As ADC Options Expand, Sequencing and Toxicity Management Become the Next Challenges in Gynecologic Oncology

During the 2026 ASCO Annual Meeting, a panel of gynecologic oncology specialists convened for a live OncLive® Scientific Interchange and Workshop to examine the rapidly expanding landscape of antibody-drug conjugates (ADCs) across cervical, ovarian, and endometrial cancers. This included the 3 FDA-approved agents now in clinical use, alongside a robust investigational pipeline targeting folate receptor alpha (FRα), cadherin-6 (CDH6), TROP2, HER2, and beyond.¹

Faculty agreed on one foundational premise: the field is no longer asking whether ADCs work, but rather how to sequence agents with overlapping payloads and how to manage a constellation of distinct toxicities in patients who will likely receive multiple ADCs across their treatment course.

“We’re going to be able to talk about this for the next 5 or 6 years at least based on what’s coming out,” moderator Brian Slomovitz, MD, director of Gynecologic Oncology at Mount Sinai Medical Center and professor at Florida International University in Miami Beach, stated.

What is the current status of tisotumab vedotin and mirvetuximab soravtansine in practice?

Tisotumab vedotin-tftv (Tivdak) was granted full FDA approval in the second line for recurrent or metastatic cervical cancer in April 2024 based on data from the phase 3 innovaTV 301 trial (NCT04697628).² In this trial, tisotumab vedotin (n = 253) produced a median overall survival (OS) of 11.5 months (95% CI, 9.8-14.9) compared with 9.5 months (95% CI, 7.9-10.7) with chemotherapy (n = 249; HR, 0.70; 95% CI, 0.54-0.89; P = .0038). Although this agent is used by most faculty as second-line therapy, it was viewed as the ADC most likely to be displaced.¹ Fatigue requiring dose reduction, neuropathy, and the mandated ophthalmology exam cadence were the principal tolerability challenges cited by panelists.

“This is the first ADC I hope gets knocked off the podium. The response rates just aren’t what we’re seeing with the other ADCs. I’m going to be excited when we have something to replace this,” said Tiffany Redfern, MD, FACOG, a gynecologic oncologist at Texas Oncology in Austin.

Meanwhile, the real-world use of mirvetuximab soravtansine-gynx (Elahere) is expanding beyond its FDA-approved indication, with faculty reporting use in moderate FRα expressors, PARP inhibitor progressors in the platinum-sensitive setting, and low-grade serous ovarian cancer, for which the label includes no histologic restriction. Slomovitz shared his own practice pattern of adding bevacizumab (Avastin) to mirvetuximab soravtansine both for medium expressors and as a salvage addition for early radiographic progression.

Linda R. Duska, MD, MPH, a professor and Lawrence Penniston Family Endowed Professor of Women’s Oncology Research at the University of Virginia School of Medicine in Charlottesville, endorsed the approach, stating that “mirvetuximab soravtansine seems to work well in the post-PARP progression setting—better than platinum, because we know…that platinum just doesn’t work well in that setting.”

Although near-consensus emerged against the use of ADCs as maintenance therapy, Duska offered a reframe that gained traction: “It’s really not maintenance; it’s sequential therapy—that’s the way I think of it.”

Jubilee Brown, MD, a professor and division director of gynecologic oncology at Levine Cancer Institute, Atrium Health, in Charlotte, North Carolina, raised concerns about safety lead-in data from the phase 3 DESTINY-Ovarian01 trial (NCT06819007), evaluating trastuzumab deruxtecan (Enhertu) plus bevacizumab (n = 21) as first-line maintenance in HER2-expressing ovarian cancer, which showed dose delays and reductions in 28.6% and 23.8% of patients, respectively, arguing that patients who have just completed chemotherapy deserve a better recovery window.^1,3

Which investigational FRα-targeted ADCs are generating the most interest?

Panelists noted that the next-generation FRα-targeted ADCs rinatabart sesutecan (Rina-S), LY4170156, and AZD5335 have shown single-agent objective response rates (ORRs) ranging from 31% to 56% in platinum-resistant ovarian cancer cohorts.¹

Lyndsay Willmott, MD, a medical oncologist at Arizona Center for Cancer Care in Scottsdale, characterized her experience with Rina-S as compelling: “[There was] no ocular toxicity and no real pulmonary toxicity. [I’m just seeing] neutropenia, which is easily manageable. We even have a whole screening paradigm now [to identify] who’s likely to experience neutropenia so we can try to prevent that. I’m really excited about this drug.”

