Expert: Mirvetuximab Soravtansine-Gynx Does Not Use Up the "Precious Reserves” of Patients with Ovarian Cancer


The folate alpha receptor (FRα) does have a toxicity profile, but unlike other chemotherapies, it does not severely compromise bone marrow and may improve ability to receive more therapies.

Inpart 2 of a Pharmacy Times ASCO video series with 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, Moore provides one of the most in-depth and illuminating discussions about the toxicity profile of mirvetuximab soravtansine-gynx, one of the leading immunotherapies for folate receptor alpha (FRα)-positive and platinum-resistant ovarian cancer (OC).

PT Staff: What factors are important to consider before administering FRα-targeted treatment like mirvetuximab soravtansine-gynx (Elahere; ImmunoGen)?

Kathleen N. Moore, MD, MS: Sure, sure. So the toxicity of mirvetuximab is what we call a differentiated safety profile. So it's not nontoxic, although it's pretty nontoxic. So its not nontoxic, it does have some toxicities, but they are very different than systemic chemotherapy. And we learned this in the first phase 3 study which was FORWARD 1 (GOG 3011). And then we see it very consistent, almost identical, again in MIRASOL (NCT04209855).

And so you see, as compared to any chemotherapy or systemic cytotoxic chemotherapy, really negligible hematologic toxicities, with mirvetuximab, and it's about 10% heme neutropenia, anemia, thrombocytopenia (10% or less). And the vast majority, if not 100% of toxicities, are grades 1 and 2 compared to what you see with the comparators which were pegylated liposomal doxorubicin (PLD), topotecan, and weekly paclitaxel (Taxol; Bristol-Myers Squibb), which has 30% to 60% all grade hematologic toxicities. so that’s 1 very key differentiator for mirvetuximab, and [also] we really don't hammer the bone marrow which is very nice. In addition to the fact that the medicine works, you'll sometimes have patients who have seen several lines of platinum or other bone marrow- challenging agents, and they kind of come into the platinum-resistant setting with borderline counts. Neutrophil counts that are right at 1,500 and a hemoglobin that's kind of sitting at 9 platelets that are like 110. They're okay to treat but not robust. And this is a medicine that you can use very safely in those patients. And it allows their bone marrow to recover somewhat, which is, I think, 1 of (other than just the efficacy of the drug) the reasons I do think we see an overall survival (OS) advantage; it is because it works. Number 1, it shrinks tumors and that helps patients live longer because they can go on to another line of therapy and they feel better. So then when they do recur, they feel well enough to get another line of therapy and we haven't compromised their bone marrow to an extent that they can't get into a line of therapy. So, it's sort of an effective therapy that doesn't use up some of our patients’ precious reserves, so they can go on to receive subsequent lines of therapy.

I think that probably contributes to the OS advantage you see as compared to standard chemotherapies. You see really no alopecia. Really none with mirvetuximab as compared to paclitaxel. You see less peripheral neuropathy, but you still see some, so that is one of the side effects we see with mirvetuximab that tends to be a little later than weekly paclitaxel. But with mirvetuximab, the conjugate ravtansine (DM4), which is a microtubule toxin. So it makes sense that we would see some neuropathy and it's managed very much like paclitaxel with dose holds until recovery and then dose modification if you need it, but it is something that happens kind of cumulatively later than you see with paclitaxel, so the kinetics of it are a little different, but it is a side effect you have to watch for.

We do see some gastrointestinal (GI) toxicities with mirvetuximab, mainly diarrhea—we see that about 30% of patients have diarrhea, almost entirely grade 1/2, and we just treat it with over-the-counter medications. So like what we see with paclitaxel, but of course (more than [what you’d see with] PLD or topotecan) you'll see nausea, that's about the same rate that you see with standard chemotherapies that we mitigate with pre medications. It’s very low grade though, no high-grade nausea. There’s almost no stomatitis (around 3%) and you'll see maybe 10% to 15% with the other medication. So a little less with that.

