Refined Definition of Platinum Resistance, Novel ADCs Could Bring More Changes to Ovarian Cancer Treatment

Kathleen N. Moore, MD, MS

The treatment paradigm for platinum-resistant ovarian cancer has advanced with the integration of therapies like mirvetuximab soravtansine-gynx (Elahere); however, improved definitions for platinum resistance and the development of other antibody-drug conjugates (ADCs) could also create more shifts in this treatment paradigm in the future, according to Kathleen N. Moore, MD, MS.

“With additional data, we're about to change a lot of these paradigms for the betterment of patients [by providing a] better selection of drugs,” Moore said in an interview with OncLive^®.

In the interview, Moore discussed how mirvetuximab soravtansine has altered the ovarian cancer treatment paradigm, expanded on the evolving definition of platinum resistance, and highlighted other ADCs currently under development.

Moore is a professor in the Section of Gynecologic Oncology, associate director of Clinical Research at Stephenson Cancer Center, and director of the Oklahoma TSET Phase I Program at the University of Oklahoma College of Medicine in Oklahoma City.

OncLive: How has the treatment landscape evolved for patients with platinum-resistant ovarian cancer?

Moore: The treatment paradigm for patients whose tumors are no longer expected to respond to platinum has changed somewhat. However, it is about to change much more with [various] trials that are expected to read out.

[First], the definition for [which] patients are [considered platinum-resistant] is under some evolution. [The definition] used to be very strict, and it still is from a regulatory standpoint, referring to patients whose tumors progress within 6 months of their last platinum[-based treatment]. That's still a regulatory requirement, but I do think that there's an increasing understanding; that is not the absolute definition of tumors that are probably inappropriate for platinum. It also includes patients who received platinum, and the tumor didn't shrink at all. Maybe they were on some kind of maintenance therapy, [such as] bevacizumab [Avastin], and [the tumor] didn't grow for eight months. That tumor is not platinum-sensitive, as it did never respond to platinum.

There's an increasing understanding of these nuances, [and ineligibility also includes] patients who have allergies to platinum and can't receive platinum anymore. There is also a group of tumors that have progressed during PARP inhibitor maintenance and are still considered platinum-sensitive because of the length of time from their prior platinum, but we are starting to understand that some of these tumors respond less robustly to platinum. They're not entirely resistant, but they're not as sensitive as we might otherwise think, and we may be looking at differently at those tumors, as well. The definitions are shifting as we get more definitive data in those spaces.

What have been some of the other key updates in the advanced ovarian cancer space?

We have had 2 important [developments] in the past year to 2 years. The first is mirvetuximab soravtansine, which is now fully FDA approved and is pending global approvals for patients whose tumors are platinum-resistant and are folate receptor–alpha [FRα] high.

In the United States, the National Comprehensive Cancer Network [NCCN] Guidelines allow for the use of mirvetuximab soravtansine plus bevacizumab in FRα-expressing tumors. That's based on the data from [the phase 1b] FORWARD II trial [NCT02606305]. [Mirvetuximab soravtansine] is the first [ADC] to gain approval and a compendium listing in the NCCN Guidelines for ovarian cancer, and it has been a great addition to the armamentarium, at least in the FRα-high population as a monotherapy, [where we have seen] improvements in progression-free survival, overall survival [OS], and overall response rate [ORR]. We've never seen improvements in OS in this setting, so that's a big accomplishment.

The second is a little less [eye-catching] but it is also important, and that is the fact that we have pulled out weekly paclitaxel with or without bevacizumab as a very different agent for the platinum-resistant setting. It used to be lumped into these investigator choice arms, and you'd have this historical benchmark of expectations of response of about 15%. However, weekly paclitaxel has been looked at alone in 3 big phase 3 studies that have read out.

One trial [NCT03398655] was the VBL gene therapy. Another study [INNOVATE-3 (NCT03940196)] investigated tumor-treating fields, and [the other] one was [the phase 3 AXLerate-OC trial (NCT04729608)] of batiraxcept (AVB-S6-500)]. All of these [studies] added a new drug to weekly paclitaxel vs weekly paclitaxel alone, and all 3 of those studies were negative. All 3 of those studies showed the impressive performance of weekly paclitaxel, with ORRs [ranging from] 30% to 50%.

Mirvetuximab soravtansine and weekly paclitaxel [represent] new drugs into the armamentarium. [Regarding the latter], weekly paclitaxel [may be a preferred regimen] in the eyes of treating physicians as the preferred regimen. I would call it the preferred regimen for anyone who's FRα low or medium. I would use that potentially first, and it would be my go-to after I use mirvetuximab soravtansine. That’s how I would sequence those medications.

That's important for patients and for providers to understand. Weekly paclitaxel and docetaxel are entirely different agents from an efficacy standpoint. There are differences in adverse effects, scheduling, and things that go into shared decision-making, and those are important for patient-centered care. However, purely from an efficacy standpoint, [paclitaxel and docetaxel] are very different agents.

What other ADCs are under development for patients with ovarian cancer?

We're [also] going to see several ADCs with different targets, different payloads, and different linker technology [move into] late-phase clinical trials in ovarian cancer. One is raludotatug deruxtecan [DS-6000], which targets CDH6, and it has a deruxtecan payload. That drug is in phase 2/3 testing right now. The other is rinatabart sesutecan [PRO1184], which is another FRα[-targeted] ADC with an exatecan payload.

These are camptothecin payloads, which are different than microtubule toxin payloads like mirvetuximab soravtansine. These are distinctly different agents, and you could see a patient potentially getting [these agents] in sequence. There are a number of other [ADCs] that are a little bit farther behind [in development]. We just saw readouts in the phase 1 expansion cohorts for several of the TROP2-directed ADCs, and we saw [promising data for] TORL-1-23, which [targets] Claudin-6 with another microtubule toxin [payload].

There are a number of [ADCs] that are vying for a spot in the [ovarian cancer treatment] paradigm. We're going to see some big shifts in the sequencing of these medicines in the platinum-resistant space, and we will also see the incorporation of some of these medications into earlier lines of therapy. [The] platinum-sensitive setting is a space I'm interested in putting something head-to-head with platinum to see if platinum really is the best agent in that particular setting. We don't know yet, and that requires a trial. However, that’s a space I'm interested to look at, and many are interested in studying these [ADCs] as maintenance [therapy], which is an exciting opportunity, but it comes with some questions about tolerability of long-term use, potential resistance mechanisms, and how the sequencing of drugs will look [in later lines]. There's a lot of excitement about ADCs moving forward across the treatment paradigm, not just in the resistance setting.