raludotatug deruxtecan (DS-6000) / Daiichi Sankyo, Merck (MSD) - LARVOL DELTA

Raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (PROC): A subgroup analysis of Asian patients from the phase II, dose-optimization part of the REJOICE-Ovarian01 study (ESMO Asia 2025) - P2/3 | "CDH6, a mediator of cell adhesion, is aberrantly expressed in 65–85% of epithelial OC tumors. Patients (pts) with PROC (high-grade serous or endometrioid OC, primary peritoneal, or fallopian tube cancer) who received 1–3 prior lines of systemic therapy (LOT), including bevacizumab (bev) if eligible, were enrolled in REJOICE-Ovarian01 (NCT06161025), irrespective of tumor CDH6 expression. Following review of overall safety data, R-DXd 5.6 mg/kg is considered the optimal dose for further evaluation in phase 3. R-DXd demonstrated promising efficacy and a manageable safety profile in Asian pts with PROC."

Clinical • Late-breaking abstract • P2 data • Platinum resistant • Fallopian Tube Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • CDH6

KEYMAKER-U01 phase II substudies 01H/01I: Ifinatamab deruxtecan (I-DXd), raludotatug deruxtecan (R-DXd), or docetaxel in stage IV non-small cell lung cancer (NSCLC) (ESMO 2025) - P2 | "Background The anti–PD-1 pembrolizumab plus chemotherapy (chemo) is a standard of care first-line therapy for metastatic NSCLC with no targetable genetic mutations. Legal entity responsible for the study Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Funding Daiichi Sankyo Company, Limited and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA."

IO biomarker • Metastases • P2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CDH6 • EGFR • ROS1

A Clinical Study of Raludotatug Deruxtecan in People With Ovarian Cancer (MK-5909-003) (clinicaltrials.gov) - P1/2 | N=280 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | N=78 ➔ 280

Enrollment change • Platinum resistant • Platinum sensitive • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

Raludotatug deruxtecan (R-DXd) in patients (pts) with platinum-resistant ovarian cancer (PROC): Primary analysis of the phase II dose-optimization part of REJOICE-Ovarian01 (ESMO 2025) - P2/3 | "Methods Pts with platinum-resistant high-grade serous or endometrioid OC, primary peritoneal, or fallopian tube cancer who received 1–3 prior lines of systemic therapy (LOT), including bevacizumab (bev) and/or PARP inhibitor (PARPi) if eligible, were enrolled in the phase 2, dose-optimization part of REJOICE-Ovarian01 (NCT06161025), irrespective of tumor CDH6 expression by immunohistochemistry. Table: LBA42 4.8 mg/kg n=36 5.6 mg/kg n=36 6.4 mg/kg n=35 Total N=107 ORR by BICR, % (95% CI) 44.4 (27.9–61.9) 50.0 (32.9–67.1) 57.1 (39.4–73.7) 50.5 (40.6–60.3) Best overall response, n (%) CR PR 1 (2.8) 15 (41.7) 2 (5.6) 16 (44.4) 0 20 (57.1) 3 (2.8) 51 (47.7) Disease control rate, % (95% CI) 75.0 (57.8–87.9) 80.6 (64.0–91.8) 77.1 (59.9–89.6) 77.6 (68.5–85.1) Median time to response, weeks (range) 7.1 (5.4–18.7) 6.6 (5.1–18.3) 7.2 (5.3–19.1) 7.1 (5.1–19.1) Any-grade TEAEs, n (%) 35 (97.2) 36 (100) 35 (100) 106 (99.1) Gr ≥3 TEAEs, n (%) 16 (44.4) 20 (55.6) 20 (57.1) 56..."

Clinical • Late-breaking abstract • P2 data • Platinum resistant • Fallopian Tube Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • CDH6

Raludotatug deruxtecan in participants with gastrointestinal cancers: Phase II REJOICE-GI01 trial (ESMO 2025) - P2 | "Pts in cohort 1 will have PDAC treated with 1 prior line of gemcitabine (gem)-based therapy...Pts in cohort 3 will have CRC, locally determined pMMR or not-MSI-H tumor status, treated with 1 prior line of chemotherapy (chemo; including a fluoropyrimidine + oxaliplatin regimen); pts must also have been treated with anti-VEGF treatment, anti-EGFR mAb, or encorafenib + anti-EGFR mAb if indicated and available...Secondary end points are DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Enrollment is ongoing."