The phase 3 RAINFOL-02 trial (NCT06619236), evaluating Rina-S vs investigator’s choice of chemotherapy in platinum-resistant ovarian cancer after 1 to 4 prior lines of therapy, recently closed to accrual ahead of schedule.⁴ The phase 3 RAINFOL-04 trial (NCT07225270), evaluating Rina-S plus standard-of-care therapy as maintenance treatment after second-line platinum-based doublet chemotherapy in recurrent platinum-sensitive ovarian cancer, and the phase 3 RAINFOL-03 trial (NCT07166094), comparing Rina-S with investigator’s choice of chemotherapy in patients with recurrent or progressive endometrial cancer, are both actively enrolling.^5,6

Faculty also debated whether biomarker expression levels would remain relevant for next-generation agents, with Duska posing the provocative question of whether bystander effect and payload delivery—rather than target-specific binding—may drive most ADC activity.¹ Sarah Ackroyd, MD, MPH, an assistant professor of obstetrics and gynecology at the University of Chicago in Illinois, agreed, stating that “some of these newer ADCs are going to become biomarker agnostic, and maybe the older generations are more reliant on a higher level of biomarker expression.”

How are TROP2-targeted ADCs shaping the endometrial cancer landscape?

Two TROP2 ADCs are approaching potential approval in endometrial cancer: sacituzumab govitecan-hziy (Trodelvy) and sacituzumab tirumotecan (sac-TMT). The phase 3 ASCENT-GYN-01 trial (NCT06486441), comparing sacituzumab govitecan with treatment of physician’s choice (doxorubicin or paclitaxel) in patients with endometrial cancer who progressed after platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy, is ongoing and near completion of accrual.^1,7 Additionally, the phase 3 TroFuse-005 trial (NCT06132958), evaluating sac-TMT vs treatment of physician’s choice in a similar post-platinum, post–immune checkpoint inhibitor population, has already reported positive topline data, meeting its dual primary end points of OS and progression-free survival (PFS).⁸

Faculty split approximately evenly on which agent they predict will win broader adoption if both receive approval.¹ Sacituzumab govitecan causes primarily diarrhea and neutropenia on a day 1/day 8 dosing schedule, while sac-TMT causes significant mucositis in some patients on a dosing schedule of every 2 weeks. Additionally, Willmott and Noelle Gillette Cloven, MD, chair of the Gynecologic Research Program at Sarah Cannon Research Institute and Texas Oncology–Fort Worth Cancer Center in Fort Worth, Texas, both noted that sacituzumab govitecan’s existing footprint in community medical oncology, given its prior approvals in breast and urothelial cancer, confers a real-world adoption advantage.

Krishnansu S. Tewari, MD, a professor and gynecologic oncologist at the University of California, Irvine Medical Center in Orange, articulated the probabilistic view: “If only one [drug is] going to have efficacy, I say sac-TMT because of the press release. But if they’re both approved and both positive, I think the uptake is going to be greater with sacituzumab govitecan because of the toxicity profile. The drugs are very different.”

The broader implications of these trial readouts were not lost on faculty. Slomovitz warned that when data from ASCENT-GYN-01 and TroFuse-005 report out, multiple ongoing phase 2 programs evaluating investigational ADCs such as Rina-S, B7-H4 ADCs, and HER2 ADCs may require modification or closure.¹ The phase 3 TroFuse-033 trial (NCT06952504), evaluating sac-TMT plus pembrolizumab (Keytruda) vs pembrolizumab alone as first-line maintenance in mismatch repair–proficient endometrial cancer, remains active alongside ongoing TroFuse trials in second-line and first-line cervical cancer.^1,9

The REJOICE platform, evaluating the CDH6-targeted ADC raludotatug deruxtecan (R-DXd), also drew significant discussion. The dose-optimization portion of the phase 2/3 REJOICE-Ovarian01 trial (NCT06161025) showed ORRs ranging from 44% to 57% with various doses of R-DXd in platinum-resistant ovarian cancer.¹⁰ Of note, in the phase 2 dose-optimization portion of REJOICE-Ovarian01 (NCT06161025), 1 adjudicated treatment-related grade 3 ILD event was reported among 107 treated patients. Investigators considered the overall safety profile manageable and selected the 5.6-mg/kg dose for phase 3 evaluation. Nevertheless, given the recognized risk of ILD with deruxtecan-based ADCs, careful monitoring remains warranted, particularly as R-DXd is evaluated in combination regimens in studies such as the phase 1b/2 REJOICE-Ovarian02 trial (NCT06843447).¹¹ However, Cloven described her experience with single-agent R-DXd as compelling: “Patients respond very quickly. By the time they get their first CT [scan], they’ve already responded, and the responses are very durable.”

