Sequential Neoadjuvant HER2 Blockade Plus Polychemotherapy Elicits Antitumor Activity in HER2+ Breast Cancer

Breast Cancer

Neoadjuvant treatment with pegylated liposomal doxorubicin (PLD) and cyclophosphamide, followed by a taxane, such as docetaxel or nab-paclitaxel (Abraxane), concomitant with trastuzumab (Herceptin) and pertuzumab (Perjeta) elicited responses in patients with HER2-positive breast cancer, according to data from a phase 2 study presented at the 2023 San Antonio Breast Cancer Symposium.

Data from the single-arm, open-label, multicenter study indicated that patients (n = 78) treated with the combination experienced a total pathologic complete response (tpCR) rate of 60.3% (95% CI, 48.5%-71.2%) and a breast pCR (bpCR) of 62.8%.

When broken down by age, those under 40 years, between 40 and 50 years, or older than 50 years experienced tpCRs of 50.0%, 59.3%, and 66.7%, respectively. Those with hormone receptor–positive or negative status experienced tpCRs of 56.0% and 67.9%, respectively. The tpCRs in those with positive or negative lymph nodes were 63.6% and 52.2%, respectively, and those with stage II or III disease had tpCRs of 56.4% and 69.6%, respectively. In terms of TOP2A IHC expression, those with less than 15% expression or greater than 15% expression experienced tpCRs of 46.7% and 59.3%, respectively; those with unknown status, had a tpCR of 88.9%.

“This dual HER2 blockade plus chemotherapy as a sequential neoadjuvant regimen demonstrated promising antitumor activity and acceptable tolerability for patients with HER2-positive breast cancer,” lead study author Yapin Yang, MD, and colleagues, wrote in a poster presentation of the data. Yang is a medical oncologist and associate professor in the Department of Breast Surgery in the Breast Tumor Center at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, in Guangzhou, China.

The optimal neoadjuvant treatment regimen for this population remains unclear, particularly in terms of anthracycline use. To garner insights on this, the prospective study was launched.

Eligible patients were recruited from 4 independent hospitals in China and were treated with the study combination between May 27, 2020, and May, 11, 2022. These patients were treated with 4 cycles of PLD at 35 mg/m2 and cyclophosphamide at 600 mg/m2, followed by 4 cycles of docetaxel at 100 mg/m2 or nab-paclitaxel at 260 mg/m2, concomitant with 8 cycles of trastuzumab at a loading dose of 8 mg/kg, then a 6-mg/kg dose, and pertuzumab at a loading dose of 840 mg, and then 420 mg every 3 weeks. Moreover, 53.8% of patients underwent breast-conserving surgery.

The primary end point of the study was tpCR (ypT0/is ypN0) and secondary end points included the evaluation of bpCR, objective response rate (ORR), disease control rate, the proportion of patients requiring breast-conserving surgery, and safety.

Investigators also collected baseline tumor tissues for biomarker analyses. They evaluated them for expression of TOP2A; this was assessed prospectively with an immunohistochemistry (IHC) assay by independent pathologists.

Of the 78 eligible patients, 23.1% were under the age of 40 years, 34.6% were between the ages of 40 and 50 years, and 42.3% of patients were older than 50 years. Moreover, 64.1% of patients had hormone receptor–positive status and all patients had an ECOG performance status of 0.

More than half of patients were premenopausal (62.8%) and the remainder were postmenopausal. Most patients had lymph node positivity (70.5%) and stage II disease (70.5%). Regarding TOP2A IHC expression, 17.9% of patients had expression of less than 15%, 39.7% had expression between 15% and 30%, and 29.5% had expression of greater than 30%; 1.3% of patients did not express TOP2A and this information was unknown for 11.5% of patients.

“[The] ORRs were 76.9% [95% CI, 66.0%-85.7%] and 93.6% [95% CI, 85.7%-97.9%] after 4- and 8-cycle neoadjuvant therapy, respectively,” the study authors wrote in the abstract. “All patients achieved disease control since the end of the first cycle.” In cycles 1, 2, and 6, the ORRs were 15.4%, 30.8%, and 82.1%, respectively.

Biomarker analysis indicated that TOP2A status was not associated with pCR or fourth-cycle ORR.

In terms of safety, grade 3 or higher adverse effects (AEs) occurred in 44.9% of patients. Moreover, 11.5% of patients had asymptomatic left ventricular ejection fraction reduction of 10% or greater from baseline, but all with a minimum value of greater than 55%. No surgical delays or deaths related to study treatment were reported.

Reference

Yang Y, Jin L, Li Y, et al. Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/ cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study. Presented at: San Antonio Breast Cancer Conference; December 5-9, 2023; San Antonio, TX. Poster PO1-01-02.