Pertuzumab Plus High-Dose Trastuzumab Induces Clinical Benefit in HER2+ Metastatic Breast Cancer With CNS Metastases

Nancy U. Lin, MD

Despite a modest central nervous system (CNS) overall response rate (ORR), the combination of pertuzumab (Perjeta) and high-dose trastuzumab (Herceptin) was found to induce clinical benefit in 68% of patients with HER2-positive metastatic breast cancer enrolled to the phase 2 PATRICIA trial (NCT02536339).¹

Results from the primary efficacy analysis of the trial, which were recently published in the Journal of Clinical Oncology, showed that among the 27 patients who received the doublet, the CNS ORR per Response Assessment in Neuro-Oncology Brain Metastases criteria (RANO-BM) criteria was 11% (n = 4; 95% CI, 3%-25%). A total of 4 patients achieved a partial response with the combination, and the median duration of response (DOR) in these patients was 3.2 months, 3.3 months, 4.6 months, and 5.6 months, respectively.

The clinical benefit rate (CBR) in the CNS at 4 months was 68% (n = 25; 95% CI, 50%-82%), with a median duration of 6.6 months (range, 3.2-36.8). All patients who experienced clinical benefit in the CNS had either stable or better extracranial disease. Moreover, the CBR in the CNS at 6 months was 51% (n = 19; 95% CI, 34%-68%), with a median duration of 9.2 months (range, 3.2-36.8). One patient had disease stability for over 2 years, while another had stable disease for longer than 3 years.

“These data suggest that pertuzumab plus high-dose trastuzumab may have clinical utility in some patients with HER2-positive metastatic breast cancer and progressive CNS metastases and there is potential to further optimize the dose and schedule of monoclonal antibodies to combat CNS disease,” lead study author Nancy U. Lin, MD, of Dana-Farber Cancer Institute, and colleagues, wrote. “Future studies may be warranted to clarify whether additional CNS gains could be made by combining high-dose trastuzumab with chemotherapy and/or other targeted agents.”

Approximately 40% to 50% of patients with HER2-positive metastatic breast cancer develop CNS metastases and systemic therapies for this population remain limited, even with the April 2020 FDA approval of tucatinib (Tukysa). Trastuzumab has been shown to improve survival in patients with early-stage, HER2-positive disease, and data from prior studies suggest that the agent can also prolong survival in those with CNS metastases.

Moreover, an exploratory analysis of the phase 3 CLEOPATRA study (NCT00567190) has shown that when frontline pertuzumab plus trastuzumab/docetaxel was given in patients with HER2-positive, metastatic breast cancer, it resulted in delayed CNS disease onset compared with trastuzumab/docetaxel alone.²

Based on these preclinical and clinical data, investigators set out to examine pertuzumab in combination with high-dose trastuzumab in patients with HER2-positive, metastatic breast cancer who present with progressive brain metastases. Specifically, they hypothesized that high-dose trastuzumab would result in CNS efficacy in those who had progressed on standard-dose trastuzumab and that there would not be an increase in cardiotoxicity.

The open-label, single-arm, phase 2 study enrolled a total of 40 patients at 16 cancer centers across the United States. To be eligible for enrollment, patients needed to be at least 18 years of age and have confirmed HER2-positive metastatic breast cancer with CNS progression, despite previous radiotherapy. Patients also needed to have stable extracranial disease.

Additional criteria required patients to have completed radiotherapy more than 60 days prior to study entry, to have at least 1 measurable CNS metastasis, and to have an ECOG performance status of 0 or 1. Those with leptomeningeal disease, symptomatic pulmonary disease, a history of intolerance or hypersensitivity to study drugs, significant cardiac disease, or active infection were excluded.

Study participants were given intravenous (IV) pertuzumab at a loading dose of 840 mg, and at 420 mg every 3 weeks thereafter, plus high-dose IV trastuzumab, given at 6 mg/kg once weekly. Treatment was administered until CNS or systemic disease progression, intolerable toxicity, withdrawal, or study termination.

