De-escalated Trastuzumab Plus Pertuzumab Regimen May Be Feasible for Subsets of HER2+, HR– Early Breast Cancer

A regimen of de-escalated trastuzumab (Herceptin) plus pertuzumab (Perjeta) resulted in strong survival rates among patients with HER2-positive, hormone receptor–negative early-stage breast cancer who achieved a pathological complete response (pCR) regardless of additional paclitaxel, according to findings published in Lancet Oncology.

These results from the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy (WSG-ADAPT) trial, an open-label phase 2 study, showed that among patients treated with trastuzumab plus pertuzumab alone or in combination with paclitaxel, there were no significant differences between the treatment groups in invasive disease-free survival (iDFS), relapse-free survival (RFS), locoregional RFS, distant DFS, and overall survival (OS).

“With the advances in anti-HER2 therapies, de-escalation strategies have aimed at reducing chemotherapy use, which is responsible for most of the acute and late toxic effects caused by standard regimens,” Ulrike Nitz, MD, of the West German Study Group in Moenchengladbach, Germany, and colleagues wrote. “This proportion of patients with a pathological complete response is in line with that reported for dual HER2-blockade alone in more advanced tumour stages.”

The investigators randomly assigned patients with HER2-positive, hormone receptor–negative breast cancer in tumor stages cT1 to cT4c in a 5:2 fashion to receive either trastuzumab plus pertuzumab alone (n = 92) or the combination plus paclitaxel (n = 42). Patients with any nodal status were included in the trial but were required to have no evidence of distant metastases to participate. Median follow-up time was 59.9 months (interquartile range, 53.4-61.4).

All patients received intravenous trastuzumab at an 8-mg/kg loading dose followed by 6 mg/kg every 3 weeks, as well as intravenous pertuzumab at an 840-mg loading dose followed by a dose of 420 mg every 3 weeks. Those assigned to paclitaxel, which was also administered intravenously, were treated with a dosage of 80 mg/m² each week. All patients underwent surgery within 3 weeks of completing the trial therapy.

The rate of iDFS at 5 years was 98% (95% CI, 84%-100%) in the paclitaxel group and 87% (95% CI, 78%-95%) with trastuzumab/pertuzumab alone (HR, 0.32; 95% CI, 0.07-1.49; P = 015). The 5-year RFS rates were 98% (95% CI, 84%-100%) for the paclitaxel group and 89% (95% CI, 79%-94%) for the chemotherapy-free group (HR, 0.41; 95% CI, 0.09-1.91; P = 0.25). Corresponding 5-year rates of locoregional RFS were 100% (95% CI, not estimable) and 95% (95% CI, 88%-98%; HR, 0.41; 95% CI, 0.05-3.75; P = 0.43). Reported 5-year distant DFS rates with and without chemotherapy were 98% (95% CI, 84%-100%) and 92% (95% CI, 83-96), respectively (HR, 0.35; 95% CI, 0.04-3.12; P = 0.36), and corresponding rates of OS were 98% (95% CI, 84%-100%) and 94% (95% CI, 86%-97%; HR, 0.41; 95% CI, 0.05-3.63; P = 0.43).

Nitz and colleagues reported that a pCR was linked with improved iDFS (HR, 0.14, 0.03-0.64; P = 0.011), with no noted associations for any other clinical factors analyzed and outcomes of iDFS, distant DFS, or OS.

The investigators noted that the study was limited by its sample size, which hindered their ability to detect subtler, possibly clinically relevant differences in survival among specific subgroups.

“This trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Our results show that such a de-escalation trial in HER2-positive early breast cancer is safe and benefits patients,” wrote the investigators. “Further trials evaluating de-escalated neoadjuvant approaches with HER2-targeted therapies alone need to be restricted to pre-selected cohorts. For neoadjuvant therapy strategies aiming to individualize adjuvant therapy based on pathological complete response status, 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated regimen.”

References

Nitz U, Gluz O, Graeser M, et al. De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):625-635. doi:10.1016/S1470-2045(22)00159-0