Mirvetuximab Soravtasine-gynx (Elahere)

First-line platinum-based chemotherapy regimens for patients with ovarian cancer usually elicit good responses until resistance develops, requiring a switch to non–platinum-containing regimens. Studies have shown that the addition of bevacizumab to non–platinum-containing chemotherapy regimens can improve progression-free survival in patients with platinum-resistant tumors.¹ However, there is little benefit in terms of overall survival,² highlighting the need for other options.

Mirvetuximab soravtansine-gynx (Elahere) was approved by the U.S. Food and Drug Administration in November 2022 for the treatment of adult patients with folate receptor alpha (FRa)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received prior treatment.³ Identification and measurement of target expression—FRa—is performed with a companion diagnostic assay, also approved in 2022.

Accelerated approval of mirvetuximab soravtansine-gynx was based on results of the SORAYA trial.^{4, 5} The subsequent full approval was supported by the confirmatory data from the MIRASOL trial,⁶ which demonstrated a significant improvement in progression-free survival, overall survival, and overall response rate for patients with FRa-positive, platinum-resistant ovarian cancer.

FRa expression occurs frequently, especially in the common high-grade, high-stage serous ovarian and other epithelial tumors that are most likely to recur.⁷ Mirvetuximab-gynx is a first-in-class antibody-drug conjugate that targets FRa using a humanized monoclonal antibody, and, upon internalization of the antibody, delivers a potent tubulin inhibitor, maytansinoid DM4, via a cleavable linker.⁸

Targeting Folate Receptor Alpha

Based on the FDA label for mirvetuximab soravtansine-gynx, patients with platinum-resistant, high-grade serous ovarian cancer whose tumors are not highly positive for FRa—defined as at least 75% of tumor cells with at least 2+ staining intensity—would not be eligible for treatment with this agent.³ However, the NCCN Clinical Practice Guidelines in Oncology® for Ovarian Cancer additionally indicate that among tumors with FRα expression, mirvetuximab-gynx “may be helpful in certain circumstances.”⁹ Kathleen N. Moore, MD, MS, Professor of Gynecologic Oncology at the University of Oklahoma and Deputy Director/Co-Director of the Cancer Therapeutics Program at Stephenson Cancer Center at Oklahoma University Health, noted that these recommendations provide patients access to a treatment “that may be of benefit in real life.”

Mirvetuximab soravtansine … has some efficacy in tumors with all levels of FRa expression, with the highest efficacy and superiority over single-agent chemotherapy in those tumors found to be FRα-high.”

According to Dr. Moore, who was the principal investigator for the MIRASOL trial, “mirvetuximab soravtansine certainly has some efficacy in tumors with all levels of FRa expression, with the highest efficacy and superiority over single-agent chemotherapy in those tumors found to be FRα-high.” Dr. Moore told JNCCN 360, “Distinguishing tumors that are high expressors carries a predictive expectation of benefit. Using PS2 scoring to identify those tumors that are high expressors of FRa helps guide treatment selection over other options in this setting, which can include weekly paclitaxel, pegylated liposomal doxorubicin, and topotecan, as well as sequencing decisions.”

The importance of accurate measurement of FRa levels was demonstrated in an analysis of an earlier trial, FORWARD I.¹⁰ Although the study did not show a significant benefit of treatment with mirvetuximab soravtansine-gynx overall, Dr. Moore highlighted that “when we went back and re-scored the tumors from participants, those who clearly had high-expressing tumors responded as we would anticipate based on findings from the MIRASOL trial.” She further noted that those tumors that were scored as “medium expressors” still had higher responses (28%) to mirvetuximab-gynx compared with standard-of-care therapies (18%), “but progression-free survival wasn’t that much better.” Furthermore, in those patients whose tumors were re-scored as “low” (< 50% 2+ expression), the response rate was exactly the same as for those who were treated with standard chemotherapy. 

“In summary,” Dr. Moore observed, “the level of FRa expression helps position mirvetuximab soravtansine among available treatment options—in terms of predictive value—along with other variables, such as what the patient has already received and what is available for use moving forward.”

Advantages of Antibody-Drug Conjugates

Antibody-drug conjugates have a differentiated safety profile compared with systemic chemotherapy, Dr. Moore said, also noting that second-, third-, and even fourth-generation molecules are currently in development. “We are hopeful that antibody-drug conjugates are more efficacious because of the higher dose levels of the cytotoxic components in these molecules hitting the tumor more directly,” she said.

Nevertheless, Dr. Moore stressed that antibody-drug conjugates are “still systemically delivered chemotherapy. With standard chemotherapy, you can’t really dose up to the highest tumoricidal levels, because the systemic toxicity to the host is too high.” Dr. Moore cautioned that “we can’t yet administer these antibody-drug conjugates with no collateral damage.… We haven’t yet discovered the magic bullet.”

