FDA Grants Breakthrough Therapy Designation to R-DXd in CDH6-Expressing Ovarian Cancer

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The FDA has granted breakthrough therapy designation to raludotatug deruxtecan (R-DXd), a potential first-in-class CDH6-directed antibody-drug conjugate (ADC), for the treatment of adult patients with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancers expressing CDH6 who have received prior treatment with bevacizumab (Avastin).1

The FDA’s decision was based on efficacy and safety data from a phase 1 study (NCT04707248) of R-DXd in patients with advanced ovarian tumors, as well as from the ongoing phase 2/3 REJOICE-Ovarian01 trial (NCT06161025) of the ADC in patients with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer.

Findings from subgroup analyses of the phase 1 trial were presented at the 2023 ESMO Annual Meeting, the 2024 SGO Annual Meeting on Women’s Cancer, and the 2025 ESMO Gynaecological Cancers Congress. In the phase 1 study, among patients with platinum-resistant ovarian cancer who had received a median of 4 prior lines of therapy (n = 49) and were treated with R-DXd at doses ranging from 4.8 mg/kg to 8.0 mg/kg, the confirmed overall response rate (ORR) per RECIST 1.1 criteria was 46% (95% CI, 32%-61%), including 1 complete response and 22 partial responses.2 Additionally, at a data cutoff date of July 14, 2023, 4 patients had ongoing unconfirmed responses. The disease control rate (DCR) was 98%.

“Patients have limited treatment options once ovarian cancer becomes resistant to platinum-based chemotherapy, highlighting the urgent need for new medicines that can improve patient outcomes,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, shared in a news release.1 “The receipt of breakthrough therapy designation represents an important step forward in our efforts to advance R-DXd as a novel medicine for patients with CDH6-expressing platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers previously treated with bevacizumab.”

What Was the Design of the Phase 1 Study of R-DXd in Advanced Ovarian Cancer?

The 2-part, multicenter, open-label, first-in-human trial is investigating the safety and efficacy of R-DXd in adult patients with advanced ovarian cancer who have previously received platinum-based chemotherapy and a taxane. Initially, patients with renal cell carcinoma (RCC) that was resistant or refractory to standard-of-care therapy were also included; however, this cohort was later discontinued.

The first part of the study consisted of a dose-escalation phase with a primary objective of assessing the safety and tolerability of increasing doses of R-DXd to determine the maximum tolerated dose and/or recommended dose for expansion. The second part of the study, the dose-expansion phase, was designed to further evaluate the safety and efficacy of R-DXd in patients with advanced ovarian cancer and, originally, in patients with advanced RCC.

Safety end points in the trial include dose-limiting toxicities and AEs. Efficacy end points include ORR, duration of response (DOR), DCR, clinical benefit rate, time to response, and progression-free survival (PFS). Pharmacokinetic (PK) and exploratory biomarker end points are also being assessed.

The trial enrolled 179 patients across study sites in Asia and North America.

What Was the Design of the REJOICE-Ovarian01 Trial of R-DXd in Platinum-Resistant Ovarian, Primary Peritoneal, or Fallopian Tube Cancer?

REJOICE-Ovarian01 is a global, multicenter, randomized, open-label trial assessing the efficacy and safety of R-DXd in patients with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancers.1,3 Eligible patients must have experienced disease progression following at least 1 but no more than 3 prior lines of systemic therapy, including prior treatment with mirvetuximab soravtansine-gynx (Elahere) in those with documented high folate receptor alpha expression. Maintenance therapy with agents like bevacizumab or PARP inhibitors is considered part of the preceding line of therapy.

The phase 2 portion of REJOICE-Ovarian01 investigated the safety and tolerability of 3 R-DXd dose levels (4.8 mg/kg, 5.6 mg/kg, and 6.4 mg/kg) to determine the recommended dose for the phase 3 portion. The primary end point of the phase 2 portion was ORR as assessed by blinded independent central review (BICR). Secondary end points included ORR as assessed by investigator, DOR, PFS, and overall survival (OS).

The phase 3 portion of the trial is evaluating the efficacy and safety of R-DXd at the selected 5.6-mg/kg dose compared with investigator’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan). The dual primary end points in the phase 3 portion are ORR and PFS as assessed by BICR. Key secondary end points are PFS and ORR as assessed by investigator, DOR and DCR as assessed by both BICR and investigator, and OS. PK and biomarker end points are being explored across both study phases.

REJOICE-Ovarian01 aims to enroll approximately 710 patients across study sites in Asia, Europe, North America, and Oceania.

“The FDA’s breakthrough designation is a reflection of our commitment to advancing research for patients impacted by women’s cancers,” Eliav Barr, MD, senior vice president, head of Global Clinical Development, and chief medical officer of MSD Research Laboratories, added in the news release.1 “R-DXd has the potential to one day become an important option for the treatment of patients with CDH6-expressing platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers previously treated with bevacizumab, and we are excited to share data from REJOICE-Ovarian01 with the scientific community at an upcoming medical meeting and to continue working closely with the FDA.”

References

  1. Raludotatug deruxtecan granted breakthrough therapy designation by U.S. FDA for patients with CDH6 expressing platinum-resistant ovarian, primary peritoneal or fallopian tube cancers previously treated with bevacizumab. News release. Daiichi Sankyo. September 15, 2025. Accessed September 15, 2025. https://daiichisankyo.us/press-releases/-/article/raludotatug-deruxtecan-granted-breakthrough-therapy-designation-by-us-fda-for-patients-with-cdh6-expressing-platinum-resistant-ovarian-primary-peritoneal-or-fallopian-tube-cancers-previously-treated-with-bevacizumab
  2. Moore KN, Philipovskiy A, Harano K, et al. Raludotatug deruxtecan (R-DXd; DS-6000) monotherapy in patients with previously treated ovarian cancer: subgroup analysis of a first-in-human phase I study. Ann Oncol. 2023;34(suppl 2):S510. doi:10.1016/annonc/annonc1089.
  3. A study of raludotatug deruxtecan (R-DXd) in subjects with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer. ClinicalTrials.gov. Updated August 7, 2025. Accessed September 15, 2025. https://clinicaltrials.gov/study/NCT06161025

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