Raludotatug Deruxtecan Shows Activity in Platinum-Sensitive Ovarian Cancer

Raludotatug Deruxtecan in Ovarian
Cancer | Image Credit: ©Sebastian Kaulitzki -
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The antibody-drug conjugate (ADC) raludotatug deruxtecan (R-DXd) demonstrated clinical activity in patients with platinum-sensitive, heavily pretreated ovarian cancer, according to subgroup findings of a first-in-human trial (NCT04707248) presented at the ESMO Gynaecological Cancers Congress 2025.1

Results showed that in the platinum-sensitive subgroup of patients (n = 18), the confirmed overall response rate (ORR) was 72.2% (95% CI, 46.5%-90.3%), which comprised all partial responses (PRs). The stable disease (SD) rate was 16.7%; 1 patient had progressive disease (PD), and 1 patient was not evaluable for response.

For those with platinum-sensitive disease who progressed on a prior PARP inhibitor (n = 12), the ORR was 58.3% (95% CI, 27.7%-84.8%), which also consisted of all PRs. Twenty-five percent of patients had SD, and 1 patient each had PD and was not evaluable.

“This little study shows preliminary strong evidence of response rate in a heavily pretreated platinum-sensitive population,” lead study author Kathleen Moore, MD, associate director of clinical research at Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program, and professor in the Section of Gynecologic Oncology at The University of Oklahoma Health Sciences in Oklahoma City, in an oral presentation of the data.

“We would argue that this data supports further development and exploration of raludotatug deruxtecan in this population, and more to come in the near future on that,”

Approximately 70% to 80% of patients with advanced epithelial ovarian cancer will experience relapsed disease within 3 years of surgery and/or frontline chemotherapy. Moreover, cadherin-6 (CDH6) expression is seen in 65% to 85% of all patients with ovarian cancer.

R-DXd is an ADC comprised of a humanized anti-CDH6 immunoglobulin monoclonal antibody covalently linked with a TOPO I inhibitor payload through a tetrapeptide-based cleavable linker.

In the ongoing, 2-part, phase 1 trial, patients with previously treated ovarian cancer who were not selected based on their tumor CDH6 tumor expression, were treated with doses of R-DXd at 1.6 mg/kg (n = 1), 3.2 mg/kg (n = 4), 4.8 mg/kg (n = 7), 6.4 mg/kg (n = 4), 8.0 mg/kg (n = 8), or 9.6 mg/kg (n = 3) in the dose-escalation phase (part A). Moore noted that the 8.0 mg/kg cohort was previously closed due to a higher incidence of serious and grade 3 or higher treatment-emergent adverse effects (TEAEs).

In the dose-expansion phase (part B), patients were treated with R-DXd at 4.8 mg/kg (n = 40), 5.6 mg/kg (n = 42), and 6.4 mg/kg (n = 40). In both phases, R-DXd was administered intravenously every 3 weeks.

To be eligible for enrollment, patients had to have advanced or metastatic ovarian cancer not amenable to standard treatment, an ECOG performance status of 0 to 1, have received a prior taxane and platinum-based chemotherapy, and have not received prior CDH6-targeting agents or ADCs linked to a TOPO I inhibitor.

The coprimary end points were safety and tolerability, maximum-tolerated dose and recommended dose for expansion, and ORR per RECIST v1.1 criteria in the dose-expansion phase. Secondary end points were pharmacokinetics, ORR per RECIST v1.1 criteria in the dose-escalation phase, duration of response (DOR), disease control rate (DCR), and clinical benefit rate (CBR) per RECIST v1.1 criteria, and immunogenicity.

Preliminary data showcased manageable safety and activity, specifically a 48.6% ORR; 89% of these patients had platinum-resistant disease.2

In the subgroup analysis data presented at the meeting, investigators highlighted results of the 18 enrolled patients with platinum-sensitive disease across 3 dose levels: 4.8 mg/kg (n = 4), 5.6 mg/kg (n = 9), and 6.4 mg/kg (n = 5).

The data cutoff date was January 10, 2025. Baseline characteristics of the 18 patients showed a median age of 65 years (range, 50-81), most patients being from the US (77.8%), and having an ECOG performance status of 1 (77.8%). The median number of prior systemic therapies was 4 (range, 2-6) and 77.8% of patients received prior bevacizumab (Avastin); 83.3% of patients had received a prior PARP inhibitor, of which 80% experienced disease progression on one. There was a median 67.5% (range, 20%-100%) of patients with tumor CDH6 membrane positivity.

Across the 4.8-mg/kg, 5.6-mg/kg, and 6.4-mg/kg dose levels, 2, 3, and 0 patients were ongoing with treatment, respectively. Overall, 13 patients had discontinued treatment with R-DXd due to progressive disease (n = 9), AEs (n = 3), and clinical progression (n = 1). The median duration of R-DXd therapy was 6.9 months (range, 0.7-12.2).

