HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer

Abstract

Background: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab - however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody-liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations.

Methods/design: HERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab.

Discussion: The HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage.

Trial registration: Clinicaltrials.gov identifier: NCT02213744 . Registration date: 06AUG2014.

Keywords: Advanced/metastatic breast cancer; Antibody–conjugate; Cardiotoxicity; Doxorubicin; HER2-targeted liposomal doxorubicin; HERMIONE; Human epidermal growth factor receptor 2/HER2/Erb2; Immunoliposome; MM­302; Trastuzumab.

Fig. 1

Decline in the use of anthracyclines to manage breast cancer [20]. Panels show monthly trends and fit curves of anthracycline and taxane use among a 4458 Medicare patients and b 30 422 Marketscan patients who were receiving adjuvant chemotherapy for breast cancer. Figure reproduced with permission [Copyright permission request is underway and the copyright line will be updated following manuscript acceptance]

Fig. 2

Schematic of MM-302, a novel HER2-targeted antibody–liposomal doxorubicin conjugate. MM-302 consists of doxorubicin encapsulated by a liposome that is conjugated to an anti-HER2 scFv antibody via a polyethylene glycol spacer (PEG-DSPE). MM-302 thus directly targets PEGylated liposomal doxorubicin to HER2-overexpressing tumor cells

Fig. 3

Mechanism of action of MM-302. a MM-302 binds to HER2 extracellular subdomain I, whilst trastuzumab binds to subdomain IV. b MM-302 remains in circulation for long periods of time, providing an opportunity to accumulate in tumors via leaky vasculature. Once in the tumor microenvironment, MM-302 binds specifically to tumor cells that overexpress HER2 (>200 000/cell) and undergoes receptor-mediated endocytosis, releasing doxorubicin inside the cell. By contrast, the vasculature of the heart is more intact and prevents extravasation out of the blood vessels. Furthermore, cardiomyocytes express HER2 below the threshold required for uptake; therefore, MM-302 does not inhibit HER2-mediated signaling in cardiomyocytes [34, 35]

Fig. 4

HERMIONE study design and assessment schedule

Fig. 5

Examples of the most common previous treatment pathways for eligible patients