In an interview with OncLive, Kathleen Moore, MD, discusses the MIRASOL trial and the hope for mirvetuximab soravtansine in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression.
Kathleen Moore, MD
Folate receptor alpha (FRα) expression is an attractive marker for targeted therapies in advanced, high-grade epithelial ovarian cancer, according to Kathleen Moore, MD, who added that the antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) could potentially prolong survival in those with FRα-high tumors.
In the ongoing, randomized, open-label, phase 3 MIRASOL trial (NCT04209855), investigators are comparing the safety and efficacy of the ADC with standard-of-care chemotherapy in patients with platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer with a high FRα expression.The primary end point of the trial is progression-free survival (PFS) and key secondary end points include objective response rate, quality of life (QOL), overall survival (OS), as well as safety and tolerability.1,2
Previously, the phase 3 FORWARD 1 study (NCT02631876), examined mirvetuximab soravtansine in patients with FRα-positive, platinum-resistant ovarian cancer and failed to show a significant improvement in PFS.3 Although the trial was negative, it yielded many insights that were subsequently incorporated into the design of MARISOL, according to Moore.
“We're not doing 10x scoring again [for MARISOL]; we've gone back to the original scoring of the assay that was done in the phase 1 study. Even though it's not simplified, it is a methodology that pathologists are familiar with and are able to do, so it's not some new scoring [system] that we've made up,” explained Moore. “We're doing this in a centralized way. We've retrained the pathologists and many quality checks are going to be done throughout MIRASOL to double-check the patients who are included and how they're characterized. Moreover, this time, we're only focusing on [patients with] FRα-high [tumors].”
In an interview with OncLive, Moore, director of the Oklahoma TSET Phase 1 Clinical Trials Program; an associate professor in the Section of Gynecologic Oncology, Jim and Christy Everest Endowed Chair in Cancer Research; director of the Gynecologic Oncology Fellowship Program; associate director of Clinical Research; and medical director of the Clinical Trials Office at Stephenson Cancer Center, discussed the MIRASOL trial and the hope for mirvetuximab soravtansine in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression.
OncLive: Could you start off by discussing the unmet need for patients with platinum-resistant ovarian cancer?
Moore: Fortunately, and unfortunately, in ovarian cancer, we are in a situation right now where despite no change in the incidence or mortality of the disease, we have more women surviving than we ever had at any point in our history. The prevalence of ovarian cancer in the United States and Europe is very high. Why is that? Through better supportive care, the incorporation of maintenance [treatment], and the discovery and incorporation of novel effective [agents all] [prolong] PFS for women. The OS [in these patients] is increasing incrementally, as well. It's hard to show that in any individual study, but with the increased prevalence of women living with ovarian cancer, we know that these patients are also living longer. That's a good thing, although, of course, we would prefer that they were living longer without disease and cured.
What it brings into focus is the fact that you commonly have women now who are in their third, fourth, fifth, or even sixth line [of therapy], and they still are working and feeling fine and doing well, but they don't have a therapy available to them with a reasonable expectation of efficacy. You get into these monotherapy cytotoxics where, based on historical benchmarks, your expected response rates are only about 10% to 15% at best, aside from biomarker-directed therapies like [those targeting] BRCA [mutations].
Once women have gone through frontline therapy, a large fraction of them will be cured with all of the advancements. However, once patients recur and they’re no longer curable, once their disease becomes resistant to platinum, and they receive that initial AURELIA-type regimen comprised of chemotherapy plus bevacizumab (Avastin), no effective agents are available for them. These patients will cycle through this series of drugs that have variably low response rates unless they're fortunate enough to be in a place [where] clinical trials [are available], and most aren't.
There's this high unmet need for agents that are ideally biomarker-directed, so you can get the right patient on the drug at the right time, [get the agent to] work, and [have it] work for clinically relevant long periods of time. Something that works for 2 months is not what I'm interested in, but something that buys another year with good QOL? That's missing. Many women are in this situation and there’s really an urgent need for development in this space.
What makes FRα an attractive target in this area?
FRα is not a new target. Several shots on goal have been made with this target, including mirvetuximab. For whatever reason, high-grade serous ovarian cancer cells are coated in these FRα receptors, this transmembrane protein. It's not the normal sort of FRα that manages folate homeostasis; it’s something particular to malignancies. Its presence is on the extracellular membrane, whereas normal folate transmembrane proteins that are used in homeostasis are not facing the bloodstream. FRα is on the surface of ovarian cancer cells very commonly, and we don't really know why.
There's some suspicion that this might be related to prognosis, although that hasn't really borne out. It's there about 80% of the time, albeit in various degrees; it's very consistently expressed and appears to be, based on biopsy studies as compared with archival tissue, a relatively conserved expression. Most likely, if you had it in the past, you have it now; for that reason, it’s an attractive target. A new biopsy isn’t needed to determine whether [a certain] therapy may be helpful for a particular patient. You can just go back to archival tissue instead, which saves a patient an unnecessary biopsy.
What adjustments were made for the MIRASOL trial compared with the FORWARD 1 trial?
