Early Phase Study Shows MM-302 Has Activity in Heavily-Pretreated HER2-Positive Breast Cancer

MM-302, a novel antibody-drug conjugate that specifically targets cancer cells overexpressing the HER2 receptor, showed signs of clinical activity in heavily pretreated patients with metastatic, HER2-positive breast cancer, according to phase 1 findings presented at the 2015 American Association for Cancer Research (AACR) Annual Meeting.

“The main purpose of our study was to establish whether MM-302, alone or in combination with trastuzumab, was safe and tolerable for patients with metastatic, HER2-positive breast cancer whose disease had progressed following numerous prior treatments,” said Patricia LoRusso, associate director of innovative medicine at Yale Cancer Center and Professor of Medicine (Medical Oncology) in the Division of Oncology at Yale University in New Haven, Connecticut, in a news release. “We found that the drug was well tolerated when administered to these women.”

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.

Unlike other HER2-targeted agents, MM-302 is not designed to inhibit the HER2 signaling pathway. Instead, the drug relies on the HER2 receptor to identify and gain access to the cancer cell. Once inside the cell, the liposome breaks down and releases doxorubicin, promoting cell death.

The study enrolled 69 patients who had received at least four prior systemic therapies. Patients were randomized to receive treatment with MM-302 alone, MM-302 plus Herceptin (trastuzumab) at two doses and schedules, or MM-302 plus Herceptin and cyclophosphamide.

In patients treated with ≥30 mg/m2 MM-302 alone or in combination with Herceptin, the response rate was 11 percent and median progression free survival (PFS) was 7.6 months. In a subset of anthracycline-naïve patients, the median PFS of 11 months was observed, with a response rate in this subset of 24 percent. The median PFS was 10.6 months in the 13 patients receiving MM-302 plus Herceptin and cyclophosphamide.

“We also saw responses in these women, particularly in those that were anthracycline-naïve,” said LoRusso. “Given that many of the patients had disease that had progressed following treatment with trastuzumab, T-DM1, and pertuzumab, these results are encouraging.”

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

Alopecia and hand-foot syndrome were observed in 10 percent and 4 percent 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.

The promising results of the phase 1 study led to the ongoing randomized, phase 2 HERMIONE clinical trial, which is looking at MM-302 (30 mg/m² every 3 weeks) plus Herceptin as a treatment for patients with anthracycline-naïve HER2-positive locally advanced or metastatic breast cancer following previous treatment with Herceptin, Perjeta (pertuzumab) and Kadcyla (T-DM1).

“If the results of HERMIONE are positive, MM-302 may provide another therapeutic option for women with HER2-positive breast cancer,” LoRusso said.

Future clinical studies may explore MM-302’s potential in other types of HER2-postive cancers, tumors with leaky vasculatures and in combination with other agents, according to Merrimack Pharmaceuticals, the company responsible for the drug.

The company has plans to develop MM-302 in other HER2-positive cancers in conjunction with an imaging diagnostic, which would aid in identifying patients who would most likely benefit from this therapy. In previous studies, a radioactive label has been incorporated into MM-302 and used as a means to measure its tumor accumulation.