In an interview with JNCCN 360, Danna Michelle Markides, MD, Assistant Professor of Emergency Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, described the differences between standard chemotherapy and antibody-based treatment. “Traditional chemotherapy targets how quickly a cell divides. The problem, of course, is that systemic chemotherapy also hits every rapidly dividing cell, including off-target ones, such as skin, hair, and the gastrointestinal system. With targeted therapies,” she continued, “the antibodies are able to focus on antigens that are overexpressed on tumor cells.” Reiterating Dr. Moore’s observation that these drugs are not perfect, Dr. Markides observed, “Every cancer cell is still your own cell ‘gone bad.’ Sometimes the toxins can leak out. That can be a good thing, if the toxin hits some cancer cells within the tumor that don’t harbor the antigen, such as FRa, in the case of mirvetuximab soravtansine.” On the other hand, some nontumor human cells will have the target antigen, “so the targeting is never going to be perfect.”

Safety Profile and Toxicity Management

In the Emergency Department (ED) at MD Anderson, Dr. Markides primarily sees patients with cancer. “The bar for seeking immediate assessment is quite low because patients with cancer have so much that could potentially go wrong,” Dr. Markides commented. She further explained that “it is often difficult for the cancer care team to get a handle on what is going on or how bad it is over the phone, so when in doubt, they will often recommend an emergency visit, especially at night or on weekends.”

Patients with cancer tend to be well informed about their condition and treatments, Dr. Markides told JNCCN 360. However, some adverse events associated with mirvetuximab soravtansine-gynx, such as ocular disturbances, are less common in oncology settings. Although oncologists are familiar with preventing and managing toxicities of standard chemotherapy regimens, dealing with ocular issues may require additional education for the care team.

Our patients tolerate a lot from us … in the effort to help them stay alive longer. But disturbing someone’s vision is very frightening—and for some patients, it’s a dealbreaker.”

According to Dr. Moore, the FDA label is very clear on the mitigation strategies and monitoring for ocular disturbances related to treatment with mirvetuximab soravtansin-gynx.¹¹ “Our community is following those guidelines very closely because preservation of patients’ vision is important both to our patients and to us,” she explained. “Our patients tolerate a lot from us (eg, neuropathy, hair loss, skin rashes) in the effort to help them stay alive longer. But disturbing someone’s vision is very frightening—and for some patients, it’s a dealbreaker.”

Preventing and Managing Ocular Issues

In the MIRASOL trial, in addition to standard protocols that may include acetaminophen, dexamethasone, and diphenhydramine, prophylactic glucocorticoid eye drops were initially given six times daily (on days -1 to 4) and four times daily thereafter (on days 5 to 8 of each cycle). Additionally, daily use of preservative-free lubricating artificial tears was mandated.¹²

“My patients are very fortunate,” Dr. Moore said, because “we have an outstanding Eye Institute [Dean McGee Eye Institute] right across the street. But even in parts of the country without ophthalmic research centers, the recognition of eye-related side effects related to mirvetuximab soravtansine use across the eye care professional (ECP) community has been robust and impressive—and has improved access to this treatment as a result. In a broader sense, there has been a growing cooperation between the medical oncology and ECP communities as our arsenal of medications expands and sometimes requires ophthalmic expertise. Also, ocular disturbances aren’t all the same. They may vary by posterior chamber/anterior chamber, with overlapping but differing toxicities.”

The recognition of eye-related side effects related to mirvetuximab soravtansine use across the eye care professional community has been robust and impressive—and has improved access to this treatment as a result.”

For gynecologic oncologists, ocular issues are not entirely novel. “For instance,” Dr. Moore told JNCCN 360, “we have been using tisotumab vedotin for patients with cervical cancer.¹³ With that drug, the patient has to see an ECP for every treatment cycle.” Although the actual toxicities and treatments are different with tisotumab vedotin-tftv, the need to manage ocular issues is not new, she pointed out. Treatments may include steroid eye drops, constricting eye drops, and cooling packs.

Of interest, Dr. Moore observed that quality-of-life assessments indicate that there were no significant differences in symptom burden and sense of well-being among patients in the MIRASOL study who developed ocular symptoms vs those who did not.¹² “Some of these results are dependent on the timing of when we asked patients about these symptoms,” Dr. Moore continued. “Nevertheless, these issues are quite short-lived; once they are treated and resolved, the patient is essentially fine. So, that was reassuring,” she told JNCCN 360.

