The antibody-drug conjugate mirvetuximab soravtansine demonstrated a favorable benefit-risk profile in a prespecified subset of patients with folate receptor alpha–positive ovarian cancer, following a comprehensive analysis of the phase III FORWARD I trial.
The antibody-drug conjugate mirvetuximab soravtansine demonstrated a favorable benefit-risk profile in a prespecified subset of patients with folate receptor alpha (FRα)—positive ovarian cancer, following a comprehensive analysis of the phase III FORWARD I trial, according to ImmunoGen, the manufacturer of the agent.1
The news follows the company’s March 2019 announcement that mirvetuximab soravtansine missed the study’s primary endpoint of progression-free survival (PFS) compared with chemotherapy in patients with FRα—positive, platinum-resistant ovarian cancer and in an overall patient population.2 Although PFS was longer with mirvetuximab soravtansine in the prespecified high FRα—positive subgroup (HR, 0.69; P = .049), it was not enough to reach statistical significance as per a prespecified statistical analysis plan.
In the overall study population, no significant difference in PFS was observed (HR, 0.98; P = .897).
“Following the readout of the topline results from FORWARD I, we have undertaken a comprehensive analysis of the data and see a consistent efficacy signal across a range of parameters in the pre-specified subset of ovarian cancer patients with high FRα expression,” Mark Enyedy, president and chief executive officer of ImmunoGen, said in a press release. “Specifically, in comparison to chemotherapy, we have observed higher response rates, more durable responses, and longer progression-free and overall survival in patients with high FRα expression treated with mirvetuximab.
With the benefit of this analysis and input from our clinical and regulatory advisors, we will be meeting with the FDA this quarter to discuss a potential path to registration for mirvetuximab as a monotherapy.”
ImmunoGen also stated in the press release that it also plans to meet with the European Medicines Agency regarding conditional marketing authorization for mirvetuximab soravtansine in this setting.
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 comprised 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 ≤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 from enrollment.
Beyond 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 the P value of the primary endpoint in either population is greater than .05, then the P value in the other population must be less than or equal to .025 to achieve statistical significance.
The confirmed ORR in the overall population was 22% for mirvetuximab soravtansine and 12% for chemotherapy (P = .15).
In the prespecified high FRα subgroup (n = 218), 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).
There were fewer rates of grade ≥3 adverse events (AEs; 46%) with mirvetuximab soravtansine than with chemotherapy (61%). Moreover, 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.
Earlier findings 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.3 This 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.
Additionally, 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.
The ongoing phase I/II FORWARD II trial (NCT02606305) is currently enrolling patients. Results of an expansion cohort of the study, which is exploring the combination of mirvetuximab soravtansine plus bevacizumab (Avastin) in patients with platinum-resistant, advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer, will be presented at the 2019 ASCO Annual Meeting.