Further efficacy data showed that, in the platinum-sensitive subgroup, the DCR was 88.9% (95% CI, 65.3%-98.6%), the CBR was 77.8% (95% CI, 52.4%-93.6%), the median time to response (TTR) was 1.4 months (95% CI, 1.2-2.7), the median DOR was 5.7 months (95% CI, 4.2-not estimable [NE]), and the median progression-free survival (PFS) was 8.1 months (95% CI, 4.1-NE). The median follow-up for DOR and PFS was 6.9 months (95% CI, 1.6-10.5) and 8.3 months (95% CI, 0-11.7), respectively.

In those who progressed on a prior PARP inhibitor, the DCR was 83.3% (95% CI, 51.6%-97.9%), the CBR was 66.7% (95% CI, 34.9%-90.1%), the median TTR was 1.4 months (95% CI, 1.2-NE), the median DOR was 5.1 months (95% CI, 2.8-NE), and the median PFS was 7.1 months (95% CI, 2.8-NE). The median follow-up for DOR and PFS was 6.9 months (95% CI, 1.6-6.9) and 8.3 months (95% CI, 0-11.4), respectively.

“Just as in prior presentations, we’re still not showing a strong correlation between CDH6 expression and clinical benefit,” Moore said, when showing responses in patients with both high and low tumor CDH6 expression.

Regarding safety, all platinum-sensitive patients experienced treatment-emergent AEs (TEAEs), 77.8% of which were grade 3 or higher; any-grade treatment-related AEs occurred in 88.9% of patients, half of which were grade 3 or higher. Any-grade and grade 3 or higher serious AEs occurred in 27.8% and 27.8% of patients, respectively.

The most common all-cause TEAEs consisted of nausea (any-grade, 50.0%), anemia (38.9%; grade ≥3, 22.2%), fatigue (38.9%; 5.6%), urinary tract infection (27.8%; 5.6%), decreased neutrophil count (22.2%; 16.7%), hypokalemia (22.2%; 11.1%), decreased weight (any-grade, 22.2%), vomiting (any-grade, 22.2%), alopecia (any-grade, 22.2%), increase alanine aminotransferase (16.7%; 5.6%), ascites (16.7%; 5.6%), aspartate aminotransferase (16.7%; 5.6%), decreased platelet count (16.7%; 5.6%), and abdominal pain, increased blood creatinine, diarrhea, fall, malaise, and stomatitis (all any-grade, 16.7%).

Treatment discontinuations, interruptions, and reductions occurred in 11.1%, 38.9%, and 22.2% of patients, respectively.

Grade 2 treatment-related interstitial lung disease/pneumonitis occurred in 1 patient who received a starting dose of 6.5 mg/kg.

Moore noted that the safety profile in the platinum-sensitive subgroup was consistent with the overall study population.

Disclosures: Moore cited research grants with Agenus, Amgen, Artios Pharma, Bolt Biotherapeutics, Bristol Myers Squibb, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo/Lilly, Genentech, Immunocore, ImmunoGen Novogen, Lilly, Lilly Foundation, MSD, Novartis, PTC Therapeutics, Regeneron Pharmaceuticals, Takeda, Tesaro, Verastem Oncology; advisory roles with AADI Bioscience, Alkermes, AstraZeneca, Blueprint Medicines, Caris Life Sciences, Clovis Oncology, Eisai, Genentech/Roche, GlaxoSmithKline/Tesaro, ImmunoGen, Janssen Oncology, MSD, Mereo BioPharma, Mersana Therapeutics, Myriad Genetics, Novartis, Onconova Therapeutics, OncXema Therapeutics, Regeneron Pharmaceuticals, Schrödinger, VBL Therapeutics, Verastem/Pharmacyclics, Zentalis Pharmaceuticals, and Zymeworks; expert testimony for Great Debates & Updates, Physicians’ Education Resource, Prime Oncology, and Research to Practice; on the board of directors for GOG Partners and NRG Oncology; travel support with AstraZeneca and GlaxoSmithKline; and funding from Daiichi Sankyo, Inc.

References

1. Moore K, Philipovskiy A, Sudo K, et al. Raludotatug deruxtecan (R-DXd) monotherapy in patients with heavily pretreated platinum-sensitive ovarian cancer: subgroup analysis of a phase 1 study. Presented at: ESMO Gynaecological Cancers Congress; June 19-21, 2025; Vienna, Austria. Abstract 77M0.
2. Moore K, Philipovskiy A, Harano K, et al. Raludotatug deruxtecan monotherapy among patients with previously treated ovarian cancer: Subgroup analysis of a first-in-human phase I study. Gynecol Oncol. 2024;190(suppl 1):S6-S7. doi:10.1016/j.ygyno.2024.07.017