Dr. Markides observed that patients receiving mirvetuximab soravtansine-gynx for advanced ovarian cancer are rarely seen in the ED with ocular issues. “This is because preventive strategies are generally well followed and effective. Patients are aware of and prepared for the development of dry eye, a bit of blurry vision, and/or irritation,” she said. Nevertheless, keratitis can become severe, so if the reaction is intense, where the eye is highly inflamed and painful, a visit to the ED may be considered. “I would treat it as I would any case of keratitis. If I saw deep ulcerations, severe pain, or a pressure difference, then an ophthalmology consult might become urgent to emergent.” She also offered that steroid drops might be tried in the ED, “to see whether they make things better” and can provide enough relief to allow the patient to visit the ophthalmology office when it opens.

Other Adverse Events

Dr. Markides noted that hematologic adverse effects (ie, neutropenia, anemia, thrombocytopenia) occur rarely in patients treated with mirvetuximab soravtansine-gynx, and generally would not be severe enough to land them in the ED. Interstitial pneumonitis is also not a common adverse effect; incidence is about 10%, with only about 1% of treated patients developing a grade 3 or greater condition. “Grade 1 is basically a computed tomography scan finding, whereas grade 3 will probably require hospitalization,” she explained. 

The critical issue is distinguishing between pneumonitis and pneumonia, because treatments differ. “Even though I recognize that this may be a case of pneumonitis,” Dr. Markides stated, “I would usually start treating for pneumonia because all the findings will take some time to come in. If we don’t get antibiotics into the patient quickly, she may do worse, whereas if they are started and turn out not to be necessary, we can stop them. We can’t go back in time to start the antibiotics earlier,” she stressed. Once something like pneumonitis has been confirmed, the initial treatment will be with steroids.

Sequencing Strategies

A general approach to treating patients with advanced-stage malignancies, Dr. Moore said, is that “we try to alternate therapies so that there is recovery from certain types of adverse events, and patients are not subjected to the same toxicities in each treatment cycle. We try,” she emphasized, “to keep patients healthier for longer by not exposing them to repeated insults to bone marrow, for instance.”

The ‘Drop-Off’ Phenomenon

Delving further into the sequencing question, Dr. Moore focused on the phenomenon of "drop-off". She explained that “if the probability that a patient will be healthy enough to receive a subsequent line of therapy is less likely, it may behoove us to use our best treatment option upfront, even if it diminishes the potential efficacy of a next-line option. In other words, if you try to ‘save’ your best treatment for a subsequent line, you may never get there.”

Best Drug First? Or Saving the Best for Last?

With the goals of extending progression-free survival and helping patients live longer, Dr. Moore told JNCCN 360, “We try to go with the adage of using our best drugs first, which makes a lot of sense. Nevertheless, if a tumor recurrence after treatment with the best drug means that the next-best drug isn’t going to work anymore, would it have been better to have reversed the order?” she asked. “That would allow,” she explained, “both drugs to have been used and potentially a longer survival.” The bottom line about prioritizing and sequencing therapies, Dr. Moore concluded, comes down to the “likelihood of patients being healthy enough to get that next line of therapy.”

[To better understand sequencing,] we may have to start paying attention to biomarkers, levels of biomarkers, and mechanisms of resistance along with adverse event profiles, cumulative toxicities, and patient experience.”

These questions were not critical in gynecologic oncology until recently, because “we never had drugs that worked very well in the recurrent disease setting, and ineffective medications are ineffective whatever order you used them in.” Now, with antibody-drug conjugates and other targeted therapies, Dr. Moore explained that “mechanisms of resistance may become important for how we sequence these medications, especially as we start moving some of these options into front-line and platinum-sensitive settings.” To better understand sequencing, “we may have to start paying attention to biomarkers, levels of biomarkers, and mechanisms of resistance along with adverse event profiles, cumulative toxicities, and patient experience.”

In conclusion, Dr. Moore commented, “the future is looking brighter for patients with advanced ovarian cancer. There are so many new medications in development, in addition to mirvetuximab soravtansine, that will push us to really figure out how to individualize treatments based on patient and tumor-based features.”

Disclosures

Kathleen N. Moore, MD, MS, has served as a consultant or on advisory boards for AbbVie, AADI, AstraZeneca, Blueprint Medicines, BioNTech, BeOne (formerly BeiGene), Corcept Therapeutics, Caris Life Sciences, Daiichi Sankyo, DualityBio, Eisai, Genmab, GSK, ImmunoGen, Iovance Biotherapeutics, Janssen Pharmaceuticals, Loxo/Lilly, Merck, Mersana Therapeutics, Novartis, Regeneron, Schrödinger, Takeda Pharmaceuticals, Verastem Oncology, and Zymeworks; has given educational talks for Research to Practice, PRIME, Clinical Education Alliance, Clinical Care Options, and Great Debates and Updates; and serves as Associate Director for GOG Partners and is on the GOG Foundation and ASCO Board of Directors.

Danna Michelle Markides, MD, reported no potential conflicts of interest.

References

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