Mirvetuximab Soravtansine Fails to Delay Disease Progression in FRα-positive Ovarian Cancers, Trial Shows

Mirvetuximab soravtansine, an investigational antibody-drug conjugate targeting the folate receptor alpha (FRα) protein, was no better than chemotherapy at delaying disease progression or death in ovarian cancer patients included in the FORWARD I Phase 3 trial.

The treatment failed to extend survival without disease worsening in the overall study population — all patients had medium to high FRα levels in their tumors and were resistant to platinum-based chemotherapy — and in a subgroup of patients with high FRα levels, failing to met the trial’s primary goal.

Nonetheless, mirvetuximab soravtansine had a favorable safety profile and increased response and survival rates among patients with high FRα levels, which is encouraging its developer, ImmunoGen, to continue studying the treatment in combination approaches.

“Even though FORWARD I did not meet its primary endpoint, I continue to be impressed with the efficacy and tolerability of mirvetuximab soravtansine in ovarian cancer patients, especially in the subset with high FRα expression,” Kathleen Moore, associate director of clinical research at the Stephenson Cancer Center at the University of Oklahoma, said in a press release.

“I look forward to continuing to work with ImmunoGen to analyze the Phase 3 data and determine the most appropriate path to bringing mirvetuximab soravtansine to those patients who benefit most from it.”

Mirvetuximab soravtansine is an antibody-drug conjugate targeting the folate receptor alpha (FRα). This means the drug combines an antibody against this receptor bound to a toxic compound. Once the antibody binds to a cell positive for FRα, it releases its payload, killing the cancer cell without harming healthy cells.

It is estimated that approximately 60 percent of ovarian cancers have medium or high FRα expression.

A prior Phase 1 trial (NCT01609556) that included patients with recurrent ovarian, endometrial, kidney, and lung cancers had shown that mirvetuximab soravtansine had promising safety and efficacy, with more than half of patients responding to treatment.

Because most patients in this trial had ovarian cancer, the findings propelled the therapy into an ovarian cancer Phase 3 trial — FORWARD I (NCT02631876) — designed to study mirvetuximab soravtansine in women with medium or high levels of FRα in their tumors, whose cancer was resistant to platinum-based chemotherapy, and who had received up to three prior lines of therapy.

The trial included 333 women across North America and Europe who received either mirvetuximab soravtansine or a chemotherapy of the physician’s choice — Taxol (paclitaxel), Doxil (pegylated liposomal doxorubicin), or Hycamtin (topotecan) — for up to two years.

In addition to measuring the time to disease progression or death —the trial’s primary goal — researchers also evaluated the objective response rate, overall survival, and quality of life as secondary measures.

In the overall population, more patients responded to mirvetuximab soravtansine (22%) than to chemotherapy (12%) but no differences were seen in the time to disease progression or death or overall survival.

In the subgroup of patients with high FRα levels, the treatment also increased response rates — 24% vs. 10% — and reduced the risk of death by 38% compared to chemotherapy. There was a trend toward longer survival without disease progression, but the findings did not reach statistical significance.

Overall, the treatment was well-tolerated, with fewer patients experiencing severe or worse adverse events (46% vs. 61%), requiring dose reductions (20% vs. 31%), or discontinuing treatment due to treatment-related adverse events (5% vs 8%). The most common adverse events were nausea, diarrhea, and blurred vision.

ImmunoGen plans to present additional data from FORWARD I at an upcoming medical meeting.

“This study with mirvetuximab did not result in the outcome that we had hoped for in platinum-resistant patients. We will further assess the data from FORWARD I to determine potential next steps with a monotherapy approach,” said Mark Enyedy, ImmunoGen’s president and chief executive officer.

Mirvetuximab soravtansine is also being evaluated in combination with chemotherapies for both platinum-resistant and platinum-sensitive disease in the FORWARD II Phase 1b/2 trial (NCT02606305).

So far, results from the trial indicate that the combo therapy of mirvetuximab soravtansine with Avastin (bevacizumab) or Paraplatin (carboplatin) shows promise for women with advanced ovarian cancer, particularly those who have received multiple prior lines of therapy.

“We have generated encouraging data with mirvetuximab combination regimens and will evaluate our ongoing studies as an independent path forward to support a registration in ovarian cancer,” Enyedy said.