Disappointing data from a closely watched phase III trial testing Immunogen Inc.'s mirvetuximab soravtansine against platinum-resistant ovarian cancer added yet another bead to the string of challenges folate receptor alpha (FRa)-targeting agents have faced in the clinic. The antibody-drug conjugate failed to meet its primary endpoint of progression-free survival (PFS) in both the entire study population and the prespecified subset of patients with high folate receptor alpha expression.

J.P. Morgan analyst Jessica Fye called it "a meaningful setback for the mirv development program," which she suggested would require "substantially more data" to regain value. Immunogen shares (NASDAQ:IMGN) plunged 46.8 percent to $2.51 on Friday as managers contemplated the monotherapy program's future and touted a potentially sunnier outlook for combination regimens still under evaluation.

The trial, called Forward-1, enrolled 366 patients with medium to high FRa, randomized 2-to-1 to get either mirvetuximab soravtansine or investigator's choice single-agent chemotherapy. Eligibility criteria included patients with platinum-resistant ovarian cancer whose tumors expressed FRa at medium or high levels and who were treated with up to three prior regimens.

In the eligible patient cohort, the drug previously achieved a confirmed overall response rate of 47 percent and a median PFS of 6.7 months. That earlier experience fared well against approved agents in this setting that serve as the control arm in Forward-1 trial, which are typically associated with response rates of 15 percent to 20 percent and median PFS of three to four months. (See BioWorld, Jan. 22, 2019.)

Not quite there

When analyzing data from Forward-1, Immunogen's investigators applied a statistical analysis approach called the Hochberg procedure, enabling them to test both patient groups simultaneously. Under the procedure, if the "p" value for the primary endpoint in both groups was 0.05 or below, success could be claimed in both groups, Immunogen President and CEO Mark Enyedy explained during a conference call held to discuss the trial's outcome. "If one of the groups has a "p" value above 0.05, as was the case in Forward-1, you need the "p" value in the other group to be 0.025 or below for the results to be considered statistically significant," he said.

In the entire study population, the confirmed overall response rate was higher for mirvetuximab soravtansine than for chemotherapy (22 percent vs. 12 percent, p=0.015), but without a significant difference in the primary endpoint of PFS (HR 0.98, p=0.897) or overall survival (HR 0.81, p=0.248).

In the prespecified high FRa subgroup, PFS was longer in patients who received mirvetuximab soravtansine compared with chemotherapy, but with a "p" value of 0.049, exceeding the 0.025 threshold that would have been required to achieve statistical significance (HR 0.69).

Still, Immunogen's chief medical officer, Anna Berkenblit, said the data showed "consistent efficacy signals for mirvetuximab in the high FR alpha subgroup" — something she said the company will be conducting additional analyses around to further understand and evaluate the potential benefit of single-agent therapy with the ADC for that subset.

"Patients with platinum-resistant disease remain in need of effective well-tolerated therapies that improve upon the modest response rates in progression-free survival seen with standard-of-care chemotherapy options," Berkenblit said. She cited recent attempts to improve upon that, including lurbinectedin in the CORAIL trial, pembrolizumab in the KEYNOTE trial, and avelumab in the JAVELIN trial, which have failed, "highlighting how difficult this population is to treat," she said.

Combos for the win?

Jefferies analyst Biren Amin downgraded his firm's rating on Immunogen from "buy" to "hold" in the wake of Forward-1's outcome, which "suggests that mirvetuximab is likely effective in a specific high FR expresser cohort," he said, adding that "the company will have to evaluate whether it wants to pursue a monotherapy or combo strategy moving forward." Both strategies would require additional registration studies, which could take more than three years to complete, he said.

Asked Friday whether there's merit in exploring another single-arm study of mirvetuximab soravtansine, Enyedy said that it remains to be determined. "I think the data that we see is a consistent efficacy signal as a monotherapy. And so, one of the things that we weigh is overall investment in time to an outcome," he said.

Last year, Immunogen completed enrollment in a triplet combination study evaluating mirvetuximab with carboplatin and Avastin (bevacizumab, Roche Holding AG) in patients with recurrent platinum-sensitive disease. The company has also generated data from 100 patients treated with mirvetuximab doublets. Later this year, initial data from both cohorts will be presented, Enyedy said.

Beyond mirvetuximab, Immunogen is working to identify a phase II dose for its CD123-targeting candidate, IMGN-632, so it can move ahead with an expansion monotherapy cohort in blastic plasmacytoid dendritic cell neoplasm as well as additional studies in acute myeloid leukemia (AML), with a focus on combination. The company is also working to identify a recommended phase II dose for the CD33-targeting IMGN-779 to enable further development in combination regimens for AML. Enyedy said his team expects to share data from both programs at the American Society of Hematology meeting in December, a point that could prove significant for Jazz Pharmaceutical plc, which has an option on both programs. (See BioWorld, Dec. 4, 2018.)

Additionally, the company will file an investigational new drug application for its next development program, IMGC-936, an ADAM9-targeting ADC that's being co-developed with Macrogenics Inc.

Enyedy said Immunogen has about $295 million in cash remaining on its balance sheet, a sum it will presumably seek to stretch by following whatever recommendations arise out of a planned operational review.