The main kind of toxicity that's unique to mirvetuximab, as compared to the other medicines, is the ocular disturbances. In MIRASOL, we saw this in 41% of participants, which is really consistent. It's a little bit less than what we saw on FORWARD 1, but in the range—I always tell patients it's 50%. So it's 41%, grades ½ predominantly and less than 10% for grade 3. And this can be blurred vision, alone, or it can be blurred vision accompanied by keratopathy, or dry eyes, so patients can experience all of those are just one of those. The mechanisms of this toxicity are still really under discovery, although there's some emerging data that we may be able to share sometime soon. But really, the big hypothesis is just damage to the limbus of the cornea, which is kind of like skin. And so if you damage it, it flakes off and floats across the visual field, and so patients have blurry vision. The ophthalmologist sees these things called micro-cysts, which are just debris of the damaged limbus. And then just like the skin it swaps off. You were always swapping off epithelial cells from our eye, and as the debris just flops off the vision returns to normal. So we do believe that it's 100% reversible. In fact, we've not seen any cases of irreversibility. And the mitigation for this really is the lubricating eyedrops (steroid eyedrops), and just good eye hygiene. So we don't like contact lenses and so on, we want sunglasses on and we don't want you using perfumed facial washes or anything that could be abrasive. So those are mitigation strategies.

As I said, only 1% of patients discontinued because of the eye toxicity. And it is transient. It's not ongoing [where] someone has blurry vision the whole time. It usually happens cycle 2, Day 15. And then it resolved within a week. And then if it was low grade and resolved really fast, we just keep them on the same dose and it doesn't tend to happen again but if it was grade 2 or a little slower to resolve, than we let it clear and then we dose reduce and it doesn't tend to happen again. And then patients remain on for as long as it's working. So we do take it very seriously. The eyedrops require some education, we carry them in our pharmacy to make it very convenient for patients. Patients must be seen by an ophthalmologist at baseline and every other cycle to cycle 8 that is per the FDA label. And so that is important. And after that they don't have to have that anymore after cycle 8 unless they had you know a toxicity which case we continue to follow them. So we do take it seriously. But can be mitigated. And we're working hard on other strategies to make it less common and that may be seen in upcoming trials.

PT Staff: What research is needed to better understand the clinical outcomes of FRα-targeted treatment?

Kathleen N. Moore, MD, MS: I appreciate the opportunity. We’re very excited about the approval of mirvetuximab, now known as Elahere, in November of last year (2022), it opened the door for women in the United States to access this medication and it's picked up very quickly. In fact, the demand to test was so high [that] many of the vendors ran out of kits. So, I think that just speaks to the need for novel therapeutics that are well that are effective and well-tolerated in this space. Because we ran out of kits nationally, I mean, that just tells you how much interested and how much there need is for medications like this. So we're grateful for the accelerated approval opportunity, but very, very excited to present MIRASOL with a comparison group.

The accelerated approval was based on the SORAYA study that was led by Ursala Matulonis, PhD, and Dr. Robert Coleman—single arm phase 3 MIRASOL now has the comparator on randomized phase 3 so you can really see the performance of standard medicine versus mirvatuximab in this space of platinum-resistant OC. And the benefit of for PFS and OS are both clinically and statistically significant. And I will note, and I may have to double-check on this because maybe there's something 3 decades ago that I forgot, but there has not been any study in the platinum-resistant OC setting that has [ever] shown an OS advantage, ever. That includes AURELIA, the standard of care of platinum resistant OC, single-arm chemotherapy with bevacizumab (Avastin; Genentech), which of course we love to use, but there's no advantage there. It's PFS advantage.

So here we have both, which is the first in a biomarker-selected population. So I do think that, again, we always strive to do better. So this is the new standard of care, I think, a new basis. And we're going to build from here and try to keep improving outcomes for our patients. But this is a big win for patients and should be used and why feel like folate alpha testing is a must know, I think you must know this. I have a medicine that's going to help you live longer. I think you got to know whether or not you're eligible. So I think this is important.

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