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New Treatment for Recurrent Ovarian Cancer Improves Survival

<ѻý class="mpt-content-deck">— Susana Campos, MD, MPH, leads a roundtable discussion on the MIRASOL trial
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A study presented at the recent American Society of Clinical Oncology (ASCO) annual meeting found that mirvetuximab soravtansine (Elahere), an antibody and microtubule inhibitor conjugate, significantly improved progression-free and overall survival among patients with platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, and fallopian tube cancers with high folate receptor alpha (FRα) expression.

ѻý brought together three expert leaders in the field -- moderator , from the Dana-Farber Cancer Institute in Boston, is joined by , of Mass General Cancer Center in Boston, and , also from the Dana-Farber Cancer Institute -- for a virtual roundtable discussion. This third of four exclusive episodes focuses on the updated findings from the international phase III MIRASOL randomized clinical trial.

Following is a transcript of their remarks:

Campos: So we've had a nice little discussion about uterine cancer, cervical cancer, and not to be undone, but let us turn our attention to platinum-resistant ovarian cancer. And I think there have been some very interesting abstracts presented at ASCO.

I'm going to start with one of our favorites, and it's the MIRASOL study. And I'd ask Dr. Lee if she could probably just give us a little bit of briefing on the MIRASOL study, which was basically on the heels of the SORAYA study also.

Lee: Absolutely. So the MIRASOL study was meant to be a confirmatory phase III study following the SORAYA study. And this was intended to support approval globally for the use of mirvetuximab soravtansine. So I would just preface all of this by saying the SORAYA study within the United States had led to accelerated FDA approval of mirvetuximab soravtansine within the folate receptor alpha high-expressing group of [patients] platinum-resistant to ovarian cancer.

And so MIRASOL, this was a randomized phase III study, again looking at a very similar patient population to platinum-resistant ovarian cancer with high upper alpha expression. And I think important to know that the definition of high folate receptor alpha expression is 75% or greater with a 2+ standing intensity by IHC [immunohistochemistry].

Important to note also, this was only in the high-grade serous histologic subtype of ovarian cancer. One to three prior lines of therapy were allowed, but unlike SORAYA, prior bevacizumab [Avastin] use was not mandated. It was allowed, but it was not mandated.

And so these patients were randomized in a 1:1 fashion to receive either mirvetuximab soravtansine or investigator's choice chemotherapy, with a choice of either paclitaxel, pegylated liposomal doxorubicin, or topotecan. And I believe the primary endpoint here was looking at the progression-free survival by investigator assessment, but they did also report out by BICR [blinded independent central review] as well.

Campos: Yeah, it's pretty impressive. I mean the approval of mirvetuximab really has changed the way we treat patients with platinum-resistant ovarian cancer. Dr. Penson, your take on MIRASOL, please. Or SORAYA. Or both.

Penson: So both were exciting. November [2022] was the approval of this agent now that is the standard; [it] has really changed how we do things. Previously we bucketed into can we cure patients with frontline therapy and then potentially platinum-sensitive recurrent ovarian cancer, and then platinum-resistant if the recurrence is within 6 months? That's about a third of patients as what happens for them in terms of choice of second-line therapy.

And those patients typically do poorly. So the really impressive message that I thought [Kathleen] Moore delivered beautifully was this was the first and only time that we had seen an improvement in overall survival. And so the amount of overall survival was huge. The hazard ratio was 0.67, under 0.7, which is one of those important thresholds. And median overall survival improved for just under 13 to about 16.5 months. So more than a clinically relevant improvement of like 3 to 6 months as defined by ODAC [Oncologic Drugs Advisory Committee].

The good thing was the toxicity wasn't really worse. No new signals, and they didn't put all of the toxicity data up at ASCO, but the blurred vision, keratopathy, and dry eye clearly were consequences of this agent. They didn't sort of report pneumonitis, but it's not a big issue. I tend to tell patients some GI [gastrointestinal] toxicity, some fatigue, rarely anything else -- headache and neuropathy. But the two big things is keratitis, blurry vision. About half the patients about halfway through the second cycle are going to get some blurry vision if they're compliant with steroid and lubrication drops. And then pneumonitis is like 5% or less and rarely an issue. It's much more of a CT scan finding than a big clinical issue. It's not like bleomycin or tyrosine kinase inhibitor-induced pneumonitis.

