Targeting Folate Receptor Alpha Provides Therapeutic Benefits for Platinum-Resistant Ovarian Cancer

Kathleen N. Moore, MD, MS, a gynecologic oncologist, and professor of gynecologic oncology at the Stephenson Cancer Center at the University of Oklahoma College of Medicine, Oklahoma, joins Pharmacy Times to discuss new data that suggests that targeting folate receptor alpha (FRα) is a significant innovation in cancer therapy at the 2023 American Society of Clinical Oncology (ASCO) 2023 Annual Meeting in Chicago, Illinois from June 2 to 6.

PT Staff: What is the significance of targeting folate receptor alpha (FRα) in cancer tumors that express FRα (ie FRα-positive, platinum-resistant ovarian cancer (OC))?

Kathleen N. Moore, MD, MS: The knowledge of the presence of folate receptor alpha (FRα) overexpression or expression on OC has been longstanding. This has been a target that investigators have been trying to exploit for probably a decade with some kind of notable early promising agents that just didn't quite make it over the finish line. But that has changed, of course, with mirvetuximab soravtansine-gynx (Elahere; ImmunoGen) as will be reported at ASCO.

So I guess my first comment is that FRα is not new— we've known that it is highly overexpressed on OC and really minimally expressed on normal tissues with some rare exceptions, such as type 2 pneumocytes in the choroid plexus. But for the most part, you avoid targeting normal tissue, when you target FRα because it really is overly tumor specific. And the transmembrane receptor is also noteworthy because it can allow endocytosis of whatever binds to it. So it's not just a surface receptor that you bind and activate something. You bind and then you can transport a molecule into the cell; in this case a cancer cell. And so that opens opportunities to exploit that sort of mechanism with drugs such as antibody drug conjugates (ADCs) or other conjugates where you're trying to deliver some sort of cytotoxic, immunogenic, or therapeutic payload that otherwise may be too toxic to give a systemic drug, but you can give it on these conjugates and transport it into a tumor cell with therapeutic benefit. So with FRα (I think [coming] with a lot of understanding and learning from prior and unsuccessful clinical trials) I think we finally have hit on the first of what may be several upcoming agents that can target this protein to therapeutic benefit.

PT Staff: You’ve mentioned in a previous interview that FRα status is a ‘must know’ for all OC patients- could you elaborate?

Kathleen N. Moore, MD, MS: We have an FDA approval for mirvetuximab soravtansine-gynx in the platinum-resistant OC setting that came as an accelerated approval in November of 2022. Again, the confirmatory trial is MIRASOL and will be presented at ASCO 2023. It is a positive study. And we anticipate and hope for a confirmed approval in the United States. But really, perhaps more importantly, [we hope for] global access to this medicine for women suffering with platinum-resistant OC. And so because of that, I do think you need to know the biomarker. You know, I think just like we think it's imperative to know BReast CAncer (BRCA) [gene] status so that we can appropriately allocate poly ADP ribose polymerase (PARP) inhibitors in the frontline and potentially cure patients who have that. So that's a must know; you must know BRCA, I mean there's just no excuse not to unless a patient herself says she does not want to know. That is the standard of care.

This is another therapy with a clinically and statistically important improvement in not just progression free survival (PFS), as you will see at ASCO, but overall survival (OS) in a difficult-to-treat setting. I mean, I wish I could say we were curing women. We are not. But we are helping them live longer. And I think the toxicity data we will prevent shows that we're helping them live longer and better. And that is in and of itself an important achievement and really justifies widespread testing for FRα. It's an immunohistochemistry test that can be part of any panel. As we send all these assays that are commercially available that have immunohistochemistry, it's going to be a part of those panels. So I think, honestly, it's just going to be something that's done upfront or early on in someone's treatment course and then can move it into kind of therapeutic action when clinically indicated. In this case, in a platinum-resistant OC setting, there are ongoing clinical trials and pending report in earlier lines of therapy in a platinum-sensitive setting. So I think that we should just start testing and know who your patients are so you can use this medicine, if desired, at the earliest possible opportunity.

PT Staff: Mirvetuximab soravtansine has been one of the most well-received ADCs for FRα-positive, platinum-resistant OC. What could a patient treatment plan look like using ADCs/ FRα target therapy?

Kathleen N. Moore, MD, MS: Well how mirvetuximab soravtansine will be used is highly dependent right now on the label. I think that what we have to say is that we have to follow the FDA guidance and label. And so for the most part, it will be used as a monotherapy in a setting of FRα high, which is 75% of cells expressing 2 plus or more FRα. And in the platinum-resistance setting, it’s for 1 to 3 priors. And so I feel like that's the label and that's where people will use it.

The other thing to note is that it is listed based on a pretty large, single arm phase 2 experience in combination with bevacizumab (Avastin; Genentech) in both platinum-resistant and -sensitive settings. The patients who are technically platinum-sensitive (for a variety of reasons) cannot receive platinum. Maybe they have an allergy or are not really platinum- sensitive. So they all enrolled in this clinical trial, which demonstrated very high overall response rates (ORR) in both of those settings with very long duration of response (DOR) and a very reasonable toxicity profile—really just what you see with each agent alone. And that trial allowed women to come on who were not just FRα high, but really low, medium, and high. It is mostly medium and high. And so the National Comprehensive Cancer Network (NCCN) guidelines list bevacizumab and mirvetumximab for FRα-expressing tumors, not just high. It is a category 2b, and so I think the caution there is that you do really have to make sure that the patient's insurance is authorized use of that combination outside of FRα high because it is technically off-label, but it is with data that is quite strong for enhanced response. So I do think there will be a population of patients who will receive that combination as well.

That's where it's going to be us now. I think that's the confirmed approval. It has completed a clinical trial called PICCOLO (IMGN853-0419) that was led by my friend Angeles Alvarez Secord, MD, from Duke. She's a professor at Duke that was testing monotherapy mirvetuximab in a platinum-sensitive setting in patients who'd received at least 2 prior platinums. And they could have received several platinums. And so that data will be presented at an upcoming Congress. And so I would suggest people watch for that, because that may lead to an expanded indication. And then the ongoing GLORIOSA (NCT05445778) study in first recurrence, platinum-sensitive, platinum-based chemotherapy with bevacizumab. And then the maintenance component amongst FRα high-expressing tumor patients is randomization to continue to bevacizumab or bevacizumab and mirvetuximab. And we have data for that from prior study. And so that is ongoing, currently accruing, and activated last year. So I think you will see, should those 2 studies change the indications, I think you'll see mirventuximab move up a line of therapy in the future. And I would probably predict that would happen. But we'll have to let those studies play out.