Drug Conjugate Tested in Resistant Ovarian Cancer

CUREWomen's Cancers 2017
Volume 1
Issue 1

The investigational compound targets overexpressed folate receptor-alpha.

A NEW TARGETED THERAPY compound, mirvetuximab soravtansine (IMGN853), is being investigated as a monotherapy for patients with advanced, platinum-resistant epithelial ovarian cancer with high expression levels of folate receptor—alpha (FR-alpha) in the hopes of providing an effective option for a population facing a difficult prognosis.

The phase 3 FORWARD I trial, which is currently enrolling patients, is seeking to randomize 333 women in a 2:1 ratio to either the experimental mirvetuximab soravtansine or to chemotherapy consisting of investigator’s choice of paclitaxel, pegylated liposomal doxorubicin or topotecan (NCT02631876). If successful, the novel drug would offer an alternative to patients who have not responded to platinum-based chemotherapy, and possibly to individuals who have become resistant to chemotherapy.

“This is a bold initiative to try and bring what we think is a very active drug to market for patients who desperately need therapies,” says Kathleen N. Moore, M.D., a co-principal investigator on the study. “It’s an exciting trial, and we’re hoping for it to accrue quickly, so that we can get this drug to people who need it.”

Mirvetuximab soravtansine is an antibody—drug conjugate that targets FR-alpha, a cell-surface glycoprotein found on approximately 80 percent of epithelial ovarian cancer tumors; overexpression of receptors may be associated with negative outcomes in patients treated with chemotherapy, Moore and colleagues reported in earlier research.

One element that composes the drug is a monoclonal antibody, a laboratory-created protein that can bind to chemicals on the surface of cancer cells — in this case, the FR-alpha receptor. That monoclonal antibody is linked to a chemotherapy agent. Once in the body, the antibody delivers the drug to the tumor cell, where the chemotherapy agent is released; then, the molecule further diffuses into the surrounding tumor cells in a secondary effect.

The FORWARD I study is open to women with advanced epithelial ovarian, primary peritoneal or fallopian tube cancers that have been defined as platinum-resistant, meaning the disease has progressed within six months of treatment with platinum-containing chemotherapy. To be eligible, participants must have received from one to three prior chemotherapy treatment regimens.

Patients with platinum-resistant ovarian cancer currently have a poor prognosis; in the primary setting, the response rate to subsequent therapies is less than 20 percent, and in the acquired resistance setting, median overall survival is 21.9 months.

Mirvetuximab soravtansine “would give another option for standard of care, and it would introduce another drug for patients with platinum-resistant disease where there’s not much that works well at this point,” says Moore, associate director for clinical research and director of the TSET Phase I Drug Development Unit at the Stephenson Cancer Center in Oklahoma. “It would give another line of therapy that really has a very well-tolerated safety profile.”

Strong Early-Phase Findings

In a phase 1 expansion study, mirvetuximab soravtansine demonstrated a confirmed objective response rate (ORR) of 26 percent among 46 patients with FR-alpha—positive platinum-resistant ovarian cancer, including one complete and 11 partial responses. The median progression-free survival (PFS) was 4.8 months and the median duration of response was 19.1 weeks. Notably, patients who had received three or fewer prior lines of therapy (n = 23) had an ORR of 39 percent, median PFS of 6.7 months and median duration of response of 19.6 weeks.

FR-alpha expression was determined by immunohistochemistry (IHC) testing on archival tissue, with samples put into categories. Low expression was defined as 25 to 49 percent of tumor cells having a staining intensity of 2 or more; medium meant that 50 to 74 percent of cells had an intensity of two or more; and high indicated that 75 percent of cells or more had a staining intensity of two or more.

Although most patients experienced tumor shrinkage regardless of FR-alpha expression level, participants with medium and high scores were more likely to respond, with median ORR rates of 28.6 percent and 26.1 percent, respectively.

Side effects in the phase 1 trial were generally mild (grade 2 or lower), with diarrhea (44 percent), blurred vision (41 percent), nausea (37 percent) and fatigue (30 percent) being the most commonly observed all-grade treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4 percent). There has been some neuropathy, according to Moore, observed in less than 10 percent of patients, and no reported alopecia compared with chemotherapy.

Similar side effects are expected during the FORWARD I trial, and investigators will be counseling patients about diarrhea and administering prophylactic medications. There is also a risk of keratopathy (a disease of the cornea), which surfaced in 12 patients (13 percent) at grades 1-2 severity in the phase 1 trial. Keratopathy “is 100 percent reversible, but we want to prevent it from happening rather than having it reverse,” says Moore. To achieve this, investigators are mandating the use of steroidal eye drops in the study protocol.

Moore notes that ease of administration is another benefit of mirvetuximab soravtansine treatment. Patients will receive the drug intravenously at a dose of 6 mg/kg every 21 days.

Looking toward the future, researchers also have opened the four-arm phase 1 FORWARD II trial in patients with advanced ovarian cancer, in which mirvetuximab soravtansine is being tested in combination with either the anti-angiogenic drug Avastin (bevacizumab), the chemotherapy carboplatin, the chemotherapy pegylated liposomal doxorubicin or the immunotherapy Keytruda (pembrolizumab).

“The combination studies are aimed at getting a better idea of what the biomarker should be in selecting patients for this treatment, and potentially exploring it in frontline chemotherapy in combination with carboplatin,” says Moore. “I also think there’s potentially a role for this drug in other malignancies where FR-alpha is overexpressed, and there are several studies that are launching across the United States that are exploring those questions.” ImmunoGen, Inc, is developing mirvetuximab soravtansine. The company is working with Ventana Medical Systems to develop an IHC-based FR-alpha assay for use as a companion diagnostic with the drug. Visit clinicaltrials.gov to learn about eligibility and enrollment.

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