Kathleen N. Moore, MD, MS, on Groundbreaking Result in MIRASOL: “This Is What Patients Want”

In November 2022, FDA granted accelerated approval for mirvetuximab soravtansine-gynx (Elahere) for adult patients with folate receptor alpha (FRα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, for those previously treated with 1 to 3 systemic regimens. That approval was based SORAYA (NCT04296890), a single-arm trial of 106 patients.^1,2

mirvetuximab soravtansine-gynx

Along with mirvetuximab soravtansine, FDA approved the Ventana FOLR1 RxDx Assay as a companion diagnostic device to select patients who meet treatment criteria.¹

Would the phase 3 MIRASOL trial (NCT04209855) confirm the efficacy and safety seen in SORAYA? On June 4, 2023, attendees at the American Society of Clinical Oncology (ASCO) Annual Meeting got their answer and the results did not disappoint: The trial produced the first overall survival benefit ever seen in phase 3 trial for platinum-resistant ovarian cancer.³

Kathleen N. Moore, MD, MS, professor of gynecologic oncology, associate director of clinical research and codirector of the Cancer Therapeutics program at the Stephenson Cancer Center at the University of Oklahoma, presented data showing a 35% reduction in the risk of disease progression or death compared with investigator’s choice of chemotherapy in patients with FRα-high, platinum-resistant ovarian cancer. Following ASCO, Evidence-Based Oncology™ (EBO) spoke with Moore about the findings and what’s next for mirvetuximab soravtansine.

The following has been lightly edited for clarity and length.

EBO: Can you describe the mechanism of action of mirvetuximab soravtansine?

Moore: Mirvetuximab soravtansine is an antibody drug conjugate. Many of these are already FDA approved in solid tumors, and many are under development in gynecologic cancers. As a class, they are composed of a monoclonal antibody, which will target a tumor-associated antigen that has the potential to bind the molecule as well as internalize it, mainly through a process of endocytosis of a tumor-associated antigen [that] is actually quite important in that it does have the capability to internalize the molecule.

The molecule is conjugated by very sophisticated linkers, which are either cleavable or noncleavable. This is a cleavable linker to a cytotoxic payload. In this case, the cytotoxic payload is maytansinoid or DM4, which is a very potent microtubule toxin.

So this particular monoclonal antibody binds folate receptor α, which is highly expressed in predominantly hybrid serous ovarian cancer, but highly overexpressed in about 35% to 40% of cases, but it exists in like 80%. And it does have that capability to internalize. So the molecule binds, gets internalized, goes through 2-step endocytosis, during which the cytotoxin is cleaved and then hopefully kills the cancer cell, and then the cancer cell dies. Also, because it’s hydrophilic, it can get into kind of surrounding cancer cells—even if they don’t have folate receptor α high—and kills them as well, in a mechanism called the bystander effect. So there’s a direct tumor-killing effect and then a bystander effect that contribute to the efficacy of mirvetuximab soravtansine.

EBO:That bystander effect—that is the same effect we heard about last year during ASCO with trastuzumab deruxtecan in DESTINY-Breast04?

Moore: Yes, that’s another antibody drug conjugate, with a very different target and a different payload, but it’s the same class of drugs.

EBO: Can you discuss the importance of the overall survival results that you presented during ASCO?

Moore: The importance of the overall survival benefit seen in the MIRASOL study is, No. 1, that there’s an overall survival benefit that is clinically and statistically significant. This is what patients want—to be cured—and we want to cure them. But until then, they want to live longer; they want to live as long as possible. And so we’ve shown that treating with mirvetuximab soravtansine in this clinical setting does extend overall survival. The greater significance of this finding is that it’s never been shown before in ovarian cancer in the platinum-resistance setting, in a phase 3 study of a novel agent. We have never in the history of ovarian cancer shown an overall survival advantage of any kind.

In fact, one of my European colleagues pointed out when I made that statement in a practice session, he said, well, actually there is a study that showed an overall survival benefit, but it shows for the control arm. So in whatever experimental study they had open, the experimental arm did worse; the patients who had standard of care did better. That’s just how lacking we’ve been in anything that has improved overall survival for decades. It’s an achievement in and of itself that we’ve finally done that. And it’s done with a targeted therapy—an individualized therapy given at the right time, to the right patient. Hopefully we’ll see more of this moving forward.

EBO: Can you elaborate on the safety and quality-of-life results for mirvetuximab soravtansine vs what we typically see with chemotherapy?

