Ovarian malignant tumor: ©MohammedElAmine – stock.adobe.com
The US FDA has granted breakthrough therapy designation to the novel antibody-drug conjugate (ADC) raludotatug deruxtecan (R-DXd; DS-6000a) for the treatment of patients with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancers expressing CDH6 who received prior treatment with bevacizumab (Avastin).1
The breakthrough therapy designation is intended to accelerate the development and review of new agents that treat serious conditions and fill unmet medical needs. The designation is supported by data from a phase 1 trial (NCT04707248) and the ongoing phase 2/3 REJOICE-Ovarian01 trial (NCT06161025).
“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,” said Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, in a press release.1 “The receipt of breakthrough therapy designation represents an important step forward in our efforts to advance raludotatug deruxtecan as a novel medicine for patients with CDH6 expressing platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers previously treated with bevacizumab.”
What Were the Objectives of the Phase 1 Study of R-DXd?
Complete and partial responses
Data from the phase 1 study were presented at the 2023 European Society for Medical Oncology (ESMO) Annual Congress.2 In a subgroup of 50 patients with measurable ovarian cancer receiving R-DXd, the confirmed overall response rate (ORR) was 46% (95% CI, 32%–61%) consisting of 1 complete response and 22 partial responses. There were also 4 unconfirmed responses. The disease control rate (DCR) was 98%, the median duration of response (DOR) was 11.2 months (95% CI, 3.0–not estimable), and the median progression-free survival (PFS) was 7.9 months (95% CI, 4.4–12.4).
The phase 1 study enrolled a total of 179 patients across 13 sites in the US and Japan to assess R-DXd in patients with ovarian cancer and renal cell carcinoma.3 The primary end points are number of patients with dose-limiting toxicities, incidence of treatment-emergent adverse events (TEAEs), and ORR. Secondary end points include pharmacokinetics, DOR, DCR, clinical benefit rate, time to response, and PFS.
To be eligible for study participation, patients were required to have an ECOG performance status of 0 or 1, adequate organ function, and adequate treatment washout prior to study initiation. Those who previously received an exatecan-derived ADC, have a history of or current central nervous system metastases, have multiple primary malignancies, or have a history of myocardial infarction were not eligible for enrollment.
What is REJOICE-Ovarian01 Evaluating?
The phase 2/3 REJOICE-Ovarian01 study is a global, multicenter, randomized study of R-DXd in patients with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancers.4 The study’s primary end points are ORR and PFS. Secondary end points include DOR, DCR, overall survival, incidence of TEAEs, and pharmacokinetics.
Part A will assess R-DXd at doses of 4.8 mg/kg, 5.6 mg/kg, and 6.4 mg/kg administered every 3 weeks to determine the recommended phase 3 dose. The recommended dose will then be compared with investigator’s choice of paclitaxel, pegylated liposomal doxorubicin, or topotecan in part B.
Patients must have received at least 1 but no more than 3 prior lines of anticancer therapy, platinum-resistant disease, an ECOG performance status of 0 or 1, and required baseline laboratory levels. Those with clear cell, mucinous, or sarcomatous histology; inadequate washout before cycle 1; clinically active brain metastases; or a history of interstitial lung disease are not eligible for enrollment in the study.
The study is anticipated to enroll approximately 710 patients and has an estimated completion date of December 2029.