Many adjustments were made to MIRASOL. The way the assay was scored was thoroughly reevaluated. The actual antibody that's used to stain the slide is the same. What happened in FORWARD 1, which was the prior study, is that the scoring methodology changed. When we looked at FRα in the earlier-phase studies, which had hundreds of patients, we used pS2 scoring; this takes into account the staining intensity and percentage of tumor cells staining at either 0, 1, 2, or 3+. For example, a pS2 score positive would be greater than 50% of tumor cells with FRα membrane staining that is greater than or equal to 2+ intensity; [this incorporates] both intensity and percentage, which is kind of cumbersome but doable.
This bridging study was done with 10x scoring, which is a simplified scoring method that only uses the percentage of cells with membrane staining by less than 10x magnification without regard to intensity. In this bridging study that was done; they looked to be correlated, but they weren't at all.
In FORWARD 1 where, the eligibility was for patients with a medium to high expression of FRα. The distribution on that study, per how it was scored, was that 40% of patients were FRα medium and 60% were FRα high; this was already a bit of a red flag because we saw more [patients who were] FRα high than we expected just based on the phase 1 data. When that was all rescored—initially by a single pathologist just to see what happened and then subsequently by several blinded pathologists—it looks like about one-third of the patients who were enrolled in FORWARD 1 were actually never eligible because their FRα expression was below the cutoff point. Then 30% [of patients] were FRα medium and 35% were FRα high. As such, we had one-third of patients who were ineligible.
In FORWARD 1, our primary end point was PFS in FRα-high population and then in the intent-to-treat (ITT) population. Our ITT group was diluted by 35% of patients who were never eligible and our FRα-high population was diluted by half the patients characterized as not being FRα high. That was a problem.
A tremendous amount of work has been done to ensure that the way the assay is being scored accurately reflects the patient population who we expect to gain the most benefit from mirvetuximab. We have a lot of confidence that this is the correct way [to go about this], that we will enroll patients who we expect to benefit, and we'll show that the [agent] works in this population.
Ultimately, what is the objective of the MIRASOL trial? Pending those results, how do you anticipate this research to impact the landscape?
MIRASOL is similar but not exactly the same as FORWARD 1. As I said, this trial is only allowing patients with FRα-high [expression], which we expect to [account for] about 40% of [all] patients with high-grade serous ovarian cancer. Participants are allowed to have received 1 to 3 prior lines of chemotherapy, inclusive of prior bevacizumab and previous PARP inhibitors. This time, these patients will be randomized 1:1—in FORWARD-1, patients were randomized 2:1—to mirvetuximab or investigator’s choice of chemotherapy. The primary end point of the trial is investigator-assessed PFS, and secondary end points include response rate, OS, and patient-reported outcomes. This study is open and accruing. We have patients receiving treatment right now and sites are getting activated in the United State; global sites are coming soon. The COVID-19 [pandemic] has set us all back a little bit, but we do have patients actually screening and enrolling on this trial right now.
We anticipate that this will be a positive study and that we'll finally get mirvetuximab approved and made available to women with recurrent ovarian cancer. [This agent can serve as] an option for patients whose disease is no longer responsive to platinum, those whose tumors have progressed through an AURELIA-type regimen with bevacizumab and chemotherapy, or for those who are not eligible for bevacizumab; these patients can come right onto mirvetuximab. It provides women with another treatment option in this space of platinum-resistant ovarian cancer, where many options are needed to serially continue to improve PFS and prolong OS. This is where the agent will be positioned initially, as a monotherapy in that platinum-resistant space.
Is there any other element of the trial that you wanted to emphasize?
The trial is very similar to FORWARD 1. We did learn a lot from FORWARD 1 and we did see positive signals. For example, we saw a trend toward an improved OS [with the agent]; we hope that is real and that we'll see the same thing in MIRASOL. We did briefly get, as I mentioned, quite a bit of additional safety data demonstrating that the [agent] is safe to use.
[Mirvetuximab] has a very differentiated safety profile from that of chemotherapy monotherapy. It differs in a favorable way; specifically, far less hematologic toxicity [is observed with the agent] compared with paclitaxel, and far less neuropathy. We do see some gastrointestinal adverse effects that are common, but [they are] low grade, so we can manage them and mitigate those effects preemptively.
The visual disturbances [occur in] about 50% [of patients] and include dry eye and blurred vision; however, those toxicities are very low grade and were well managed across the United States and globally. Sites were very much able to prevent them and manage most patients with those low-grade visual toxicities without dose modification, which emphasizes the differential toxicity profile and the ability to mitigate the toxicities that are unique to this [agent], so that patients can continue to have a good QOL. The QOL data that we collected in that study would reflect that.
We made some tweaks and did see some more nausea than we thought we would in the initial days after mirvetuximab; as such, in MIRASOL, we're using more pre-medication to prevent that. We've made some little adjustments to try and improve the patient experience overall. We wanted to help patients receive this [agent], tolerate it well, and have great QOL. We hope to prolong the length of their lives, as well.