In an interview with Targeted Oncology, Ursula A. Matulonis, MD, discussed the pooled analysis of 3 studies which examined single agent mirvetuximab in patients with FRα-high platinum-resistant ovarian cancer.
A pooled analysis of findings from 3 trials demonstrated extended treatment benefit (ETB) with mirvetuximab soravtansine (mirvetuximab) monotherapy in patients with folate receptor alpha (FRα)-positive recurrent ovarian cancer.
Mirvetuximab is a first-in-class antibody-drug conjugate which consists of a FRα-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin-targeting agent, in order to kill targeted cancer cells.
Currently, mirvetuximab is under review by the FDA for accelerated approval with a PDUFA date of November 28, 2022. Recently, top-line data from the phase 3 SORAYA trial (NCT04296890) showed that the study’s primary end point of achieving meaningful anti-tumor activity with consistent safety and favorable tolerability was met.
In the pooled analysis, findings of the phase 1 IMGN853-0401 trial (NCT01609556), the phase 3 FORWARD I trial (NCT02631876), and the phase 3 SORAYA trial were included. Each of these 3 studies have examined the use of mirvetuximab as a monotherapy.
In the pooled analysis, ETB was defined as progression-free survival (PFS) for more than 12 months per investigator assessment. Findings from the analysis showed that 40 patients (9%) of the 466 included demonstrated ETB.
In an interview with Targeted OncologyTM, Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, discussed the pooled analysis of 3 studies which examined single agent mirvetuximab in patients with FRα-high platinum-resistant ovarian cancer.
Targeted Oncology: Can you discuss mirvetuximab and how it's currently used?
Matulonis: Mirvetuximab soravtansine is an antibody drug conjugate composed of the folate receptor alpha binding antibody. It's cleavable linker and the payload is DM4, which is a maytansinoid. It is a drug that is currently under investigation. It's not for use currently outside the context of a clinical trial, but currently, [it is being evaluated in the] SORAYA study, which I've presented a few times, firstly at Society of Gynecologic Oncology in 2022, again at American Society of Clinical Oncology in 2022, then recently at European Society for Medical Oncology in 2022, and again at the International Gynecologic Cancer Society Meeting.
SORAYA is a phase 3 study. It is not a randomized phase 3 study, but it's looking at mirvetuximab single agent in patients with platinum-resistant recurrent, high-grade serous ovarian cancer, all of whom had received prior bevacizumab [Avastin]. All the cancers have high levels of expression of folate receptor alpha. As previously presented, of the 106 patients enrolled, we saw a response rate of 32.4%. Those were confirmed response rates and then a median duration of response of 6.9 months. Both of those results held up regardless of how many prior lines the patients had received of prior treatment and whether patients had received a prior PARP inhibitor. Patients were allowed to have received up to 3 prior lines of treatment. It was a pretty heavily pretreated population and about half of the patients had received a prior PARP inhibitor.
Can you discuss the exposure response analysis and how that was designed?
The exposure response analysis was essentially 3 pooled studies of single agent mirvetuximab. Mirvetuximab was given a single agent in all these trials. The dosing is based on adjusted ideal body weight, and the dose is 6 mg/kg. The 3 trials included a phase 1 of mirvetuximab leading up to that 6 mg/kg dose, the SORAYA study, and a trial called FORWARD I, which is a previous phase 3 trial using a different measurement of how patients with folate receptor alpha expression were entered into the trial. Now, we're focused on SORAYA and the completed but the results are not presented, MIRASOL [NCT04209855] stud. All those patients had 3 plus or high levels of expression of FRα.
The abstract I presented at ESMO was about the 3 trials, FORWARD 1, SORAYA, and phase 1, all looking at 6 mg/kg. We looked at efficacy, so overall response and progression-free survival, and then looked at ocular toxicity. One can see ocular toxicities with mirvetuximab. It's an antibody drug conjugate related side effect. About 50% of patients receiving mirvetuximab will have an ocular toxicity. About 20% of the 50% are grade 1, 24% end up being grade 2, a very small percentage or grade 3, and less than 1% of grade 4. These are reversible eye toxicities; they can manifest as blurred vision. That's the most common way of finding it. Sometimes patients can be asymptomatic. In the trials, we focused on the patient's ocular exams. There you can have micro cysts or corneal micro cysts that occur with mirvetuximab. They can be asymptomatic, but they can be seen on exams. The ophthalmologist could call something that would be graded as an eye toxicity, but the patient might not have manifestations of that. They may think their vision is just fine or it could be grade 1 or grade 2 blurred vision.
The important point is that the eye toxicities are low grade. The vast majority are grade 1 and grade 2, and they're reversible. There are no permanent eye toxicities with mirvetuximab and if patients are getting 6 mg/kg, they have persistent grade 1 or grade 2 blurred vision, the doses drop down to 5 mg/kg. Again, these are all well tolerated. What we found is that the area under the curve, and the C trough were correlated with efficacy, specifically response rates and progression-free survival, and that the area under the curve, so the amount of of time and drug that the patient was exposed to, did correlate with the ocular toxicity. The more drugs, the higher the level of eye toxicities. Everything made sense and there were no surprises here.
What do these findings mean for mirvetuximab?
Mirvetuximab is currently under accelerated review by the FDA for accelerated approval. The PDUFA date is November 28, 2022, so we expect a decision relatively soon. The confirmatory MIRASOL phase 3 trial has completed accrual and some early results are anticipated for 2023. The level of response, the overall response rate of a little over 32%, the median duration of response of 6.9 months [were promising], and within those response rates, we saw complete responses and partial responses. Additional data that was presented as by my colleague, Kathleen Moore, MD, showed profound improvements in quality of life that patients saw. She presented FORWARD 1 data, but I think what we're seeing is that level of response can translate into patients feeling better.
Again, SORAYA is impressive because these are heavily pretreated patients who all had received bevacizumab. We're hoping that this is a new standard of care for our patients with platinum-resistant ovarian cancer. There hasn't been a drug approved for platinum-resistant ovarian cancer since 2014. That was nearly 8 years ago. We're hoping that the FDA will rule in favor of mirvetuximab and again, we'll know that by the end of November.