Antibody-Drug Conjugate Under Study in Platinum-Resistant Ovarian Cancer

Kathleen N. Moore, MD

A novel targeted therapy, mirvetuximab soravtansine (IMGN853), is being investigated as a single-agent treatment for patients with advanced, platinum-resistant epithelial ovarian cancer with medium and high expression levels of folate receptor—alpha (FR-alpha) in an effort to provide an effective option for a population facing a difficult prognosis.

The phase III 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 arm 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 therapy and possibly to individuals who have become resistant to chemotherapy.¹

“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,” said Kathleen N. Moore, MD, 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% of epithelial ovarian cancer tumors; overexpression of receptor levels may be associated with negative outcomes in patients treated with chemotherapy.¹

Mirvetuximab Soravtansine in Ovarian Cancer

Phase III FORWARD I Trial

The drug consists of a monoclonal antibody that binds to the FR-alpha receptor and is linked to a tubulin-disrupting maytansinoid DM4 chemotherapy that is delivered directly into the tumor cell. Patients with platinum-resistant ovarian cancer, defined as disease progression within 6 months of treatment with a platinum-containing therapy, have a poor prognosis. In the primary setting, the response rate to subsequent therapies is less than 20%, and in the acquired resistance setting, median overall survival is 21.9 months.1

Strong Early Phase Findings

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,” said Moore, who is 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.”The drug has demonstrated encouraging activity in patients with platinum-resistant epithelial ovarian cancer.² In 1 study, patients with 1 to 3 lines of prior therapy and medium or high FR-alpha expression (n = 16)—the same subset eligible for the FORWARD I study—the objective response rate (ORR) was 44%, with a progression-free survival (PFS) of 6.7 months and a duration of response (DOR) of 26.1 weeks. In a phase I expansion study, mirvetuximab soravtansine demonstrated a confirmed ORR of 26% among 46 patients with FR-alpha—positive platinum- resistant ovarian cancer, including 1 complete and 11 partial responses.

The median PFS was 4.8 months and the median duration of response was 19.1 weeks.1 Notably, patients who had received 3 or fewer prior lines of therapy (n = 23), had an ORR of 39%, a median PFS of 6.7 months, and a median DOR of 19.6 weeks.¹

FR-alpha expression was determined by immunohistochemistry (IHC) testing on archival tissue, with samples categorized as: low, 25% to 49% of tumor cells with ≥2+ staining intensity; medium, 50% to 74% of cells with ≥2+ intensity; or high, ≥75% of cells with ≥2+ intensity. 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% (95% CI, 8.4-58.1) and 26.1% (95% CI, 10.2- 48.4), respectively.

Adverse events (AEs) in the phase I trial were generally mild (grade 2 or lower), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed all-grade treatment-related toxicities. Grade 3 fatigue and hypotension were reported in 2 patients each (4%).¹ There has been some reported neuropathy, according to Moore, but it has been seen in less than 10% of patients, and there is no reported alopecia compared with standard chemotherapy.

Similar AEs 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, which surfaced in 12 patients (13%) at grades 1-2 severity in the phase I trial. Keratopathy “is 100% reversible, but we want to prevent it from happening rather than having it reverse,” said Moore. To achieve this, investigators are mandating steroidal eye drops and lubrication in the study protocol.

Looking toward the future, researchers also have opened the 4-arm phase I FORWARD II trial in patients with advanced ovarian cancer, in which mirvetuximab soravtansine is being tested in combination with either bevacizumab, carboplatin, pegylated liposomal doxorubicin or pembrolizumab (NCT0260635).

“The combination would enable the potential to move into earlier lines of therapy while continuing to understand the biomarker,” said 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.

References

1. Moore KN, Martin LP, O’Malley DM, et al. Safety and activity of mirvetuximab soravtansine (IMGN853), a folate receptor alpha—targeting antibody–drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a phase I expansion study [published online December 27, 2016]. J Clin Oncol. doi: 10.1200/JCO.2016.69.9538.
2. Moore KN, Martin LP, Matulonis UA, et al. IMGN853 (mirvetuximab soravtansine), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC): single-agent activity in platinum-resistant epithelial ovarian cancer (EOC) patients (pts). Poster presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 5567. meetinglibrary.asco. org/content/169854-176.