Precise Targets and Drug Sequencing Potential Characterize the State of ADCs in Ovarian Cancer

The emergence of antibody-drug conjugates (ADCs) in the ovarian cancer treatment paradigm has highlighted the importance of understanding individual patients’ biomarker expression and engaging in multidisciplinary collaboration, according to Kathleen N. Moore, MD, MS.

“As more of these [ADCs become] available, a full understanding of the molecular settings in which these medications work, along with their toxicities, will be important for selecting which of the drugs I’m going to use in a schedule,” Moore said in an interview with OncLive® during the 2025 SGO Winter Meeting.

In the interview, Moore discussed the clinical relevance of the full FDA approval of mirvetuximab soravtansine for patients with folate receptor α (FRα)–positive, platinum-resistant ovarian cancer; ongoing clinical trials of novel ADCs in gynecologic oncology, such as those targeting FRα and HER2; and the complexity of this class of agents, the use of which necessitates considerations of toxicity management and the differing clinical contexts between malignancies.

She highlighted the importance of considering FRα expression in patients with ovarian cancer based on findings from the pivotal phase 3 MIRASOL trial (NCT04209855) of mirvetuximab soravtansine-gynx (Elahere) in adult patients with FRα-positive, platinum-resistant disease who have received between 1 and 3 prior systemic treatment regimens. In this study, patients who received the ADC achieved a median overall survival (OS) of 16.5 months (95% CI, 14.5-24.6) vs 12.7 months (95% CI, 10.9-14.4) in those treated with chemotherapy (HR, 0.67; 95% CI, 0.50-0.88; P = .0046).1

She also emphasized the need for continued evaluation of HER2-directed ADCs based on positive findings from the gynecologic cancer cohorts of the phase 2 DESTINY-PanTumor02 trial (NCT04482309), which supported the first tumor-agnostic FDA approval of a HER2-directed therapy, fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of patients with unresectable or metastatic HER2-positive solid tumors.2 In the cohorts of patients with endometrial (n = 40), cervical (n = 40), and ovarian (n = 40) cancers across all HER2 immunohistochemistry (IHC) expression levels, the overall response rates (ORRs) with T-DXd were 57.5%, 50.0%, and 45.0%, respectively. These respective ORRs were 84.6%, 75.0%, and 63.6% among patients with HER2 IHC 3+ disease. Additionally, these ORRs were 47.1%, 40.0%, and 36.8%, respectively, among patients with HER2 IHC 2+ disease.3

Moore is the associate director of clinical research at the Stephenson Cancer Center, as well as the director of the Oklahoma TSET Phase I Program and a professor in the Section of Gynecologic Oncology at The University of Oklahoma Health Sciences College of Medicine.

OncLive: How has the full FDA approval of mirvetuximab soravtansine for the treatment of patients with FRα-positive, platinum-resistant ovarian cancer changed the clinical care of these patients?

Moore: I’m proud of the approval of mirvetuximab soravtansine. We had the accelerated approval [of this agent in this indication] in the United States, but now we have full approval based on [data from] MIRASOL. MIRASOL proved what many of us who worked with mirvetuximab soravtansine for many years believed: it’s a highly efficacious medication and is superior to standard-of-care options in later lines of therapy.

The other big point from MIRASOL is that it met its primary end point, which was progression-free survival [PFS]. In the phase 3 FORWARD I trial [NCT02631876], we saw signals that there might be an OS benefit [with mirvetuximab soravtansine vs chemotherapy] in the FRα-high population. [However], that was an exploratory evaluation of a negative trial. Often, those exploratory end points don’t materialize when you study them formally.

[In MIRASOL], they did. [Patients in MIRASOL with FRα-high disease] had statistically significant improvements in PFS and OS [with the ADC vs chemotherapy], which, although modest, are important for patients. [Mirvetuximab soravtansine] provides another therapeutic option. If we keep developing therapeutic options, we will continue to prolong OS.

It’s been exciting to see this approval. It’s been exciting to see the uptake [of the agent] in the community. People are active in learning about the medication and have enthusiastically embraced learning about the mitigation of eye toxicities [with the guidance of] eye care professionals. Ophthalmologists and optometrists are trying to understand how to screen patients [who are] about to start [treatment with this agent], how to do ongoing surveillance, and how to assess toxicities. That’s exciting to see as well. These ADCs require multidisciplinary, team-based care, and this [has been] coming to fruition with [the clinical use of] mirvetuximab soravtansine, which has paved the way for [evaluating and managing] different toxicities with other ADCs, as they either do or don’t make it across the [approval] finish line.

There are several new FRα-directed ADCs in development. Although not all of these will gain regulatory approval, what might success look like with these agents?

We have a lot to learn. There are many ADCs that target FRα that are under development. One of them, Luveltamab tazevibulin [STRO-002], is a microtubule toxin. However, that drug is chemically different from mirvetuximab soravtansine, so it needs to be evaluated as its own entity, and [we need to] see how its clinical trial results. [The agent has] now moved into phase 3 [testing].

Rinatabart sesutecan [PRO1184] is also in phase 3 testing. That’s a completely different drug. It has an exatecan payload.

