ImmunoGen’s investigational therapy mirvetuximab soravtansine effectively delays disease progression in women with ovarian cancer who have high levels of the folate receptor alpha (FRα) protein, compared with chemotherapy, according to exploratory analysis on the data of the FORWARD I Phase 3 trial (NCT02631876).

Previous analysis of the trial’s final data had found no significant clinical benefit of mirvetuximab over chemotherapy in this subset of patients. However, this exploratory analysis revealed that assessing FRα levels in tumor samples with the scoring method used in previous mirvetuximab studies — instead of the one employed in this trial — indeed showed statistically significant results.

These findings highlight not only which women benefit most from mirvetuximab treatment, but also how to best identify them.

That, in turn, led to the design of a future Phase 3 clinical trial which will evaluate mirvetuximab’s effectiveness in women with FRα-high ovarian cancer.

Both the final and exploratory results of the trial were part of an oral presentation, “FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC),” given at the European Society for Medical Oncology (ESMO) Congress 2019, held Sept. 27-Oct. 1 in Barcelona, Spain.

It is estimated that approximately 60% of ovarian cancers have medium-to-high levels of FRα. Mirvetuximab soravtansine is an antibody-drug conjugate that specifically targets FRα. Once the antibody binds to a cell positive for FRα, it releases a toxic compound, killing the cancer cell without harming healthy cells.

The open-label, randomized, FORWARD I study compared the safety and effectiveness of mirvetuximab to that of chemotherapy in 366 women. All had medium or high levels of FRα in their ovarian tumors, had cancer that was resistant to platinum-based chemotherapy, and had received up to three prior lines of therapy.

The trial’s main goal was to assess whether mirvetuximab prolonged the time a patient lived without signs of disease progression or death — progression-free survival (PFS) — to a greater extent than chemotherapy, both in the entire study population and in the 218 women with high-FRα (60% of all women).

Researchers also compared the women’s objective response rate (ORR) — the proportion of patients showing a reduction in tumor burden — overall survival, and quality of life between treatments as secondary goals.

The results, originally reported in March, showed that mirvetuximab had a better safety profile, and doubled the number of women responding to treatment, compared with chemotherapy. However, those results showed that the therapy failed to meet its primary goal both in the entire population and in the high-FRα subset of patients.

Still, mirvetuximab treatment in women with high FRα levels led to a trend toward prolonged PFS, and reduced the risk of death by 38%. That suggested better treatment responses in these women.

“While it is disappointing that FORWARD I did not meet the primary endpoint of progression-free survival, mirvetuximab demonstrated consistent and meaningful efficacy signals in patients with high levels of FRα expression and was well tolerated with a differentiated safety profile,” Kathleen Moore, associate director of clinical research at the Stephenson Cancer Center at the University of Oklahoma and the presenter at the ESMO congress, said in a press release.

Further analysis to explore possible explanations for these unexpected results highlighted the effects of a new scoring method used in the FORWARD I trial.

Using a simplified scoring method (10X) — instead of the one used in previous mirvetuximab trials (PS2+) — to assess the tumors’ FRα levels in this study “inadvertently introduced a population of patients into FORWARD I with lower levels of FRα than intended,” said Anna Berkenblit, MD, ImmunoGen’s senior vice president and chief medical officer.

While a smaller study indicated that the 10X method was sufficient for patient selection based on tumors’ FRα levels, it led to the inclusion of 34% of women with lower-than-intended FRα levels.

Rescoring FRα levels in FORWARD I participants using the PS2+ method showed that only 116 women — 32% instead of 60% with the 10X method — had high levels of FRα.

In these women, mirvetuximab led to a significant improvement in progression-free survival compared with chemotherapy (5.6 versus 3.2 months). It also resulted in better responses (29% versus 6%) and a trend toward better overall survival (16.4 versus 11.4 months).

“With the results of these exploratory analyses, we have developed a clear view of which patients benefit most from mirvetuximab and how to best identify those patients,” said Mark Enyedy, ImmunoGen’s president and CEO.

“We are working closely with FDA to finalize the design of a Phase 3 registration trial for mirvetuximab, which we call MIRASOL, and believe that the robust data generated from the FORWARD I analyses increase the likelihood of a positive outcome with this next study,” he said.

The company expects to enroll the first patient in the MIRASOL trial by the end of the year, and to have topline data in the first half of 2022.