Cloven closed with the observation that most encapsulates the ADC era’s impact on patient outcomes: “With platinum-resistant ovarian cancer, in every trial we did, half the patients would get their first CT scan after going on a trial. That would show progression, so they’d come off [the study]. Now we have [patients] with platinum-resistant ovarian cancer that are on study for 2 years with stable disease and good quality of life. Everything is completely different.

References

1. Antibody-drug conjugates in gynecologic cancers: navigating patient selection, treatment sequencing, and emerging agents. An OncLive® Scientific Interchange and Workshop. OncLive. June 1, 2026. Accessed June 30, 2026.
2. FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. April 29, 2024. Accessed June 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer
3. Gonzalez-Martin A, Yamamoto K, Wu X, et al. Trastuzumab deruxtecan (T-DXd) plus bevacizumab (BEV) as first-line maintenance therapy in patients with human epidermal growth factor receptor 2 (HER2)-expressing ovarian cancer: results from the DESTINY-Ovarian01 (DO-01/ENGOT-ov89/GOG-3112/APGOT-OV13) safety run-in. J Clin Oncol. 2026;44(suppl 16):5554. doi:10.1200/JCO.2026.44.16_suppl.5554
4. Study to assess the efficacy of Rina-S compared to treatment of investigator's choice in participants with platinum resistant ovarian cancer (RAINFOL-02). Clinicaltrials.gov. Updated June 8, 2026. Accessed June 30, 2026. https://clinicaltrials.gov/study/NCT06619236
5. Study to assess the efficacy and safety of Rina-S plus standard of care compared with standard of care for maintenance treatment of participants with recurrent platinum-sensitive ovarian cancer after second-line (2L) platinum-based doublet chemotherapy (RAINFOL-04). Clinicaltrials.gov. Updated June 2, 2026. Accessed June 30, 2026. https://clinicaltrials.gov/study/NCT07225270
6. Genmab announces new data demonstrating investigational rinatabart sesutecan (Rina-S®) achieved anti-tumor activity in heavily pretreated patients with advanced endometrial cancer. News release. Genmab. October 18, 2025. Accessed June 30, 2026. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-new-data-demonstrating-investigational/
7. Study of sacituzumab govitecan versus treatment of physician's choice in participants with endometrial cancer after platinum-based chemotherapy and immunotherapy (ASCENT-GYN-01/​GOG-3104/​ENGOT-en26) (ASCENT-GYN-01). ClinicalTrials.gov. Updated January 1, 2026. Accessed June 30, 2026. https://clinicaltrials.gov/study/NCT06486441
8. Merck announces TroFuse-005 trial evaluating sacituzumab tirumotecan (sac-TMT) met primary endpoints of overall survival (OS) and progression-free survival (PFS) in certain patients with advanced or recurrent endometrial cancer. News release. Merck. May 18, 2026. Accessed June 30, 2026. https://www.merck.com/news/merck-announces-trofuse-005-trial-evaluating-sacituzumab-tirumotecan-sac-tmt-met-primary-endpoints-of-overall-survival-os-and-progression-free-survival-pfs-in-certain-patients-with-advanced-or-r/
9. A study to compare sacituzumab tirumotecan (MK-2870) in combination with pembrolizumab (MK-3475) versus pembrolizumab alone as treatment in participants with mismatch repair proficient endometrial cancer (MK-2870-033/TroFuse-033/ GOG-3119/ENGOT-en29) (TroFuse-033). Clinicaltrials.gov. Updated June 3, 2026. Accessed June 23, 2026. https://clinicaltrials.gov/study/NCT06952504
10. Ray-Coquard I, Oaknin A, Monk BJ, et al. Raludotatug deruxtecan (R-DXd) in patients with folate receptor α (FRα)-expressing platinum-resistant ovarian cancer: primary analysis of the phase 2 dose-optimization portion of the REJOICE-Ovarian01 study Presented at: 2025 ESMO Congress; October 17-20, 2025; Berlin, Germany. Abstract LBA42.
11. Oaknin A, Cali J, Frommer S, et al. REJOICE-Ovarian02: a phase Ib/II study of raludotatug deruxtecan (R-DXd) with other anticancer agents in participants with relapsed ovarian cancer after platinum-based chemotherapy. Ann Oncol. 2025;10(suppl 5):105252. doi:10.1016/j.esmoop.2025.105252