Kathleen N. Moore, MD
A potential regulatory approval for mirvetuximab soravtansine could herald increased excitement for antibody-drug conjugates overall in the ovarian cancer paradigm, according to Kathleen N. Moore, MD.
Some of the key takeaways about mirvetuximab soravtansine specifically, she added, is that it is a well-tolerated agent by patients. Physicians, however, need to ensure proper assessment for ocular toxicities, which are inclusive with the therapy.
In an interview with OncLive
, Moore, the Jim and Christy Everest Endowed Chair and associate director of clinical research, associate professor, Section of Gynecologic Oncology Director, Oklahoma TSET Phase I Clinical Trials Program, Stephenson Cancer Center, The University of Oklahoma, discussed the significant unmet needs in the field of ovarian cancer and the recent findings with mirvetuximab soravtansine.OncLive: What are your impressions of the ovarian cancer treatment landscape, and what are the most current significant unmet needs?
: The number 1 unmet need in ovarian cancer is that we cannot screen for it. The second-highest unmet need is [in] finding interventions that cure patients in the frontline setting, which, hopefully, we will see with [the] SOLO-1 [trial], but that will be years to report [on] overall survival. Still, 75% of patients don’t have a BRCA
mutation and have very small hope [for a] cure after frontline therapy. Interventions in the frontline that help [individuals avoid recurrence represent] an incredibly high unmet need. After that, it would just be further development of active therapies for patients with recurrent disease. We have patients who are on their fourth, fifth, and sixth line of chemotherapy who have residual toxicities, so identification of novel assets that are active and tolerable [is important]. Moreover, a biomarker to identify the patients who should or should not receive the drugs would also go along with that. Biomarker discovery is frustrating in ovarian cancer but also incredibly important.
With the recent development of agents targeting folate receptor α (FRα), what are the practical challenges and opportunities associated with introducing a new category of drugs that target a unique receptor such as this?
FRα is a member of the folate receptor family, so it’s a transmembrane glycoprotein that facilitates [the] transport of folate into cells. Importantly, during receptor-mediated endocytosis, when something binds to the folate receptor, the receptor is endocytosed into the cell. In a way, FRα can act as the gate that lets in a Trojan horse. You can fool the receptor into binding something that it maybe should not have bound [to], and then the whole thing is escorted inside the cell to do its damage. That is why FRα has been an attractive target across the board for oncology, especially in ovarian cancer, where about 80% of ovarian cancers will express the receptor at some level with moderate to high expression by immunochemistry in 50% to 60% [of cases], which is pretty prevalent.
One of the challenges will be the question of whether [patients with] just medium or high expression should get folate receptor active drugs, like mirvetuximab soravtansine, or [whether] anybody with any expression [should] receive it. The study that was just done focused only on medium-to-high expressions because we really needed to select the population [who would] most likely benefit, to show efficacy. But if the results are positive, the challenge is deciding whether that is the only group who should receive mirvetuximab soravtansine, or are [we] excluding a group of patients with low expression who would also benefit to some degree? We don’t want to exclude people who would benefit, but we do want to exclude people who would not. I think that we still have to work [that] out with this drug.
There are also issues of tumor heterogeneity. We used archival tissue most of the time in the mirvetuximab soravtansine program. There is a study that is now in the public domain in which we biopsied pretreatment, did archival tissue testing, and found that the concordance was pretty good. We feel comfortable using archival tissue but not [particularly] in someone [who] has had many lines of therapy and many different mutations, if the FRα expression is preserved in all tumor metastases all the time—that’s true of any targeted therapy. There could [also] be spatial heterogeneity. We do not think there is too much temporal heterogeneity, so if FRα was there, it is still there; if it was not there, it is probably not still there, although there may be a little give-and-take, but spatial heterogeneity may be an issue. You do not biopsy every single metastasis in a patient. That is impractical and unethical, but then you see people with these mixed responses where something is shrinking and something is not, so you may assume that the folate receptor expression may differ. This is a challenge, but I think it is one that is difficult to overcome once you are in a recurrent setting. Many studies have tried to do imaging assessment[s] of what metastases are expressing FRα and then using that as a biomarker to select patients who should or should not get vintafolide, an agent that looked very promising in early trials. Unfortunately, in the big phase III study, [vintafolide] didn’t meet the prespecified progression-free survival analysis, and it was stopped. This idea of heterogeneity may be important, but how to overcome it is a bigger problem. Before we worry about that challenge, we need to find a drug that actually works in phase III trials, and, hopefully, mirvetuximab soravtansine will be the one.