P2 data • Biliary Cancer • Biliary Tract Cancer • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDH6 • MSI

Raludotatug deruxtecan: “In total, 94.1 % of tumors demonstrated positive CDH6 membrane by IHC”; Ovarian cancer (Daiichi Sankyo) - ESMO 2025: “The confirmed ORR was 50.5%, including three CRs (2.8%)”

P2/3 data • Oncology • Ovarian Cancer

REJOICE-OVARIAN02: A PHASE 1B/2 STUDY OF RALUDOTATUG DERUXTECAN WITH OTHER ANTICANCER AGENTS IN PARTICIPANTS WITH RELAPSED OVARIAN CANCER AFTER PLATINUM-BASED CHEMOTHERAPY (IGCS 2025) - P1, P1/2 | "We describe the phase 1b portion of a phase 1b/2, open-label, dose-escalation study (REJOICE-Ovarian02; NCT06843447) to assess safety, tolerability, and preliminary antitumor activity of R-DXd combined with carboplatin or paclitaxel in participants with platinum-sensitive recurrent OC (PSOC) or with bevacizumab in participants with platinum-resistant recurrent OC (PROC). Current Status & Future Directions: Enrollment is ongoing. Results will be used to determine recommended phase 2 doses."

P1/2 data • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDH6

Seminal Abstract: RALUDOTATUG DERUXTECAN (R-DXD) IN PATIENTS WITH PLATINUM-RESISTANT OVARIAN CANCER (PROC): PRIMARY ANALYSIS OF THE PHASE 2, DOSE-OPTIMIZATION PART OF THE REJOICE-OVARIAN01 STUDY (IGCS 2025) - P2/3 | " Patients with platinum-resistant OC (PROC), primary peritoneal, or fallopian tube cancer who received 1–3 prior lines of systemic therapy (LOT), including bevacizumab and/or PARPi if eligible, were enrolled in the Phase 2, dose-optimization part of REJOICE-Ovarian01 (NCT06161025), irrespective of tumor CDH6 expression. R-DXd 5.6 mg/kg was identified as the optimal dose for further evaluation in the Phase 3 study. R-DXd demonstrated promising efficacy and a manageable safety profile in patients with PROC. Table 1 Efficacy 4.8 mg/kg n=36 5.6 mg/kg n=36 6.4 mg/kg n=35 Total N=107 ORR by BICR, % 44.4 (27.9–61.9) 50.0 (32.9–67.1) 57.1 (39.4–73.7) 50.5 (40.6–60.3) (95% CI) Best overall response, n 1 (2.8) 15 (41.7) 2 (5.6) 16 (44.4) 0 20 (57.1) 3 (2.8) 51 (47.7) (%) CR PR Disease control rate, % 75.0 80.6 77.1 77.6 (95% CI) (57.8–87.9) (64.0–91.8) (59.9–89.6) (68.5–85.1) Median time to response, 7.1 6.6 7.2 7.1 (5.1–19.1) weeks (range) (5.4–18.7) (5.1–18.3) (5.3–19.1)..."

Clinical • P2 data • Platinum resistant • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDH6

Antibody-drug conjugates targeting the cadherin, claudin and nectin families of adhesion molecules. (PubMed, Front Mol Med) - "Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs."

Journal • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Genito-urinary Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer • CDH17 • CDH6 • CLDN18 • CLDN6

Trials-in-Progress Across Daiichi Sankyo’s Oncology Portfolio (Businesswire) - "A trial-in-progress poster will highlight the design of the DESTINY-Endometrial01 phase 3 trial...Three phase 2 trials-in-progress will include the HERTHENA-Breast03 trial (463eTiP)...the REJOICE-GI01 trial (1001TiP)...and, the KEYMAKER-U01 sub-studies 01H/01I (2081eTiP) evaluating ifinatamab deruxtecan, raludotatug deruxtecan or docetaxel in patients with stage IV NSCLC...The design of two additional early phase trials will be shared, including the phase 1/2 trial (2792TiP) evaluating ifinatamab deruxtecan and gocatamig in patients with relapsed/refractory ES-SCLC and a phase 1b trial (977P) of valemetostat..."

