De-escalated neoadjuvant paclitaxel, dual HER2 blockade effective in breast cancer subtype
A de-escalated, 12-week neoadjuvant treatment regimen of dual HER2 blockade with pertuzumab and trastuzumab plus weekly paclitaxel demonstrated high efficacy among patients with HER2-positive, hormone receptor-negative early breast cancer.
Researchers presented the first survival data from the randomized, phase 2 WSG-ADAPT-HR-/HER2+ trial — part of the ADAPT umbrella protocol — during the virtual ASCO Annual Meeting.
“For the first time, we have shown in a prospective multicenter trial both excellent pathologic complete response and survival in patients treated by de-escalated 12-week neoadjuvant weekly paclitaxel and dual HER2 blockade pertuzumab and trastuzumab, irrespective of additional chemotherapy use,” Nadia Harbeck, MD, PhD, head of the breast center, oncological therapy and clinical trials unit and chair for conservative oncology in the department of obstetrics and gynecology at University of Munich in Germany, said during her presentation.
The study enrolled 134 patients with HER2-positive, hormone receptor-negative early breast cancer. Researchers randomly assigned patients 5:2 to trastuzumab (Herceptin, Genentech) plus pertuzumab (Perjeta, Genentech) alone or with paclitaxel. The trastuzumab-pertuzumab (n = 92) and trastuzumab-pertuzumab-paclitaxel (n = 42) groups had similar baseline characteristics, including median age (54 years vs. 51.5 years) and percentage of cT2 to cT4 tumors (59.8% vs. 61.9%).
All patients received four cycles of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg/kg) every 3 weeks. Patients in the paclitaxel group also received 80 mg/m2 paclitaxel weekly for 12 weeks. Researchers obtained a biopsy of each patient before cycle 2 for early response assessment, Harbeck said.
Pathologic complete response served as the primary endpoint; those who achieved this response after 12 weeks of study treatment could skip additional chemotherapy.
The objective of the trial was to compare pathologic complete response in the paclitaxel group vs. the early responders in the pertuzumab-trastuzumab group. Investigators also assessed invasive DFS, distant DFS, OS and safety as secondary endpoints.
Median follow-up was 59.9 months (range, 0.2-75.3).
The trial ended early due to the superiority of pathologic complete response rates observed in the paclitaxel group (ypT0/is ypN0, 90.5% vs. 34.4%; ypT0 ypN0, 78.6% vs. 24.4%).
“We were pleasantly surprised by the 34% pathologic complete response rate after 12 weeks of dual HER2 blockade alone,” Harbeck told Healio. “Yet, I would like to point out that this kind of de-escalation with anti-HER2 therapy alone should currently only be done in clinical trials. Moreover, patients need to be carefully selected either upfront by HER2-enriched status, HER2 3+ or by early response to therapy after one to two cycles.”
Seventy-nine percent of patients in the paclitaxel group had no further chemotherapy after achieving pathologic complete response, compared with 29% of patients in the dual HER2 blockade group.
Harbeck described OS results as “excellent,” with only six events in the trial; 5-year OS rates were 98% in the paclitaxel group and 94% in the pertuzumab-trastuzumab-alone group (HR = 0.41; 95% CI, 0.05-3.55).
Rates of invasive DFS at 5 years also favored the paclitaxel group (98% vs. 87%; HR = 0.32; 95% CI, 0.07-1.47), as did rates of distant DFS at 5 years (98% vs. 92%, HR = 0.34; 95% CI, 0.04-2.8).
Early pathologic complete response after de-escalated therapy appeared associated with improved outcomes across the study and could be a predictive marker for further therapy de-escalation, Harbeck said. Patients with a pathologic complete response had a 5-year invasive DFS rate of 98% vs. 82% for those who did not have a pathologic complete response (HR = 0.14; 95% CI, 0.03-0.64).
No pathologic complete responses occurred in the chemotherapy-free group among patients with low HER2 expression and/or basal-like disease subtype. Low HER2 expression and/or no early response appeared associated with worse DFS (P = 0.29) and a trend toward worse invasive DFS.
Researchers observed no new safety signals.
Investigators plan to provide data for the same treatment regimen in the WSG HER2+/HR+ TPII trial soon.
“Our results are currently being validated by the ongoing COMPASS HER2 trial in the U.S. and DECRESCENDO in Europe,” Harbeck told Healio. “These trials will also answer the question for the optimal therapy for patients with no pathologic complete response after 12 [weeks of] paclitaxel plus dual blockade.”
Perspective
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In my early training as a medical oncologist, the prevailing hypothesis regarding cytotoxic chemotherapy was “more is better.” In breast cancer, this hypothesis was disproved, with the most obvious evidence coming from the autologous bone marrow transplant trials.
With the development of targeted therapies for HER2-positive breast cancer, we have a chance to revisit the role of combination cytotoxic therapy compared with HER2-targeted drugs alone.
The clinical activity of neoadjuvant pertuzumab and trastuzumab given without cytotoxic chemotherapy to patients with HER2-positive breast cancer has been tested in the NeoSphere trial, with a reported pathologic complete response (pCR) rate of 16.8%. Patients with HER2-positive, hormone receptor-negative tumors had an improved pCR rate of 27.3%. Although 5-year follow-up for these patients has been reported, those who received pertuzumab and trastuzumab received subsequent adjuvant cytotoxic therapy, and it cannot be determined if a pCR on antibody therapy alone has long-term implications similar to a pCR with HER2-targeted treatment and chemotherapy.
The pCR rates of the WSG ADAPT-HER2+/HR- neoadjuvant trial have been reported previously, with a result similar to NeoSphere for antibody treatment alone. At ASCO, Harbeck and colleagues also reported invasive DFS, distant DFS and OS results. All three long-term outcomes were excellent for each group. The high rate of subsequent adjuvant therapy in the pertuzumab-trastuzumab group, compared with the pertuzumab-trastuzumab-paclitaxel group, is likely due to physician uncertainty that a “pCR is a pCR” no matter how it was achieved and the perceived need for cytotoxic chemotherapy.
The authors looked further into predictive biomarkers for pCR to antibody therapy alone. In these exploratory inquiries, patients who had a basal phenotype, low HER2 by immunohistochemistry (despite being positive by fluorescence in situ hybridization) and lack of an early response by biopsy were identified as a “nonsensitive” subgroup; they comprised about one-third of patients enrolled. These nonsensitive patients had a very low chance of achieving a pCR — only about 7%.
This study further supports the idea that pCR is a good surrogate marker for long-term outcomes. Importantly, pCR can be obtained without cytotoxic therapy in a substantial number of patients with HER2-positive, hormone receptor-negative breast cancer. The heterogeneity of this subgroup may be further classified as “responder” or “nonresponder” by a combination of molecular classification, immunohistochemical analysis and functional analysis utilizing an early biopsy on therapy.
For the right patient, “less is more” and biologically targeted therapy may be equivalent to less well-tolerated, multiagent chemotherapy. The concept of de-escalation is firmly established in the adjuvant therapy of hormone receptor-positive breast cancers; most do not need chemotherapy. WSG-ADAPT HER2+/HR- results are an important step in establishing these concepts in HER2-positive disease, and several ongoing trials will address this concept.
References:
Berry DA, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.32.5936.
Gianni L, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(11)70336-9.
Gianni L, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)00163-7.
Spring LM, et al. Clin Cancer Res. 2020;doi:10.1158/1078-0432.CCR-19-3492.
Masonic Cancer Center, University of Minnesota
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Harbeck, N. Abstract 503. Presented at ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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