Moore: MIRASOL does have a formal patient-reported outcome end point, and [these results] will be presented at a future congress. From a safety standpoint, the results of MIRASOL were very similar, almost identical to what we presented with prior studies. In SORAYA we saw almost no hematologic toxicity; [there was] very little and if we see it, it’s low grade, no alopecia, [with] less neuropathy than the most appropriate comparator, which would be paclitaxel. The neuropathy tends to be later in onset, so it’s a little bit different than what we see with paclitaxel. We do see nausea and diarrhea—it’s similar rates [to what] we see with investigator’s choice chemotherapy—and as with all, they all tend to be low grade and have mitigation strategies that are very effective.

The class toxicity of mirvetuximab is the ocular disorders, which are common. About 42% of participants will have some constellation of ocular disorders, which could include dry eyes or blurred vision, and/or blurred vision, and/or keratopathy. Patients may have more than one. These happen usually early, within cycle 2 about 6 weeks in. We have prevention and mitigation strategies in place that make this largely reversible; in fact, I would say 100% reversible, from my experience and not repetitive. So it’s not an ocular toxicity that’s ongoing throughout the patient’s experience; with mirvetuximab it occurs, you mitigate it, and then for the vast majority of patients, this does not happen again.

Only 4 patients on MIRASOL discontinued from therapy because of the ocular toxicity. Over the whole experience of mirvetuximab, for patients at the recommended phase 2 dose to 6 mg/kg every 3 weeks, it’s about 1.5% of patients who will discontinue because of ocular toxicity. So I would say that counseling is important—it’s a big part [with] this agent. Eye drops are required as well as ophthalmologic exams every other cycle until the eighth cycle. It can be frightening for patients if they’ve not been counseled about it [so] they know what to do. But I believe that with appropriate expectation setting and mitigation strategies, we’ll see what we’ve seen in the trials, which is that for the vast majority of patients it’s acceptable, and we’re able to keep them on study, although we’re continuing to look at ways to try and mitigate this further.

EBO: Since this therapy was approved, have there been any issues with access to testing (the Ventana Assay) that patients need to determine if they are candidates for this therapy?

Moore: There were some issues early on; I believe they have been resolved. When the medication was first approved in November, there was a lot of planning that went into that launch, with multiple labs ready to do the testing as it came in. A lot of thought went into that, and I think the demand just far exceeded what was expected. Several of the vendors ran out of [assay] kits for a period of time, so it did delay testing for some patients early on. That was really an early 2023 issue, but it has since resolved. Everyone was catching up their patients…. We’re starting to see things even out.

Another thing that I believe is still in place is that testing is done centrally, through a number of vendors, some of which provide [next-generation] sequencing as well; you have Caris as an example. If a patient had already had next-generation sequencing prior to this, there was a concern about financial toxicity of sending another big test just to get the folate receptor α testing. ImmunoGen worked with the Caris lab; [the testing] was getting invoiced to the company for a period of time in those situations so that patients didn’t incur a bill for that particular test—it was just the [individual assay] that was run, [not] the next-gen sequencing; the whole panel wasn’t sent. These were the kind of quick pivots by ImmunoGen and the vendors who are participating to make sure that the kits were distributed, so they could do them and also so that we could test patients in a way that wasn’t going to be financially harmful to them. That’s really allowed widespread testing. Now it will be included in a lot of the panel tests, so you don’t have to ask for it separately.

EBO: Is there anything we haven’t covered that you’d like to add?

Moore: We hope that MIRASOL leads to confirmed approval. As you know, the SORAYA approval was an accelerated approval, so [the therapy] is available in the United States—which is great, but that leaves out the rest of the world. I’ve had patients in Europe emailing me wanting to test and get access. SORAYA was done in parts of Europe, so patients know about this, and they want it. So I’m very hopeful that MIRASOL leads to a relatively rapid approval of testing and access in the rest of the globe for women. We’re excited about that potential. And we’re excited to have a new medicine available to women that’s well tolerated, that works and not only improves progression-free but also overall survival and response rate. All these are important points for our patients to live longer and hopefully feel better. It was just a win across the board.

References

1. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. News release. FDA. November 14, 2022. Accessed June 20, 2023. https://bit.ly/42KlWCE
2. Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. doi:10.1200/JCO.22.01900
3. 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. J Clin Oncol. 2023;41(suppl 17):abstract LBA5507. doi:10.1200/JCO.2023.41.17_suppl.LBA5507