Mirvetuximab Soravtansine for Folate Receptor-Alpha High, Platinum-Resistant Ovarian Cancer

The Phase 3 MIRASOL Trial

Bradley Monk, MD, University of Arizona School of Medicine, Phoenix, Arizona, and The GOG Foundation Partners Organization, discusses the results from the phase 3 MIRASOL trial, first reported by Dr Kathleen Moore [MD, Stephenson Cancer Center, Oklahoma City, Oklahoma] at the 2023 ASCO Annual Meeting.

Dr Monk stated, "Quite frankly, what this really showed is that you can do it. ... We can help patients live longer and live better. And that's why we get up every morning. The challenge is that we have limited options, and so we need new options, and now we have mirvetuximab soravtansine."

Transcript:

My name is Brad Monk, I'm a gynecologic oncologist here in Phoenix, Arizona. It's my pleasure to be here with you. I'm a professor in the two medical schools that are here, Creighton, not Omaha, but Phoenix, University of Arizona, not Tucson, but Phoenix. And it's my pleasure to also represent the GOG Partners Organization as the director.

What is mirvetuximab soravtansine?

Mirvetuximab soravtansine is an antibody-drug conjugate comprising a folate receptor-binding antibody, a cleavable linker, and a maytansinoid-DM4 payload, which is a potent tubulin-targeted agent. As you know, folate receptor-alpha is expressed on about 90% of ovarian cancer, with 35% to 40% of platinum-resistant, recurrent ovarian cancer patients having ≥75% of the tumor cells having positivity with ≥2-plus. That's what we call high over-expressors, and as you know, this agent was brought to the clinic based on a single-arm trial called SORAYA, that led to accelerated approval on November 14th based on a 31.7% overall objective response rate.

What is the current treatment landscape for this patient population?

Platinum-resistant recurrent ovarian cancer (PROC) is a very challenging space. These are patients that have basically failed most available options. The standard of care generally is single agent chemotherapy, generally with weekly paclitaxel, liposomal doxorubicin, or topotecan, sometimes with bevacizumab. Bevacizumab is only approved in the recurrent platinum-resistant, recurrent ovarian cancer space in the second- and third-line, and in many parts of the world is only available in the frontline. That, what I would call available therapy, was how SORAYA got accelerated approval, and the patients that were enrolled on SORAYA were outside of available therapy. That means they had all had bevacizumab before, and they were in this PROC space where they had recurred during or within 6 months of their last platinum agent.

What is the rationale for the MIRASOL trial?

In addition to the accelerated approval from SORAYA, there was also a randomized phase 3 trial called FORWARD 1, which used a different scoring system that did not meet its primary endpoint, but was close. And it really started us thinking more about how to bring this medicine to the clinic. We brought it to the clinic through the single-arm SORAYA trial, but encouraged us to refine the biomarker, and quite frankly, do it again. And that repeat study, not the same, but similar based on the encouraging results from FORWARD 1 is called MARISOL. Now, although FORWARD 1 did not still show a statistically significant difference, it was very informative in this refined biomarker group, and it showed, interestingly, that mirvetuximab was more tolerable than physician's choice chemotherapy, which caused us to even get more excited, because in addition to having clinical activity, it had tolerability.

What were the results of the MIRASOL trial?

MIRASOL, a GOG study, that was the primary lead group —As you know, this is GOG 30-45, done in collaboration with the European Network of Gynecologic Oncology Trials, or ENGOT was OV-55— was a randomized phase 3 trial. Again, mirvetuximab versus investigator choice chemotherapy in platinum-resistant, advanced high-grade or recurrent high-grade epithelial ovarian, peritoneal, and fallopian tube cancer with high folate receptor-alpha expression. That pretty much defines the eligibility, other than the fact that they had to have up to 3 prior lines. Prior bevacizumab and PARP inhibitors were allowed. Patients were randomized 1-to-1 to mirvetuximab at 5 mg/kg, at an adjusted ideal body weight, every 3 weeks, versus investigator choice chemotherapy. Again, the standard regimens: paclitaxel, liposomal doxorubicin, or topotecan. The primary end points were progression-free survival by the investigator, a key sensitivity analysis with a blinded independent central review, and then key secondary end points of overall response rate, overall survival, and patient-reported outcomes.