pMMR • Trial status • Biliary Tract Cancer • Endometrial Cancer • Gastroesophageal Junction Adenocarcinoma • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Cancer • Renal Cell Carcinoma • Triple Negative Breast Cancer • Urothelial Cancer

Raludotatug Deruxtecan Demonstrated Clinically Meaningful Response Rates in Patients with Recurrent Platinum-Resistant Ovarian, Primary Peritoneal or Fallopian Tube Cancer in Phase 2 Part of REJOICE-Ovarian01 Phase 2/3 Trial (Merck (MSD) Press Release) - "These data were presented today during a late-breaking proffered paper session (LBA42) at the 2025 European Society for Medical Oncology (#ESMO25) Congress....The median overall survival for advanced ovarian cancer following recurrence can be as little as two years, with a five-year survival rate of 31.8% for those with distant stage disease....A confirmed objective response rate (ORR) of 50.5% (95% confidence interval [CI]: 40.6-60.3) was observed in patients (n=107) with platinum-resistant ovarian cancer receiving raludotatug deruxtecan across three doses (4.8 mg/kg, 5.6 mg/kg and 6.4 mg/kg)..."

Late-breaking abstract • P2/3 data • Platinum resistant • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

New data for investigational antibody-drug conjugates (ADCs) from Merck’s innovative pipeline will be presented at the Congress, including data for raludotatug deruxtecan (R-DXd), a CDH6 directed DXd ADC, and ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, both discovered by Daiichi Sankyo. (Merck (MSD) Press Release) - "Notably, research evaluating sacituzumab tirumotecan (sac-TMT), a TROP2-directed ADC being developed in collaboration with Kelun-Biotech will be shared in four presentations in certain patients with lung, breast, cervical and prostate cancer."

Clinical data • Platinum resistant • Castration-Resistant Prostate Cancer • Cervical Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Small Cell Lung Cancer

Trials Supporting Three Recent Breakthrough Therapy Designations Showcased (Businesswire) - "Data from additional late-stage trials – DESTINY-Breast09, REJOICE-Ovarian01 and IDeate-Lung01....will be showcased at ESMO."

Clinical data • Late-breaking abstract • Platinum resistant • HER2 Positive Breast Cancer • Ovarian Cancer • Small Cell Lung Cancer

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 (Daiichi Sankyo Press Release) - "The FDA granted this BTD based on data from a phase 1 trial and the ongoing REJOICE-Ovarian01 phase 2/3 trial."

Breakthrough therapy • Platinum resistant • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

A Study of Investigational Agents in Participants With Previously Treated Stage IV Nonsquamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01H/KEYMAKER-U01) (clinicaltrials.gov) - P2 | N=96 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Sep 2030 ➔ Mar 2032

Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

DS6000-A-U101: A Study of DS-6000a in Subjects With Advanced Renal Cell Carcinoma and Ovarian Tumors (clinicaltrials.gov) - P1 | N=179 | Active, not recruiting | Sponsor: Daiichi Sankyo | Trial completion date: Nov 2025 ➔ Jun 2026 | Trial primary completion date: Apr 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor

REJOICE-Ovarian01: A Study of Raludotatug Deruxtecan (R-DXd) in Subjects With Platinum-resistant, High-grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer (clinicaltrials.gov) - P2/3 | N=710 | Recruiting | Sponsor: Daiichi Sankyo | Active, not recruiting ➔ Recruiting

Enrollment open • Fallopian Tube Cancer • Oncology • Solid Tumor

KEYMAKER-01I: Substudy 01I: A Study of Investigational Agents in Participants With Previously Treated Stage IV Squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01I/KEYMAKER-U01I) (clinicaltrials.gov) - P2 | N=144 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

REJOICE-Ovarian02: A phase Ib/II study of raludotatug deruxtecan (R-DXd) with other anticancer agents in participants (pts) with relapsed ovarian cancer (OC) after platinum-based chemotherapy (ESMO-GC 2025) - P1, P1/2 | "Herein, we describe the phase Ib portion of a phase Ib/2, open-label, dose-escalation study (REJOICE-Ovarian02; NCT06843447) to assess safety, tolerability, and preliminary antitumor activity of R-DXd combined with carboplatin or paclitaxel in pts with platinum-sensitive recurrent OC (PSOC) or with bevacizumab in pts with platinum-resistant recurrent OC (PROC). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA."

