Data from a Phase I clinical trial of MM-302 (Merrimack Pharmaceuticals) presented at the annual meeting of the American Association of Clinical Research (AACR) being held in Philadelphia, April 18-22, 2015, confirmed the novel investigational ADC or antibody-drug conjugate to be safe and tolerable.  The Phase I pharmacologic open-label dose-escalation trial, using a “3+3” design, also showed signs of clinical activity in heavily pretreated patients with metastatic, HER2-positive, breast cancer (MBC).[1][2]

Worldwide, each year about 1.6 million women are diagnosed with breast cancer, and over 500,000 women will die of the disease. Approximately 20% (one in five) of these women have HER2-positive breast cancer, a particular aggressive form of the disease. [3]

Treatment of breast cancer patients improved when, during the 1990s, chemotherapy regimens containing anthracyclines, associated with lower rates of breast cancer recurrence and improved survival when compared with nonanthracycline chemotherapy regimens, largely replaced previous regimens of cyclophosphamide, methotrexate, and 5-FU (CMF). However, as a result of cardiac toxicity, the use of anthracyclines rapidly declined over the last 15 years.  One reason is that, while rare, the congestive heart failure associated with anthracyclines is largely irreversible and may, after completion of treatment, increase.

Targeted therapies
The development of trastuzumab (Herceptin®; Genentech/Roche), a targeted treatment option for HER2-positive cancers, has decreased the importance anthracyclines.  A number of trials have shown that for patients whose tumors are HER2-positive, treatment with trastuzumab, along with a non-anthracycline chemotherapy regimen, provides the same benefit as an anthracycline-containing regimen and trastuzumab, with less toxicity. [4]

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But despite impressive improvements in patient outcomes achieved in recent years, 50% of patients with advanced disease who are treated with the current standard of care will see their disease progress within 18 months. Hence, there is an unmet need for additional treatment options for patients with advanced HER2-positive breast cancer as well as for metastatic breast cancer expressing  intermediate levels of HER2+ that are still considered HER2-negative (e.g. IHC 2+, FISH-negative).[5]

Novel antibody-drug conjugate
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 doxorubicin to HER2-overexpressing breast cancer cells with minimal exposure to healthy cardiomyocytes. The study results included data from the MM-302 phase I study as monotherapy, in combination with trastuzumab and trastuzumab plus cyclophosphamide.

Patricia M. LoRusso, DO,  is a pre-eminent leader in early phase drug development committed to accelerating the process of getting new drugs to patients. LoRusso has served as co-chair of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) Investigational Drug Steering Committee. She also served on the scientific committee of the American Association for Cancer Research (AACR), the education and scientific committees of the American Society of Clinical Oncology (ASCO), numerous peer-reviewed study sections, and NCI committees.

“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,” noted Patricia LoRusso, DO, associate director of innovative medicine and professor of medicine (medical oncology) at Yale Cancer Center in New Haven, Connecticut, and professor of medicine in the Division of Oncology at Yale University. “We found that the drug was well tolerated when administered to these women.” Patricia LoRusso, DO.

Adverse events
The most common grade 3 or 4 side effect was neutropenia, which was observed in eight patients. Protocol-defined asymptomatic changes in left ventricular ejection fraction were seen in six patients. In only one patient was it significant enough to be reported as a grade 1, possibly drug-related, adverse event.

“We also saw responses in these women, particularly in those that were anthracycline-naïve,” continued LoRusso. “Given that many of the patients had disease that had progressed following treatment with trastuzumab, T-DM1 [Kadcyla®; Genentech ], and pertuzumab [Perjeta®; Genentech], these results are encouraging and led to the ongoing randomized, phase II HERMIONE clinical trial, which is testing whether MM-302 plus trastuzumab is more effective than chemotherapy of physician’s choice plus trastuzumab for locally advanced/metastatic, HER2-positive breast cancer.[5]

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

Sixty-nine patients were enrolled in the phase I clinical trial conducted by LoRusso and colleagues and assigned to one of four arms, investigating MM-302 alone or in combination with trastuzumab, or trastuzumab and cyclophosphamide.

Eleven percent of the 62 patients treated with 30 mg per m2 or more MM-302, alone or in combination with trastuzumab, responded to treatment. Overall, the median time to disease progression was 7.6 months. In the subset of patients treated who were anthracycline-naïve, a median progression-free survival of 11 months was observed, with a response rate in this patient subset of 24%.

Further study warranted
Overall, this this study showed that MM-302 had a manageable safety profile as a monotherapy, in combination with trastuzumab and with trastuzumab and cyclophosphamide. Based on the response rate (RR) and the median progression free survival (mPFS) in this heavily pretreated group of patients, the authors suggest that further study is warranted.

MM-302 at a dose of 30 mg/m2 Q3W in combination with trastuzumab is currently being evaluated in a randomized phase II trial (HERMIONE) in anthracycline naïve HER2-positive locally advanced/mBC patients previously treated with trastuzumab, pertuzumab and T-DM1.[5]

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