Can you talk about the evolution of FRα-targeting agents? Specifically, what makes mirvetuximab soravtansine different from farletuzumab and vintafolide?
Mirvetuximab soravtansine is an entirely different molecule than farletuzumab or vintafolide. Farletuzumab worked through antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity. It was combined with carboplatin and paclitaxel in a platinum-sensitive population in its pivotal trial and, unfortunately, was found to be not as active as we would have liked. Then there are small molecule drugs, where folate is linked to a chemotherapy, which is a very low molecular weight, and the folate itself is directly linked to the chemotherapy; then the folate binds to the folate receptors. This is vintafolide.
is an antibody–drug conjugate that we think is going to have more selectivity to the folate receptor. It is specific to FRα and ignores some of the other folate receptors with physiologic components. You do not want to send chemotherapy into a normal cell, [as] it is homing in on the FRα. Antibody–drug conjugates are engineered antibodies. They are very complex molecules with monoclonal antibodies conjugated to a highly potent molecule chemotherapy. It is called DM4, which is a very potent tubulin-targeting agent.
Mirvetuximab soravtansine is a very different molecule than any of the other folate drugs. In a phase I expansion cohort, it showed a very high and durable response rate, seen in both heavily pretreated and less heavily pretreated patients. Patients [who] respond best [are] those with moderate-to-high folate receptor expressers and [who have had] 1 to 3 prior regimens. [This population has] response rates that are in the 40% to 50% range, which is much higher than one would expect with chemotherapy alone or in combination. The durability was a median of 8 months, which is longer than one would normally expect with standard of care.
Based on clinical trials, what are some of the key takeaways regarding mirvetuximab soravtansine from a patient experience and tolerability perspective?
Patients like this drug thus far. They don’t lose their hair, [and] the neuropathy, if it happens, is after cumulative exposure. There is no bone marrow toxicity, patients feel good on it, [and it] is dosed [only] every 21 days [with] short infusion.
I think the 1 thing that physicians are going to have to get comfortable with is assessing for ocular toxicities that can happen with any antibody–drug conjugate, inclusive of mirvetuximab soravtansine. Physicians [are] very much able to assess and manage the keratopathy that we can see with this drug. Getting comfortable with talking to patients about using their lubricating eye drops and talking about blurred vision [is important] so we can refer them, making sure that we have knowledge of the condition. There will be a couple of steps that will require some training, but these are things that we have worked out the management for and can be quite easily managed in the community or in the academic centers once we do training.
How would you assess the significance of mirvetuximab soravtansine within the broader context of treatment in ovarian cancer if it gains FDA approval?
Antibody–drug conjugates are very exciting. Ovarian cancers, unfortunately, do not have a lot of driver mutations, so we are always looking for more targets. BRCA and RAD51 are the 2 we think we can target right now with PARP inhibitors and DNA damage response drugs, but otherwise there are not many mutations we can target. Ovarian cancers are covered with unique proteins that these antibody–drug conjugates can use to exploit—FRα is one, but many antibody–drug conjugates are in development, some of which have the same chemotherapy on the tails, some of which have different chemotherapy on the tails. This is a new frontier for exploring these highly potent drugs.
The [potential] approval of mirvetuximab soravtansine will, hopefully, herald increased excitement in this class of drugs for development in ovarian cancer. As they are approved, just like everything else, we [will] move them into earlier lines of therapy.