/hormone receptor–positive vs HER2-positive/hormone receptor–negative disease. ■

Disclosure: Dr. Harbeck reported no potential conflicts of interest.


  1. Harbeck N, Gluz O, Christgen M, et al: Final analysis of WSG-ADAPT HER2+/HR+ phase II trial. 2015 San Antonio Breast Cancer Symposium. Abstract S5-03. Presented December 11, 2015.


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