Raludotatug Deruxtecan

Shows activity

Also known as:

R-DXD DS-6000a

Cancer types include:

non-small cell lung cancer ovarian cancer small cell lung cancer

HealthScout AI Analysis

Show HealthScout AI Analysis

Overview

Raludotatug deruxtecan (R-DXd, DS‑6000a) is an investigational antibody–drug conjugate (ADC) directed at cadherin‑6 (CDH6), being developed for CDH6‑expressing tumors, with the most advanced program in ovarian cancer. Early clinical activity has been reported in heavily pretreated ovarian cancer, and a global randomized phase 2/3 trial in platinum‑resistant disease is ongoing. In September 2025, the FDA granted Breakthrough Therapy Designation for CDH6‑expressing, platinum‑resistant ovarian, primary peritoneal, or fallopian tube cancers previously treated with bevacizumab. (daiichisankyo.us)

Mechanism of action

Target: CDH6, a cadherin overexpressed in a majority of ovarian cancers and associated with poor prognosis. (daiichisankyo.us)
Construct: humanized anti‑CDH6 IgG1 linked via a cleavable tetrapeptide linker to a membrane‑permeable topoisomerase I inhibitor payload (DXd; an exatecan derivative), enabling intracellular release and a bystander effect. (aacrjournals.org)
Preclinical activity: demonstrated CDH6‑dependent cytotoxicity with tumor regressions in ovarian and kidney cancer xenograft models; acceptable toxicology in cynomolgus monkeys. (aacrjournals.org)

Efficacy

First‑in‑human phase 1 (NCT04707248)
- Ovarian cancer (heavily pretreated; doses 4.8–8.0 mg/kg every 3 weeks; unselected for CDH6): confirmed ORR 46% (95% CI 32–61), DCR 98%, median DOR 11.2 months (95% CI 3.0–NE), and median PFS 7.9 months (95% CI 4.4–12.4) at data cutoff July 14, 2023. Responses occurred across a range of CDH6 expression. (daiichisankyo.us)
- Early dose‑escalation readout (ASCO 2022): among 15 evaluable patients overall, 2 PRs (1 confirmed RCC; 1 unconfirmed ovarian), with additional CA‑125 declines in platinum‑resistant ovarian cancer. (ascopubs.org)
- Platinum‑sensitive ovarian cancer subgroup (ESMO Gynaecological Cancers Congress 2025): reported ORR 72.2% (all PRs; n=18). (Conference report.) (onclive.com)

Ongoing phase 2/3 (REJOICE‑Ovarian01; NCT06161025)
- Global, randomized, open‑label study in platinum‑resistant ovarian cancer; phase 2 dose optimization at 4.8, 5.6, or 6.4 mg/kg, followed by phase 3 versus treatment of physician’s choice (paclitaxel, PLD, gemcitabine, or topotecan). Dual phase 3 primary endpoints: ORR and PFS by BICR. Enrollment initiated February–April 2024 and remains ongoing (recruiting as of July 2025). (ascopubs.org)

Safety

In the ovarian cancer phase 1 subgroup (n≈60; evaluable n=50 for efficacy), grade ≥3 TEAEs occurred in 51.7%; discontinuations due to TEAEs in 15%. Most common grade ≥3 AEs included anemia (18.3%), neutropenia (11.7%), and thrombocytopenia (5.0%); grade ≥3 fatigue, nausea, vomiting, diarrhea, and decreased appetite each ≤3.3%. Interstitial lung disease (ILD) was observed: two grade 2 treatment‑related ILD events at 4.8–6.4 mg/kg, and two grade 5 treatment‑related ILD events at 8.0 mg/kg; the 8.0 mg/kg dose was discontinued in October 2022. (daiichisankyo.us)
Dose optimization in ongoing studies is focused on 4.8–6.4 mg/kg every 3 weeks. (daiichisankyo.us)

Active trials using Raludotatug Deruxtecan

Found 5 active trials using this drug:

KEYMAKER-U01 Substudy 01I: A Phase 2, Randomized, Umbrella Study With Rolling Arms of Investigational Agents in Participants With Previously Treated Stage IV Squamous Non-small Cell Lung Cancer (NSCLC)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 2 Start date: May 28, 2025

HealthScout AI summary: This trial enrolls adults with stage IV squamous NSCLC whose disease has progressed after both anti-PD-(L)1 immunotherapy and platinum chemotherapy, randomizing them to either standard docetaxel or investigational antibody-drug conjugates: Raludotatug deruxtecan (targeting CDH6) or Infinatamab deruxtecan (targeting B7-H3).

