The phase III FORWARD I trial fell short of its primary endpoint, as findings showed the antibody-drug conjugate mirvetuximab soravtansine did not result in a progression-free survival improvement compared with chemotherapy in patients with folate receptor alpha–positive, platinum-resistant ovarian cancer and in an overall patient population.
Kathleen N. Moore, MD
The phase III FORWARD I trial fell short of its primary endpoint, as findings showed the antibody-drug conjugate mirvetuximab soravtansine did not result in a progression-free survival (PFS) improvement compared with chemotherapy in patients with folate receptor alpha (FRα)positive, platinum-resistant ovarian cancer and in an overall patient population.1
According to a press release from ImmunoGen, the developer of mirvetuximab soravtansine, there was no significant difference in PFS in the overall study population (HR, 0.98;P= .897). Although the PFS was longer with mirvetuximab soravtansine in the prespecified high FRα-positive subgroup (HR, 0.69;P= .049), it did not reach statistical significance as per a prespecified statistical analysis plan. Additional findings will be presented at an upcoming medical meeting.
“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,” said Kathleen Moore, MD, associate director of Clinical Research at the Stephenson Cancer Center at the University of Oklahoma, in the press release. “I look forward to continuing to work with ImmunoGen to analyze the phase III data and determine the most appropriate path to bringing mirvetuximab soravtansine to those patients who benefit most from it.”
In the open-label, FORWARD I trial, 366 patients were randomized 2:1 to receive either mirvetuximab soravtansine at 6 mg/kg adjusted ideal body weight or physician’s choice of single-agent chemotherapy, which was pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel.
To be eligible for enrollment, patients must have had platinum-resistant ovarian cancer that expressed either medium or high levels of FRα and were treated with up to 3 prior regimens. Those with clear cell or low-grade ovarian cancer, primary platinum-refractory disease, serious concurrent illness or clinically relevant active infection, and who had prior treatment with mirvetuximab soravtansine were excluded.
Besides the primary endpoint of PFS, secondary endpoints included overall response rate (ORR), overall survival (OS), and quality of life. PFS was determined with the Hochberg procedure in the overall study population and in those with high FRα expression. Under this statistical analysis plan, it was determined that if thePvalue of the primary endpoint in either population is greater than .05, then thePvalue in the other population must be less than or equal to .025 to achieve statistical significance.
In addition to the PFS findings, the confirmed ORR in the overall study population was 22% for mirvetuximab soravtansine and 12% for chemotherapy (P= .15). There was no significant difference in PFS in the overall study population (HR, 0.98;P= .897).
In the pre-specified high FRα subgroup (n = 218), PFS was longer in those who received mirvetuximab soravtansine versus chemotherapy (HR, 0.69;P= .049). Therefore, it did not reach statistical significance. In this subgroup, the confirmed ORRs were 24% and 10% for mirvetuximab soravtansine and chemotherapy, respectively (P= .014). Moreover, OS was longer in the mirvetuximab soravtansine arm (HR, 0.62;P= .033).
Regarding safety, mirvetuximab soravtansine was well tolerated, with fewer patients experiencing grade ≥3 adverse events (AEs; 46%) than with chemotherapy (61%). There were fewer dose reductions (20% vs 31%) and fewer discontinuations related to treatment-related AEs (5% vs 8%) with mirvetuximab soravtansine than chemotherapy, respectively. The most common all-grade AEs with the agent was nausea (54%), diarrhea (44%), and blurred vision (43%); grade ≥3 of each of these AEs were 2%, 4%, and 3%, respectively.
“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. In parallel, 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,” said Mark Enyedy, president and chief executive officer of ImmunoGen.
Prior data from phase I pooled expansion cohorts (N = 113) showed that mirvetuximab soravtansine led to a 30% ORR (95% CI, 22-39) in patients with platinum-resistant ovarian cancer who had received 1 to 3 prior lines of therapy.2This included 3 complete responses (CRs) and 31 partial responses (PRs). The confirmed ORR was 47% (95% CI, 30-65) in a group of patients who were then eligible for FORWARD I, including 1 CR and 16 PRs.
The median PFS was 4.3 months in the pooled group (95% CI, 3.9-5.4) with a 19.3-week duration of response. Moreover, the median PFS was 6.7 months (95% CI, 4.1-8.3) in the FORWARD I eligible group with a duration of response of 25.1 weeks.