Clinical • P1/2 data • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDH6

Raludotatug deruxtecan (R-DXd) monotherapy in patients (pts) with heavily pretreated platinum-sensitive ovarian cancer (PSOC): Subgroup analysis of a phase I study (ESMO-GC 2025) - P1 | "Median number of prior lines of therapy was 4 (range, 2–6); 14 pts (77.8%) had received prior bevacizumab and 15 (83.3%) prior PARP inhibitor. Editorial acknowledgement Medical writing support was provided by Natalie Dennis of BOLDSCIENCE, Inc., and was funded by Daiichi Sankyo, Inc. Legal entity responsible for the study Daiichi Sankyo, Inc."

Clinical • Monotherapy • P1 data • Platinum sensitive • Oncology • Ovarian Cancer • Solid Tumor • CDH6

A Study of Investigational Agents in Participants With Previously Treated Stage IV Nonsquamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01H/KEYMAKER-U01) (clinicaltrials.gov) - P2 | N=96 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

REJOICE-GI01: A Study of Raludotatug Deruxtecan (R-DXd) in People With Gastrointestinal Cancers (MK-5909-005) (clinicaltrials.gov) - P2 | N=160 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: May 2029 ➔ Jan 2029

Trial completion date • Gastrointestinal Cancer • Oncology • Solid Tumor

REJOICE-PanTumor01: A phase 2 signal-seeking study of raludotatug deruxtecan (R-DXd) in patients with advanced or metastatic gynecologic or genitourinary tumors. (ASCO 2025) - P1, P2, P2/3 | "PFS and DOR will be analyzed using the Kaplan–Meier method (2-sided 95% CI). Study enrollment began in January 2025."

Clinical • Metastases • P2 data • Pan tumor • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Endometrial Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer • CDH6

Additional Data and Trials-in-Progress Across Daiichi Sankyo’s Oncology Portfolio at ASCO (Daiichi Sankyo Press Release) - "Oral presentations also will highlight initial results from the TUXEDO-3 phase 2 trial (#2005) evaluating patritumab deruxtecan in patients with metastatic breast cancer or advanced NSCLC and active brain metastases and in patients with leptomeningeal carcinomatosis/disease from advanced solid tumors, as well as results from a phase 1 trial (#10003) evaluating valemetostat, a dual EZH1 and EZH2 inhibitor, in pediatric patients with malignant solid tumors...Additional DXd ADC trials-in-progress poster presentations include the REJOICE-PanTumor01 phase 2 trial (TPS3158) evaluating raludotatug deruxtecan (R-DXd) in patients with locally advanced or metastatic gynecologic or genitourinary cancers, IDeate-PanTumor02 phase 1b/2 trial (TPS3157) evaluating ifinatamab deruxtecan in patients with recurrent or metastatic solid tumors and a substudy of KEYMAKER-U06, a phase 1/2 trial (TPS4209) evaluating ifinatamab deruxtecan in combination with pembrolizumab..."

Clinical data • Trial status • Acute Myelogenous Leukemia • Esophageal Squamous Cell Carcinoma • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer • Triple Negative Breast Cancer

QLS5133-a novel CDH6-targeting antibody-drug-conjugate for solid tumors (AACR 2025) - "Additionally, QLS5133 was able to achieve a durable response even after resistance to Mirvetuximab soravtansine (FRα ADC/ImmunoGen) in preclinical models. The promising efficacy, superior tolerability, and favorable PK profile support the potential of QLS5133 as a novel therapeutic agent to address the high unmet needs in patients with variable CDH6-expressing cancers. QLS5133 will enter clinical trials."

Endocrine Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • Thyroid Gland Carcinoma • CDH6 • FOLR1