The first overall survival analysis of the WGS-ADAPT HER2+/HR– study, which evaluated neoadjuvant therapy in patients with hormone receptor–negative, HER2-positive disease, showed that treatment with pertuzumab and trastuzumab plus paclitaxel—or with the chemotherapy-free regimen of pertuzumab/trastuzumab alone—can yield benefits in survival outcomes.1
“For the first time, we have shown both excellent pathologic complete response rates and survival in patients treated by de-escalated 12-week neoadjuvant weekly paclitaxel and dual HER2 blockade, irrespective of further chemotherapy use, in a prospective multicenter study,” said Nadia Harbeck, MD, PhD, Head of the Breast Center and Chair for Conservative Oncology at the LMU University Hospital, Munich. “Overall survival was excellent in both study arms, with only six events in the whole trial. There were also just seven distant disease–free survival events,” she added.
Nadia Harbeck, MD, PhD
The achievement of a pathologic complete response after 12 weeks of neoadjuvant pertuzumab/trastuzumab and paclitaxel heralded the best outcomes: one responding patient developed distant disease. This could potentially serve as a predictive clinical marker for further treatment de-escalation or escalation, said
The West Germany Study Group (WGS) previously reported that 12 weeks of pertuzumab/trastuzumab plus paclitaxel yielded a pathologic complete response rate of 90%, whereas the chemotherapy-free pertuzumab/trastuzumab regimen led to a 34% rate.2 Dr. Harbeck presented the survival data at the 2021 ASCO Annual Meeting.1
After a median follow-up of 5 years, no significant differences between study arms emerged in disease-free survival, distant disease–free survival, or overall survival. A total of 13 invasive disease–free survival events (7 distant) were observed in the whole intent-to-treat population, Dr. Harbeck reported.
About the Study
The optimal use of de-escalated neoadjuvant regimens—particularly chemotherapy-free therapies—in HER2-positive early breast cancer has been unclear, as survival data for such approaches have been limited, Dr. Harbeck explained. The prospective multicenter WSG-ADAPT-HER2+/HR– phase II trial, which evaluated this question, is part of the WGS ADAPT umbrella protocol.
The study enrolled 134 patients with cT1–cT4c, cN0–3 hormone receptor–negative, HER2-positive early breast cancer, of whom 60% had tumors that were cT2–4 and 42% were clinically node-positive.
Patients were randomly assigned to receive four cycles of pertuzumab plus trastuzumab (n = 92) or the same plus paclitaxel for 12 cycles (n = 42); patients underwent surgery within 3 weeks of treatment completion. If a pathologic complete response was achieved after 12 weeks of the study treatment, additional chemotherapy could be omitted at the investigator’s discretion; this was done for 29% of patients treated with dual HER2 blockade alone and 79% of those receiving trastuzumab/pertuzumab plus chemotherapy.
The trial’s objective was to compare pathologic complete response rates in patients in the pertuzumab/trastuzumab/paclitaxel arm with those of early responders in the pertuzumab/trastuzumab arm (defined as low cellularity and/or Ki67 decrease > 30% after 3 weeks). The primary endpoint was pathologic complete response (ypT0/is/ypN0), which was previously reported.2
Further investigations of chemotherapy-free regimens may need to focus on selected patients alone, such as those with high HER2 expression and non–basal-like tumors.— Nadia Harbeck, MD, PhD
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After a median follow-up of about 5 years, the invasive disease–free survival was 98% with the triplet and 87% with dual HER2 blockade alone (hazard ratio [HR] = 0.32; P = .144). The rate of distant disease–free survival was 98% vs 92%, respectively (HR = 0.34; P = .313), and the overall survival rate was 98% vs 94% (HR = 0.41; P = .422).
The achievement of a pathologic complete response after the 12-week treatment was strongly associated with improved invasive disease–free survival at 5 years, irrespective of the study arm: 98% vs 82% without pathologic complete response (HR = 0.18; P = .011). The 98% rate was seen with both treatments. “You can see that pathologic complete response status after de-escalated therapy is indeed meaningful regarding outcomes for the whole study collective,” Dr. Harbeck commented.
Is no further treatment for HER2-positive disease necessary for patients achieving pathologic complete response? “If you arrive at pathologic complete response with de-escalated therapy,” Dr. Harbeck responded, “that pathologic complete response is meaningful for patient outcomes. So, part of the equation is settled. However, for patients who do not achieve pathologic complete response in the clinic, we have no idea whether they need further chemotherapy or can be put on the KATHERINE regimen (trastuzumab emtansine [T-DM1] for 18 weeks).”3
Subtypes and Translational Findings
“Since patients in the neoadjuvant chemotherapy–free arm with pathologic complete responses had excellent outcomes, it’s clinically relevant to see whether there are biomarkers to tell us who will and will not respond to HER2 antibodies alone,” Dr. Harbeck said. To this end, the investigators examined treatment benefit according to cancer subtype, HER2 status by immunohistochemistry (IHC), and early response to treatment (by Ki67 decrease or low cellularity). They found that 72% of the tumors were HER2-enriched, 6% were luminal, and 9% were basal (13% unknown) by PAM50.
No pathologic complete responses were seen in patients who had low HER2 expression (IHC 1+/2+ and fluorescence in situ hybridization–positive) or the basal subtype. Low HER2 expression and/or lack of early response were strongly associated with worse distant disease–free survival and invasive disease–free survival.
“We found that one-third of patients in the trastuzumab/pertuzumab arm had what we designated as ‘nonsensitive tumors,’ and there were only 2 pathologic complete responses among these 31 patients,” reported Dr. Harbeck. These patients had a 5-year invasive disease–free survival rate of 79% vs 93% for all others (HR = 1.99; P = .255); in the whole cohort (both arms), patients with nonsensitive tumors also had significantly more distant disease.
The investigators also looked at RNA expression signatures and stromal tumor-infiltrating lymphocytes, reporting that dynamic stromal tumor-infiltrating lymphocytes did not appear to be predictive of early response. From RNA-expression profiling, they saw some signatures were predictive for one outcome but perhaps not another.
Dr. Harbeck commented: “Further investigations of chemotherapy-free regimens may need to focus on selected patients alone, such as those with high HER2 expression and non–basal-like tumors.” She said the COMPASS trial in the United States and the DECRESCENDO trial in Europe are exploring these questions and evaluating de-escalation strategies.
DISCLOSURE: The study was funded by Roche. Dr. Harbeck holds stock or other ownership interests in the West German Study Group; has received honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Exact Sciences, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, and SeaGen; has served as a consultant or advisor to AstraZeneca, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, and SeaGen; has an immediate family member who has served as a consultant or advisor to the West German Study Group; and has received institutional research funding from Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche/Genentech.
1. Harbeck N, Gluz O, Christgen M, et al: De-escalated neoadjuvant pertuzumab + trastuzumab with or without paclitaxel weekly in HR–/HER2+ early breast cancer: ADAPT-HR–/HER2+ biomarker and survival results. 2021 ASCO Annual Meeting. Abstract 503. Presented June 6, 2021.
2. Nitz UA, Gluz O, Christgen M, et al: De-escalation strategies in HER2-positive early breast cancer: Final analysis of the WSG-ADAPT HER2+/HR– phase II trial: Efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol 28:2768-2772, 2017.
3. von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.