So exciting data, really redefines things. And redefines, I think, a new era in platinum-resistant ovarian cancer that better-tolerated treatments can impact survival. That's a first and that is a massive change.

So now everybody should get checked for folate receptor alpha, about a third of patients are going to meet these criteria. There's lots of agents trying to expand that opportunity. And we really are trying to move this up. We've just opened a mirvetuximab/carboplatin phase II platinum-sensitive recurrent ovarian cancer [trial] within Dana-Farber/Mass General. And so we are excited to see this agent that doesn't cause alopecia, that doesn't cause bad neuropathy, really come as an essential part of our armamentarium.

Campos: No, I completely agree. It's very interesting, and you alluded to the toxicity. Anytime we have a conversation with patients regarding toxicity, and we mentioned ocular toxicity, although we've utilized this drug, we certainly know the algorithm of eyedrops, the visits with the optometrists or ophthalmologists that have to take place every other cycle with mirvetuximab. Have you in your own clinical practice -- we follow the guidelines, we follow the eyedrops -- have you seen that to be a limiting factor in patients' acceptance of mirvetuximab?

Penson: It definitely gives them pause. It's amazing how many of my patients know that they have cataracts, for example. And so certain things like when you tell them you cannot wear contact lenses on this drug, they will be like, "OK, that's a change." When we had a patient in phase I who got 7-mg/kg adjusted ideal body weight -- that's above the 6-mg/kg adjusted ideal body weight that we used in the trial -- they had complete blindness for a week. And that's super scary. Is that ever going to return? It was transient but protracted. It completely resolved. There is a globe perforation in the database, but I have never seen anything bad and I've never seen anything persistent.

This is a well-managed treatment. When you alternate between an optometrist and an eye surgeon, it's every other cycle. So you actually only need to see the eye surgeon every 3 months. And you do, as an oncologist, need to recruit somebody who's happy to help. And our experience has been very positive. It's a fabulous collaboration.

So I think recruiting a team, a village, to support patients has always been part of oncology. And so I don't think the toxicities, though they are a bit new to some clinicians, they're not a barrier to access for patients.

Campos: No, I agree. And actually we talked about this ever so briefly, and the dosing of this drug, yes, we know the dose of 6 mg/kg. But Dr. Lee, can you comment on the fact that this is dosed by adjusted body weight and that is something that is not so common as we write chemotherapy every day?

Lee: That's correct. So this is dosed by adjusted ideal body weight, which is something of course we have to pay attention to. And I think everyone who is prescribing this needs to work very closely with their pharmacists to ensure there's accurate dosing. We need to make sure that we aren't either underdosing versus overdosing our patients with mirvetuximab.

Penson: Adjusted ideal body weight was used because in the early studies when they were looking at their pharmacokinetics -- how much of the drug is in the bloodstream, what your body does to the drug -- as opposed to pharmacodynamics -- what the drug does to your body -- the association between [pharmacokinetics] and [pharmacodynamics], this was most accurate. So think of this as a drug that is getting delivered down blood vessels to the target. That's the goal of this drug. And then the bystander effect .... but really important -- but complicated -- in terms of the eventual outcome.

So lean body mass, how you were as your most beautiful self, is a much better predictor for getting the dose right. And the therapeutic window for this drug is narrow. And so in phase I, it did actually take quite a long time to get to the right dose. And that's absolutely the same for SORAYA, which dropped from 43 to 36, and the Sutro [Biopharma] drug as well, they can do a loading and a lower dose.

And so we think of antibody-drug conjugates as, you know, silver-bullet therapy and antibody takes it to the target, but actually the therapeutic windows are, in some ways, tighter, smaller than standard old chemotherapy. So it is elegant, a beautiful treatment, but does require some precision.

Campos: No, absolutely. But you know, regardless, I think with the SORAYA/MIRASOL data, survival in platinum-resistant ovarian cancer, I think we could accommodate the ocular toxicity and the calculation of adjusted body weight for this kind of responses.

Click here to watch the other videos from this ASCO roundtable series on gynecologic cancers.

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams.