Groundbreaking Results of Mirvetuximab Soravtansine for Ovarian Cancer With Kathleen Moore, MD

Oncology Data Advisor: Hi, Dr. Moore. Thanks so much for joining me today.

Kathleen Moore, MD: Absolutely. I'm happy to talk to you.

Oncology Data Advisor: You're presenting about the MIRASOL trial of mirvetuximab soravtansine for platinum-resistant advanced ovarian cancer. For background, how have patients with this disease been treated in the past?

Dr. Moore: That's a great question. For ovarian cancer, we're really—in this particular trial—talking about how high-grade serous ovarian cancers have made a ton of progress in the frontline in the last five years with poly adenosine diphosphate-ribose polymerase (PARP) inhibitors, and we actually are curing a fraction. The unfortunate reality is the vast majority of patients will recur, and once their tumors recur, inevitably, they develop resistances to platinum.

The standard-of-care for, probably for a decade, has been based on the AURELIA trial, which was a study done in 1 to 2 prior platinum-resistant patients—so, a very restricted population that we kind of extrapolate to bigger groups of chemotherapy, doxorubicin, paclitaxel, or topotecan with bevacizumab. And there's no overall survival advantage with that regimen; it's just a progression-free survival advantage. Once a patient benefits from that, or they've had bevacizumab before, which is incredibly common, all we have, really, is monotherapy chemotherapy, and it has a response rate of 15%—a very minimal duration of response. So, it's a really dismal opportunities for effective therapy.

That's really the reason why you see so much drug development in the platinum-resistant ovarian cancer space, because the need is so high to develop effective regimen.

Oncology Data Advisor: What was the essential question that the MIRASOL trial was asking?

Dr. Moore: The MIRASOL trial was the confirmatory trial for what we call the SORAYA study. It evaluates a drug called mirvetuximab soravtansine, which is an antibody-drug conjugate (ADC) that targets folate receptor alpha. Folate receptor alpha is a transmembrane protein highly expressed on ovarian cancer—about 80% of ovarian cancers. High-grade serous predominantly will have some folate receptor alpha—about 35% will be high. It's a target we're interested in, and mirvetuximab targets that. Then it's conjugated with a highly potent microtubule toxin. So, it basically acts like a Trojan horse where it binds to the folate receptor alpha, gets internalized, and then releases this payload of microtubule toxin. It's not paclitaxel, it's a completely different drug.

So, that study is extensive, a phase 1 with lots of cohorts and combinations. It had a completed accelerated approval trial called SORAYA, which was a single-arm phase 3 of mirvetuximab in platinum-resistant ovarian cancer, one to three priors, folate receptor alpha–high, and bevacizumab-pretreated. So, you're outside of that AURELIA label. The response rate there was 32%. Remember I told you, the expectation's 15% and the duration of response is about seven months. Based on that in the US, we did get accelerated approval in November of 2022.

Simultaneous with SORAYA, MIRASOL was launched as the confirmatory global trial. So, this is a randomized phase 3, almost the same design. It was platinum-resistant, one to three priors, folate receptor alpha–high, bevacizumab was not required though. They could have it, they could have a PARP inhibitor, but it wasn't required.

Patients within were randomized to mirvetuximab at 6 mg/kg, intravenous infusion (IV) every 3 weeks, or investigator's choice chemotherapy, and investigators could choose from paclitaxel weekly, pegylated liposomal doxorubicin, or topotecan. The primary end point was progression-free survival (PFS), and then secondary end points were overall response rate (ORR), overall survival (OS), and patient-reported outcomes. There's a whole bunch of other exploratory end points, but that's really what we were looking at with the MIRASOL study.

Oncology Data Advisor: Great, thank you. So, what are the results that were shown?

Dr. Moore: So, the results that we've been able to share so far, and it's very early; we just got the results about a month ago, but they are quite mature. We've demonstrated that we met our statistical primary end point of statistically and clinically significant improvement in progression-free survival with a hazard ratio of 0.65—a 35% reduction in the hazard of progression or death with use of mirvetuximab as compared to investigators choice chemotherapy.

Importantly, and I know I can't show you the slides, but there is a very early separation in the curves. From the beginning, the curves separate, and they maintain their separation. And in the control arm, we see it performs just like we always see, that 50% of patients in the control arm progress at the first disease assessment. So, there's this cliff they fall off and we see that time and time again on studies of platinum-resistant ovarian cancer. We don't see that on the mirvetuximab arm. It bumps out and it stays out. So, it really is a clinically significant effect.

Because that was statistically significant, we can move alpha to analytic secondary end points. So, these are analytic end points. Overall response rate was the first one, and we more than doubled it. We went from 16%, again, very consistent with historical benchmarks and how we set the statistical assumptions for the trial; 16% response rate in the investigator's choice, 42% for mirvetuximab, including 5% complete responses, and none in the investigator's control arm. So, the odds ratio was over 3 for that.

Because that was positive, we could roll alpha to the interim OS analysis, which was pre-planned at the time of PFS. That OS analysis was an interim. In order to be statistically significant, the P value had to be less than 0.0131. With 68% of final OS events having been reached in 13 months of follow-up, we show a 33% reduction in the hazard of death with mirvetuximab versus investigator choice chemotherapy. And that P value was less than that preset boundary.

So, this is a statistically and clinically significant improvement overall survival. That's notable because we have never in the history of platinum-resistant ovarian cancer demonstrated an overall survival benefit with a novel therapy in a phase 3 trial. Ever.

Oncology Data Advisor: Wow, that's incredible.

Dr. Moore: It is an incredible achievement for our patients and really does establish mirvetuximab as the new standard-of-care for this biomarker-selected population.

There were no new safety signals. This drug has been extensively tested and published. We see very, very differentiated safety profiles, really no hematologic toxicity, no alopecia, less neuropathy than with paclitaxel. We do see ocular toxicity that is the notable side effect of mirvetuximab, and it's common. You see about 42% of our patients have some ocular toxicity: keratopathy, dry eye, or blurred vision, predominantly low-grade. And we have very well-established prevention and mitigation strategies in play. It's important. It's something you have to counsel patients about. You have to have an optometrist in the US—ex-US they don't have optometrists, so ophthalmologists—onboard, assessing patients if they need it.

And so it is important. I would never be like, "Oh, it's not a big deal." However, our patients really are able to stay on therapy. Only 4 patients discontinued from mirvetuximab on the MIRASOL study because of ocular toxicity. So, I think it's important; it has to be mitigated, but it's not a barrier to using this medication.

Those are results—first ADC approved in ovarian cancer, first biomarker-directed therapy in platinum-resistant ovarian cancer, and really the first drug to show an OS benefit.

Oncology Data Advisor: That's absolutely incredible, and congratulations on such a successful trial. So, where do you plan on going from here with mirvetuximab? Is it being investigated in other settings?

Dr. Moore: Yes. It's already in clinical trials in the platinum-sensitive recurrent setting. It's an ongoing study called the GLORIOSA trial for full receptor alpha–high platinum-sensitive recurrent disease. Patients get whatever platinum they want with bevacizumab, and then they're randomized to continue the bevacizumab versus bevacizumab plus mirvetuximab with a PFS end point—that's open and accruing.

Then there are some smaller studies looking at in combination with carboplatin to replace paclitaxel. The PICCOLO study is done, which is monotherapy, mirvetuximab in the platinum-sensitive, more heavily pretreated population, not first recurrence, for second or third recurrence, still platinum-sensitive. That's done, and you'll see results of that probably next year.

Oncology Data Advisor: Great. Well, thank you so much for talking about this today. It's so exciting to hear about the trial.

Dr. Moore: Thanks for coming to find me at the poster.

About Dr. Moore

Kathleen Moore is the Associate Director of Clinical Research, Professor of Gynecologic Oncology, and the Director of the Oklahoma TSET Phase 1 Program at the Stephenson Cancer Center at the University of Oklahoma. Additionally, she is a member of ASCO's Cancer Communications Committee. Dr. Moore has spent the plethora of her time as a Gynecologic Oncologist, as well as helping build and expand the framework of Stephenson Cancer Center's clinical trials.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.