MM-302 Misses Endpoint in Phase II HER2+ Breast Cancer Trial

The phase II HERMIONE trial was halted after the antibody-drug conjugate MM-302 combined with trastuzumab (Herceptin) failed to improve progression-free survival (PFS) versus chemotherapy plus trastuzumab in patients with HER2-positive metastatic breast cancer who had previously received trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1, Kadcyla).

The trial was stopped after a recommendation from an independent monitoring panel was confirmed through a futility analysis showing the primary endpoint of PFS improvement would not be met, according to the company developing MM-302, Merrimack Pharmaceuticals. There were no new safety signals with the treatment, and enrolled patients have the option to continue on their assigned therapy. Merrimack plans to provide additional details about the antibody-drug conjugate in January.

"Late line HER2-positive breast cancer is very difficult to treat, especially in this new and previously unstudied group of patients who appear to experience rapid cancer progression following treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine," Istvan Molnar, MD, vice president of clinical development, Merrimack, said in a statement. "While we are disappointed with this outcome, we would like to thank the study steering committee, the investigators and, most importantly, the patients who participated in the HERMIONE trial. We will report our learnings from this study at a later date."

MM-302 is an antibody-drug conjugate composed of a HER2-targeted antibody linked to the cytotoxic chemotherapy liposomal doxorubicin. The HER2 antibody delivers the liposomal doxorubicin to HER2-positive breast cancer cells.

The phase II HERMIONE trial (NCT02213744) was evaluating MM-302 at 30 mg/m2 every 3 weeks) plus trastuzumab versus physician’s choice of chemotherapy plus trastuzumab as a treatment for patients with anthracycline-naïve, HER2-positive locally advanced or metastatic breast cancer following previous treatment with trastuzumab, pertuzumab, and T-DM1. Chemotherapy options included gemcitabine, capecitabine and vinorelbine.

In phase I data reported at the 2015 AACR Annual Meeting, MM-302 had shown promising signs of clinical activity in heavily pretreated patients with metastatic, HER2-positive breast cancer. The study enrolled 69 patients who had received at least 4 prior systemic therapies.

Patients were randomized to receive treatment with MM-302 alone, MM-302 plus trastuzumab at 2 doses and schedules, or MM-302 plus trastuzumab and cyclophosphamide. In the monotherapy arm, patients received MM-302 at 8, 16, 30, 40 and 50 mg/m²every 4 weeks. In the combination arms, MM-302 was given at 30 and 40 mg/m²every 3 weeks. Patients in the combination arms received a single 3 to 7 mg/m²dose of the imaging agent 64Cu followed by PET/CT scans to assess for MM-302 tumor deposition.

In patients treated with ≥30 mg/m²MM-302 (n = 62) alone or in combination with trastuzumab, the response rate was 11% and median progression free survival (PFS) was 7.6 months (95% CI, 3.6-11.0). In a subset of anthracycline-naïve patients, a median PFS of 11 months was observed, with a response rate in this subset of 24%. The median PFS was 10.6 months (95% CI, 1.8-10.6) in the 13 patients receiving MM-302 plus trastuzumab and cyclophosphamide.

The most common grade 3/4 side effect was neutropenia, which was observed in 8 patients, with 1 patient experiencing febrile neutropenia. Adverse events of any grade occurring in greater than 20% of the population included constipation, cough, decreased appetite, diarrhea, dyspnea, fatigue, nausea, neutropenia, stomatitis, and vomiting.

Alopecia and hand-foot syndrome were observed in 10% and 4% of patients, respectively. One patient experienced a dose-limiting toxicity due to febrile neutropenia and a maximum tolerated dose was not reached. One patient experienced grade 1 cardiac failure, resulting in treatment discontinuation.

References:

1. Patricia LoRusso P, Krop I, Miller K, et al. A Phase 1 study of MM-302, a HER2-targeted PEGylated liposomal doxorubicin, in patients with HER2+ metastatic breast cancer (mBC). Presented at: 2015 AACR Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract 8855.