ClinicalTrials.gov ID: NCT06780098

KEYMAKER-U01 Substudy 01H: A Phase 2, Randomized, Umbrella Study With Rolling Arms of Investigational Agents in Participants With Previously Treated Stage IV Nonsquamous Non-small Cell Lung Cancer (NSCLC)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 2 Start date: May 13, 2025

HealthScout AI summary: This trial enrolls adults with stage IV nonsquamous NSCLC who have progressed after both anti-PD-(L)1 therapy and platinum-based chemotherapy, randomizing them to receive either raludotatug deruxtecan (a CDH6-targeting antibody-drug conjugate), ifinatamab deruxtecan (a B7-H3-targeting antibody-drug conjugate), or standard docetaxel. Patients with EGFR, ALK, or ROS1 alterations eligible for targeted therapy are excluded.

ClinicalTrials.gov ID: NCT06780085

A Phase 1b/2 Open-label, Multicenter Study to Evaluate the Safety and Efficacy of Raludotatug Deruxtecan With or Without Other Anticancer Investigational Agents in Participants With High-grade Serous Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Who Have Relapsed After Prior Platinum-based Chemotherapy

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 1/2 Start date: April 15, 2025

HealthScout AI summary: Enrolling adults with measurable high-grade serous ovarian, primary peritoneal, or fallopian tube cancer after 1–3 prior lines (platinum-sensitive and -resistant cohorts; ECOG 0–1), excluding significant ILD/pneumonitis and other key comorbidities. Investigational CDH6-targeting antibody-drug conjugate raludotatug deruxtecan (anti-CDH6–DXd topoisomerase I payload) is combined with either carboplatin, paclitaxel, or bevacizumab, with chemotherapy for up to six cycles and continued R-DXd until progression.

ClinicalTrials.gov ID: NCT06843447

A Phase 2/3, Multicenter, Randomized Study of Raludotatug Deruxtecan (R-DXd), a CDH6-directed Antibody-drug Conjugate, in Subjects With Platinum-resistant, High-grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Sponsor: Daiichi Sankyo (industry) Phase: 2/3 Start date: Feb. 27, 2024

HealthScout AI summary: Adults with platinum-resistant high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer (1–3 prior lines; prior bevacizumab and PARP inhibitor as indicated) are randomized to the CDH6-directed antibody-drug conjugate raludotatug deruxtecan (R-DXd; cleavable linker to DXd topoisomerase I payload) given IV q3w versus investigator’s choice of weekly paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan. Requires measurable disease, ECOG 0–1, available tumor tissue; excludes prior CDH6/DXd ADCs and patients with active ILD/pneumonitis or significant uncontrolled comorbidities.

ClinicalTrials.gov ID: NCT06161025

A Phase 1b/2 Study to Evaluate the Efficacy and Safety of Investigational Agents as Monotherapy or in Combination With Pembrolizumab for the Treatment of Participants With PD-1/L1-refractory Extensive-Stage Small Cell Lung Cancer in Need of Second-Line Therapy (KEYNOTE-B98)

Sponsor: Merck Sharp & Dohme LLC (industry) Phase: 1/2 Start date: Aug. 19, 2021

HealthScout AI summary: Adults with PD‑1/PD‑L1–refractory extensive-stage SCLC after exactly one prior platinum+PD‑1/L1 regimen are enrolled to receive investigational immunotherapy or ADC regimens, as monotherapy or combined with pembrolizumab. Arms include pembrolizumab+quavonlimab (anti–CTLA‑4), pembrolizumab+quavonlimab+lenvatinib (VEGFR/FGFR TKI), pembrolizumab+MK‑4830 (anti‑ILT4), favezelimab (anti‑LAG‑3)+pembrolizumab, and raludotatug deruxtecan (CDH6‑targeted topoisomerase I ADC).

ClinicalTrials.gov ID: NCT04938817