Dual HER2 Blockade and AI for HER2+/HR+ Advanced Breast Cancer

Treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor (HR)-positive advanced breast cancer is challenging because bidirectional cross talk between the estrogen receptor and HER2 can lead to the development of resistance to both hormonal and anti-HER2 therapy. In these patients, adding anti-HER2 to aromatase inhibitor (AI) therapy demonstrated improved efficacy compared to AI alone. Furthermore, dual HER2 blockade with combination of trastuzumab and pertuzumab and chemotherapy improved survival, compared to trastuzumab and chemotherapy in HER2-positive advanced breast cancer, regardless of HR status. Based on these data, there is rationale to explore the chemotherapy-free combination of pertuzumab/trastuzumab and an AI in patients with HER2-positive, HR-positive disease.

In the randomized, open-label, phase II PERTAIN trial (N = 258), the safety and efficacy of first-line treatment with pertuzumab/trastuzumab and an AI (anastrazole or letrozole) was compared to trastuzumab and an AI in patients with HER2-positive, HR-positive advanced breast cancer. Treatment also included induction chemotherapy for 75 patients in the pertuzumab/trastuzumab/AI arm and 71 patients in the trastuzumab/AI arm.

The triplet therapy of pertuzumab/trastuzumab/AI resulted in a median progression-free survival (PFS) of 18.89 months, compared to 15.80 months for trastuzumab plus AI (HR 0.65, P = .0070). The PFS benefit of pertuzumab-based therapy was seen across all patient subgroups. In patients who did not receive induction chemotherapy, the median PFS was 21.72 months with pertuzumab and 12.45 months without pertuzumab (HR 0.55, P = .0111). For patients who did receive induction chemotherapy, the PFS was 16.89 months and 16.85 months (HR 0.75, P = .1633). The overall response rate (ORR) was 63.3% in patients receiving pertuzumab/trastuzumab/AI and 55.7% in patients receiving trastuzumab/AI (P = .2537). The median duration of response (DoR) in patients with a confirmed complete or partial response was significantly longer in patients receiving triplet therapy (27.10 months vs 15.11 months; HR 0.47, P = .0181). The median overall survival (OS) has not yet been reached and was not reported in this analysis.

The safety profile of pertuzumab/trastuzumab/AI was consistent with previous reports. There was an increase in serious adverse events (AEs) in patients receiving pertuzumab plus trastuzumab/AI compared to trastuzumab/AI (33.1% vs 19.4%). The most common AEs were diarrhea, alopecia, and nausea. In regard to cardiac toxicity, left ventricular ejection fractions remained stable and above 45% in approximately 90% of patients. Among patients receiving pertuzumab, 26.8% required treatment interruptions due to AEs, and 10.2% discontinued pertuzumab treatment. No patients died due to treatment-related AEs.

The investigators concluded that the pertuzumab/ trastuzumab/AI combination maintains good quality of life and is an effective and tolerable treatment regimen for previously untreated patients with HER2-positive, HR-positive advanced breast cancer.

J Clin Oncol. 2018 Aug 14 [Epub ahead of print].
dual-HER2 inhibition-plus-AI

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