What I’d like to see with any of these ADCs is efficacy and a clear interrogation of whether the biomarker expression is important, [for determining whether the drug works, as well as for answering the question]: Does the level [of biomarker expression] dictate the level and duration of efficacy? As we [develop] multiple [ADC] options, understanding the breakdown [of biomarker expression may] become important. If it’s not important, then it’s not important, and I want to know that, but I don’t want [these ADCs] all lumped together.

Then, hopefully we’re going to understand mechanisms of action, which I have overly simplified as a Trojan horse delivering chemotherapy. That is true, but the true activity of these medications may be dependent on that or on activity in the tumor microenvironment, which has been understudied. I’m looking for active, well-tolerated medications that don’t bankrupt patients and provide even more OS benefit [than currently available agents]. I’m also looking for a lot more correlative and translational data to help us understand the best place and time to use [these agents]. I think we’ll get there.

Of the other ADC targets that are currently understudied in gynecologic oncology, is it too early to say whether biomarker expression level is tied to response?

For mirvetuximab soravtansine, it clearly is. The caveat is that it works well in FRα-medium disease. It doesn’t work well by itself in FRα-low disease, but [its activity is not limited to FRα-high disease]. We haven’t seen enough data from the TROP2-directed ADCs yet for me to be convinced that [biomarker expression] doesn’t matter. The data that were shown at [the 2024 ESMO Congress] were highly exploratory in small numbers and indicated that at least H-score was important. However, again, these were incredibly small numbers to make definitive statements.

We will see data on CDH6 with the raludotatug deruxtecan [R-DXd; DS-6000] program, both with archival and pretreatment biopsies. [A phase 1 trial (NCT04707248) investigating R-DXd] enrolled an all-comer population [of patients with ovarian cancer and demonstrated] nice responses [with the agent]. Do we need to know the biomarker? We’re going to know from that robust, randomized phase 2 [REJOICE-Ovarian01] trial [NCT06161025] that’s now completed accrual. We’ll see what the results look like. That’s exciting.

[Regarding the target] B7-H4, we have no data yet. That’s quite early [in development]. [Regarding the target] claudin 6 [CLDN6], in the [phase 1 TORL123-001 trial (NCT05103683)] data from Gottfried Konecny, et al. with TORL-1-23, the CLDN6-positive tumors had the highest response [with the ADC]. We’ll see whether there are different cut points [regarding the importance of biomarker expression] as that medicine continues to develop that may be informative for response.

We haven’t studied HER3 [much] yet, [nor do we know much about] HER2. [The HER2-directed ADC T-DXd] did phenomenally well in the small numbers [of patients with HER2 IHC 3+ gynecologic cancers] that we saw in DESTINY-PanTumor02. I would like to see more data. The data for [T-DXd in patients with] HER2 2+ disease showed nice response rates for a short duration, but again, these were tiny numbers, so I don’t know that we fully understand even how to score HER2.

With HER2 and FRα, we have the most preliminary data. For FRα, [we have] more than preliminary [data to show] that expression level matters. For the other [targets, we have] just inklings [of the importance of expression level]. That’s going to be important to determine as these medications move forward in development.

There are 2 open clinical trials of TROP2-directed agents in endometrial cancer. One is [a phase 3 trial (NCT06132958) investigating] sacituzumab tirumotecan [SKB264/MK-2870], which has a belotecan payload targeting TROP2. The other is [the phase 3 ASCENT-GYN-01 trial (NCT06486441) evaluating] sacituzumab govitecan-hziy [Trodelvy] targeting TROP2. Both [trials are] in all-comers, with patient stratification by biomarker level that’s not in the public domain. [These agents are being compared with] inferior controls: doxorubicin and weekly paclitaxel. We’ll see what those studies look like.

I’ve learned not to [predict trial outcomes] because I’ve been wrong more times than I’ve been right. [However, if these trials are] positive, that’s great. [Those agents will have beaten] inferior control arms. [Then, we would need to see whether those ADCs are more effective] than rinatabart sesutecan, which has data in endometrial cancer, as well as [more effective than] B7H4–directed agents. Those are going to be the real questions.

[It will be important to see] more active agents [being studied] head to head; I don’t care if [they are more effective] than doxorubicin. Most agents are better than doxorubicin. I do care to know if [an agent is more effective] than T-DXd in HER2 2+ [disease]. I don’t know that yet. I want to know the toxicities and how patients feel when they’re receiving these medications. We have a bit of work to do to understand how these drugs are working.

Endometrial cancer and ovarian cancer are totally different disease types. [Studying ADCs in the] context of endometrial cancer is going to be critically important. In ovarian cancer, the context is important. [However, in] endometrial cancer, [different tumors have] no specific mutation profile vs a TP53 mutation, [for example]. Will a camptothecin payload work the same in both of those [populations]? I don’t know. I’d bet no, but I may be wrong there. I would like to know that. The molecular context is going to matter in endometrial cancer perhaps more than it does in ovarian cancer. We have to sort all this out, and we will. However, going forward, we need to start doing better than [trials that study ADCs] vs a terrible control arm in all-comer populations.

References

1. FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. FDA. March 22, 2024. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant-epithelial-ovarian
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
3. Enhertu demonstrated clinically meaningful survival across multiple HER2-expressing advanced solid tumours in DESTINY-PanTumor02 phase II trial. News release. AstraZeneca. October 23, 2023. Accessed February 11, 2025. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-survival-across-multiple-her2-expressing-advanced-solid-tumours-in-destiny-pantumor02-phase-ii-trial.html