Moreover, no dose reductions were permitted on this study. Notably, if pertuzumab was stopped because of a treatment-related toxicity, participants were permitted to continue receiving high-dose trastuzumab. However, if high-dose trastuzumab was stopped because of a toxicity, pertuzumab was also discontinued.

The primary end points of the study included confirmed CNS ORR according to RANO-BM criteria, while secondary end points were DOR, CNS CBR, and safety.

Of the 40 patients enrolled on the study, the median age was 48 years (range, 34-69), and the majority of patients were White (90%; n = 36) and had an ECOG performance status of 1 (67%; n = 26). The median left ventricular ejection fraction (LVEF) was 60% (range, 50%-75%), and 60% of patients (n = 24) presented with extracranial disease.

Additionally, 48% of patients previously received trastuzumab plus pertuzumab, 38% received trastuzumab only, 38% received trastuzumab emtansine (T-DM1; Kadcyla), while 45% received lapatinib (Tykerb) and 8% received neratinib (Nerlynx). In patients who had received prior chemotherapy (n = 17), the median number of prior therapies received was 3 (range, 2-5).

Moreover, 11 patients received concomitant on-study systemic treatment for their metastatic disease; 9% of these patients were on anastrozole, 27% received capecitabine, 9% received exemestane, 9% received fulvestrant, 9% received gemcitabine, 19% were given letrozole, 27% were given palbociclib (Ibrance), and 9% received vinorelbine.

In total, 39 patients received treatment on study, with 1 patient withdrawing before treatment began. The median treatment duration for pertuzumab was 4.8 months (range, 0.7-29.9), while it was 4.5 months (0.5-37.4) for trastuzumab. Patients received a median of 7.0 doses (range, 1-51) of pertuzumab and 20.0 doses (range, 2-145) of trastuzumab.

Ninety-five percent of patients (n = 37/39) discontinued treatment, while 5% (n = 2) remained on treatment. Of the patients who discontinued treatment, most did so because of CNS progression (n = 27), while others did so because of symptomatic deterioration (n = 4), withdrawal (n = 3), change in LVEF (n = 1), death (n = 1), and protocol deviation (n = 1). Fifteen percent of patients (n = 15) remained on the study at the time of the clinical cutoff.

Data from a subgroup analysis of CBR at 4 months per prior HER2-targeted treatments showed that patients derived a clinical benefit with the doublet, irrespective of previous treatment received.

In terms of safety, 1 or more adverse effects (AEs) were reported in the majority of patients (97%; n = 38/39). The most frequently reported AEs included diarrhea (n = 23), fatigue (n = 17), and nausea (n = 12). Additionally, 44% (n = 17) of patients reported at least 1 grade 3 (n = 14) or grade 4 (n = 3) AE, but no grade 5 AEs were observed.

Moreover, 77% of patients (n = 30) reported treatment-related AEs (TRAEs). The most commonly reported TRAEs included diarrhea (n = 16) and fatigue (n = 11). Two patients reported 3 TRAEs that were grade 3 in severity; these included left ventricular dysfunction (n = 1), asthenia (n = 1), and fatigue (n = 1). One patient experienced treatment-related grade 4 hypertension. Only 1 patient was observed to have a treatment-related cardiac AE; this patient had grade 3 left ventricular dysfunction and had previous cardiac history.

Serious AEs were experienced by 18% of patients (n = 7), with 1 patient experiencing 3 serious AEs; this included grade 3 seizure, grade 3 hydrocephalus, and grade 2 headache. Other serious AEs included seizure (n = 3), gastroenteritis viral (n = 1), hypertension (n = 1), and parainfluenza virus infection (n = 1). However, no serious AEs reported were considered to be related to study treatment, and no new safety signals emerged with either study treatment.

References

1. Lin N, Pegram M, Sahebjam S, et al. Pertuzumab plus high-dose trastuzumab in patients with progressive brain metastases and HER2-positive metastatic breast cancer: primary analysis of a phase II study. J Clin Oncol. Published online May 4, 2021. doi:10.1200/JCO.20.02822
2. Swain SM, Baselga J, Miles D, et al. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel; results from the randomized phase III study CLEOPATRA. Ann Oncol. 2014;25(6):1116-1121. doi:10.1093/annonc/mdu133