Now, here's the result. Really, although the progression-free survival was not earth-shattering, it was still statistically significant and clinically relevant with a hazard ratio of 0.65. And that's really the way we need to look at it, that at any given time along the Kaplan-Meier curve, patients were at a 35% more likely chance to not have progressed. Now, at the median, it was maybe perhaps not as impactful, 5.62 to 3.98, but still met its primary end point leading to an analytic end point of overall survival, meaning there was a P-value associated with it. And this is really where it gets interesting. Not only did it improve progression-free survival, but it improved overall survival with a hazard ratio of 0.67. And this is really where the numbers become greater at the median, again, which is only a point estimate. But at the median, it was 3.71 months better, and the response rate was better: 42% in the mirvetuximab arm, 16% in the physician's choice chemotherapy.

Okay, so almost 3 times the overall response rate. Improvement in progression-free survival, improvement in overall survival, and importantly, the adverse reactions were better. Now, clearly, mirvetuximab has some unique adverse reactions, particularly ocular adverse events: 41% of the patients had blurred vision, 32% keratopathy, and 28% dry eye. "Oh, that's a lot." It's not a lot because 8%, 9%, and 3% respectively were grade 3-plus or greater. And so what we do to mitigate that is, we integrate eyedrops, which is important, and we also require that the patients undergo ocular exam at baseline in every two cycles. So why is this important?

PROC was undefeated for nine years. Think of all the studies, all the patients, all the expense that we had done since the approval of AURELIA trial and the approval of bevacizumab with chemotherapy in 2014. And quite frankly, what this really showed is that you can do it. Working with skilled investigators like Kathleen Moore, who is the global principal and reporting investigator, working with sponsors who make these really robust and tolerable antibody drug conjugates, we can help patients live longer and live better. And that's why we get up every morning. The challenge is that we have limited options, and so we need new options, and now we have mirvetuximab soravtansine.

Now you may say, "Listen, Brad, I already have it in the clinic." Yes, you did have it in the clinic since November, but now this adds context. It creates value. The accelerated approval was only tumor shrinkage. Valuable, but not really because that's a CAT scan. What's valuable is helping patients live longer. What's valuable is helping them live longer and better together. And importantly, MIRASOL now accelerates the global footprint because the accelerated approval was only in the US, and undoubtedly, this will be filed to international regulators and authorities and payers. I'm confident that this will get approved in most countries, and I'm confident that most payers will pay for it, because this now is considered one of the standard of care options in this setting.

What are the next steps for this research?

When we see a result like SORAYA and MARISOL, what do we do? We do 3 things. Other tumor types, which we're not going to talk about here, but more importantly, we go earlier lines of therapy, because we want to expand the footprint and the opportunity, and we do novel combinations. And the GLORIOSA trial does that. GLORIOSA now evaluates the combination with bevacizumab in an earlier line of therapy, platinum-sensitive recurrent ovarian cancer, and the combination again is with bevacizumab. We're doing what we're supposed to do in expanding the opportunity, and we're doing this through combinations.

Bevacizumab and mirvetuximab has been shown to be very active beyond folate receptor high. It's NCCN recommended, level 2B. Sometimes the reimbursement threshold is 2A, but I proud and happy that the NCCN recognized its activity and I'm happy that working with the GOG, the sponsor, this time Dave O'Malley [MD, The Ohio State University Comprehensive Cancer Center - The James, Columbus, Ohio] is the Global PI, is trying to bring this to more patients.

Now, this is only in folate receptor high patients, we need to consider other options. There are other folate receptor antibody drug conjugates, as you know, which ultimately can target additional folate receptor medium and low. The one that comes to mind is luveltamab [tazevibulin], which some of you may know as STRO-002. We're going to continue to refine, not only the line of therapy and the combination, but the technology to expand the opportunity beyond patients that are foliate receptor high.

Is there anything you would like to add about this research?

I had a question today from a dear friend, he says, "Brad, I'm going to start a patient this week on mirvetuximab based on SORAYA and MARISOL. Do I need to start the patient at a lower dose?" And I told him definitively no. Assuming your patient met the eligibility criteria for MARISOL, I think we can say with confidence that that's the right dose. However, it's true that with adverse reactions, we have the opportunity to dose interrupt to allow, generally, the toxicities or adverse reactions to regress, and then dose reduce. So there is some dose flexibility, I think, that needs to be emphasized. And all of this is outlined in the US prescribing information.

Source:

Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator's choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract LBA5507