SAN ANTONIO—With only four cycles of T-DM1 in early breast cancer in the neoadjuvant setting, researchers in the West German Study Group (WSG) achieved a 41 percent pathological complete response rate (pCR) in women with HER2+/HR+ breast cancer without the use of systemic chemotherapy. That contrasted with a pCR of only 15 percent in the comparator study arm of trastuzumab plus endocrine therapy.
“Therapy de-escalation for women with early breast cancer may mean no systemic chemotherapy,” said Nadia Harbeck, MD, PhD, Professor of Medicine and Director of the Women's Clinic at the University of Münich, who presented the final analysis of the WSG-ADAPT HER2+/HR+ Phase II trial at the San Antonio Breast Cancer Symposium (Abstract S5-03).
Adding endocrine therapy to T-DM1 did not improve the pCR rate appreciably, Harbeck reported, with 41.5 percent pCR for T-DM1 with endocrine versus 41 percent for T-DM1 without endocrine therapy.
But both T-DM1 arms of the trial were far superior to the third trial arm, trastuzumab plus endocrine therapy, and that was true regardless of menopausal status, she said.
T-DM1 is a conjugate of trastuzumab linked to DM1, a cytotoxic microtubule inhibitor.
In addition, a biomarker of efficacy may have emerged from the trial: Harbeck reported that patients who had an early tumor response of low cellularity or a Ki67 drop of greater than 30 percent at the three-week biopsy point had a pCR rate almost double that of patients without early response.
The study, named WSG-ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy), was sponsored by F. Hoffmann-La-Roche.
‘Quite a High-Risk Tumor to Begin with’
Harbeck said about half of the tumors were larger than two centimeters at baseline, and about one third of the patients had clinically node-positive disease. The essential grade was G3 in more than 80 percent of the patients, and the median Ki67 level was 40 percent.
“In spite of this being a hormone receptor-positive population, I think you would agree that this is quite a high-risk tumor biology to begin with,” she said.
The current standard for HER2+ early breast cancer is neoadjuvant chemotherapy plus anti-HER2 therapy, but that is independent of hormone receptor status even though pCR rates after standard therapy differ according to hormone-receptor status. Molecular analysis, Harbeck noted, shows that HER2+/HR+ (“triple positive”) breast cancer is a distinct entity within HER2+ breast cancer, and that after neoadjuvant chemotherapy plus anti-HER2 therapy the pCR rates differ according to hormone-receptor status.
“Endocrine therapy plus anti-HER2 therapy may thus be an effective neoadjuvant strategy,” she said, explaining the rationale for this trial.
The 376 patients in WSG-ADAPT HER2+/HR+ were randomly assigned to receive 12 weeks of neoadjuvant therapy with T-DM1 at 3.6 mg/kg every three weeks (119 patients); T-DM1 plus endocrine therapy (127 patients); or trastuzumab every three weeks plus endocrine therapy (129 patients).
Endocrine therapy was tamoxifen for premenopausal women and an aromatase inhibitor for postmenopausal women. After surgery, standard chemotherapy at the investigators' discretion was recommended plus one year of trastuzumab.
The patients' median age was 51, and pathologic complete response was defined as having no invasive carcinoma in the breast or lymph nodes.
Harbeck reported a pCR rate for T-DM1 without endocrine therapy of 41.0 percent, compared with 41.5 percent for T-DM1 with endocrine therapy, and 15.1 percent for trastuzumab plus endocrine therapy.
“When pCR was added to near pCR (post treatment stage pT1a), the combined response rates were 53 percent for T-DM1, 52.9 percent for T-DM1-endocrine therapy, and 19.3 percent for trastuzumab-endocrine therapy,” Harbeck said.
Effect of Menopausal Status
Menopausal status had an effect on response, as treatment in each of the three study arms was more effective for postmenopausal patients versus those who were premenopausal.
For postmenopausal patients taking T-DM1 the pCR rates were:
- 44.1 versus 37.9 percent for premenopausal patients;
- 45.0 versus 38.1 percent for T-DM1-endocrine therapy; and
- 16.7 versus 13.6 percent for trastuzumab-endocrine therapy.
Patients who were responding to treatment at the time of the three-week biopsy had far higher pCR rates than those who did not.
“This marker is very predictive of patients who will achieve a pCR later on, with an odds ratio of 2.2,” Harbeck said. “The biomarkers' effects are the same across the treatment arms: patients with one of those positive biomarkers after one cycle of therapy have about a 40 percent pCR rate, which is double than in the patients who did not have the biomarker present at that point.”
For early responders taking T-DM1 the pCR rate was 39.9 versus 25.0 percent for those who were not early responders; in the T-DM1-endocrine therapy arm the pCRs were 47.4 and 24.0 percent, respectively; and for trastuzumab-endocrine therapy the pCR rates were 17.7 and 12.5 percent.
‘Few Significant Adverse Events’
The researchers pooled the two T-DM1 arms due to the low number of events in each individual arm, and found nothing telling about comparing the two T-DM1 arms.
The rate of significant adverse events for both T-DM1 arms was 23.2 percent, versus 9.0 percent for trastuzumab-endocrine therapy. The most common adverse events were:
- Fatigue—22.8 percent for T-DM1 pooled versus 11.5 percent for trastuzumab-endocrine therapy;
- Nausea—20.7 versus 4.9 percent, respectively;
- Thrombocytopenia—10.4 versus none; and
- Constipation—10.4 versus 4.1 percent.
Interim Report Differs
Harbeck had presented interim data on 130 patients at the most recent American Society of Clinical Oncology annual meeting (Abstract 506). In that report, the overall pCR rate for T-DM1 alone was 40.5 percent, 45.8 percent for T-DM1-endocrine therapy, and 6.7 percent for trastuzumab-endocrine therapy.
There was a slightly lower pCR rate in the premenopausal patients, but it was not substantial, she said.
“Note that these data are slightly different from what we presented in the interim analysis; this goes to show that you always have to wait for the full analysis before drawing any conclusions.”
Harbeck concluded: “T-DM1 as a single agent warrants further evaluation in early breast cancer—not just because of the efficacy, which I think is very impressive, but also because of the very favorable safety profile.”