745MO - Raludotatug deruxtecan (R-DXd; DS-6000) monotherapy in patients with previously treated ovarian cancer (OVC): Subgroup analysis of a first-in-human phase I study

Background

R-DXd is an antibody–drug conjugate comprised of a humanised IgG1 antibody against cadherin 6 (CDH6), a stable linker selectively cleaved within tumour cells, and a membrane permeable topoisomerase I inhibitor. Overexpression of CDH6, a cell adhesion protein, occurs in the majority of OVC cases and is associated with poor prognosis. In an ongoing phase 1 trial (NCT04707248), R-DXd demonstrated an acceptable safety profile and an early efficacy signal.

Methods

All patients received prior taxane and platinum therapies and were unselected for CDH6 tumour expression. Part A (dose escalation) assessed the tolerability of R-DXd at 1.6 to 9.6 mg/kg, and 8.0 mg/kg was determined to be the maximum tolerated dose. Doses of 4.8 to 8.0 mg/kg were expanded in Part B. A subgroup analysis of patients with OVC who received R-DXd at 4.8 to 8.0 mg/kg is reported here.

Results

As of 03 March 2023, 42 patients with OVC had received R-DXd at 4.8 (n = 7), 6.4 (n = 20), and 8.0 (n = 15) mg/kg: 40 (95%) had platinum-resistant disease, 29 (69%) had received prior bevacizumab, and 26 (62%) had received prior PARP inhibitors. The median prior lines of therapy was 4.0 (range 1 – 13). Twenty-one patients (50%) were still receiving study treatment. The median treatment duration was 18.1 wks (range, 3.0–93.9). Any-grade treatment-emergent adverse events (TEAEs) were experienced by 37 patients (88%), and grade ≥ 3 TEAEs were observed in 21 (50%). The most common all-grade TEAEs were nausea (55%), fatigue (40%), vomiting (38%), and diarrhoea (33%). AEs led to R-DXd discontinuation in 14% of patients. The confirmed overall response rate (RECIST v1.1) in patients with measurable disease was 38% (13 of 34): 67% (95% CI, 22.3 – 95.7; 4/6, including 1 CR) at 4.8 mg/kg, 33% (95% CI, 11.8 – 61.6; 5/15) at 6.4 mg/kg, and 31% (95% CI, 9.1 – 6.4; 4/13) at 8.0 mg/kg. Two patients with unconfirmed partial responses were still on treatment. Eleven of 21 GCIG-evaluable patients (52%) had a CA-125 response.

Conclusions

In heavily pretreated OVC patients without CDH6 preselection, R-DXd demonstrated acceptable safety and encouraging preliminary efficacy, which supports further clinical development in OVC.

Clinical trial identification

NCT04707248.

Editorial acknowledgement

Editorial assistance was provided by John McGuire, PhD, CMPP, of BOLDSCIENCE.

Legal entity responsible for the study

Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo, Inc.

Disclosure

K.N. Moore: Financial Interests, Personal, Advisory Board: Aadi, Alkemeres, Blueprint, Caris, Eisai, Hengrui, I-Mab, Myriad, Novartis, OncoNova, Pannavance, Gilead; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Daiichi Sankyo, GSK, Genentech/Roche, Immunogen, Merck; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, Aravive, Clovis, Duality, Daiichi Sankyo, GSK, Genentech/Roche, Immunogen, Lilly, Mereo, Mersana, Merck, OncXerna, VBL Therapeutics, Verastem, Zentalis, Regeneron, Exelexis; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, Duality, Daiichi Sankyo, Genentech/Roche, Immunogen, Lilly, OncXerna; Financial Interests, Personal and Institutional, Research Grant: Clovis, GSK, Genentech/Roche, Lilly, Verastem; Financial Interests, Personal and Institutional, Advisory Role: GSK, Genentech/Roche, GOG Partners Associate Director; Financial Interests, Personal, Invited Speaker: Research to Practice, OncLive, PRIME, PER, Great Debates and Updates; Financial Interests, Personal and Institutional, Leadership Role: GOG Partners Associate Director; Non-Financial Interests, Personal, Member of Board of Directors: ASCO BOD; Non-Financial Interests, Personal, Leadership Role: ASCO BOD; Non-Financial Interests, Personal and Institutional, Member of Board of Directors: GOG Foundation BOD; Non-Financial Interests, Personal and Institutional, Leadership Role: GOG Foundation BOD. K. Harano: Financial Interests, Personal, Invited Speaker: AstraZeneca, Taiho; Financial Interests, Personal, Principal Investigator: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, MSD; Financial Interests, Personal and Institutional, Principal Investigator: Chugai, MSD, Takeda; Financial Interests, Personal and Institutional, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal and Institutional, Advisory Board: Takeda; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo. B.I. Rini: Financial Interests, Institutional, Research Funding: AVEO, Arcus, Merck, Dragonfly Therapeutics, HiberCell, Incyte, Stata Oncology, ADC Therapeutics, Dracen Pharmaceuticals, Janssen, Adela, AstraZeneca, Pionyr, Tempus, VasGene Therapeutics, Gilead, POINT Biopharma, BMS, Pfizer, Daiichi Sankyo, Genentech, Arrowhead Pharmaceuticals, Exelixis, Surface Oncology, Aravive; Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Eisai, Nikang Therapeutics, EUSA, Athenex, Debiopharm, HiberCell. K. Sudo: Financial Interests, Institutional, Research Grant: Daiichi Sankyo. S. Kitano: Financial Interests, Personal and Institutional, Research Grant: Daiichi Sankyo, Nippon Boehringer Ingelheim, Eisai, Astellas, Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal and Institutional, Principal Investigator: Daiichi Sankyo, AstraZeneca, Pfizer, Nippon Boehringer Ingelheim, MSD, Eisai, Astellas, Ono Pharmaceutical Co., Ltd., GSK, Chugai, Incyte, Takeda, Eli Lilly Japan K.K., AbbVie, Loxo Oncology; Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca, Pfizer, MSD, Eisai, Ono Pharmaceutical Co., Ltd., GSK, Chugai, Takeda, Eli Lilly Japan K.K.; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Taiho, Novartis, Bristol Myers Squibb, Merck KGaA, Janssen; Financial Interests, Personal, Advisory Board: Novartis, Sumitomo Pharma, Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Role: Ono Pharmaceutical Co., Ltd., GSK; Financial Interests, Personal, Advisory Role: Rakuten Medical, Takara Bio Inc., ImmuniT Research Inc., United Immunity, Janssen; Financial Interests, Personal, Research Grant: Takara Bio Inc.; Financial Interests, Personal, Expert Testimony, Until March 2023: PMDA (Pharmaceuticals and Medical Devices Agency); Financial Interests, Personal, Research Grant, Public Research Funding in Japan: JSPS (Japan Society for the Promotion of Science), AMED (Japan Agency for Medical Research and Development). D.R. Spigel: Financial Interests, Institutional, Research Funding: AbbVie, Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus, Arrys Therapeutics, Ascendis Pharma, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceutical, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Endeavor, Erasca, Faeth Therapeutics, FujiFilm Pharmaceuticals, G1 Therapeutics, Roche/Genentech, Gilead Sciences, GSK, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, Ipsen, Janssen, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo Oncology, Lyell Immunopharma, MacroGenics, MedImmune, Merck, Millennium Pharmaceuticals, Moderna, Molecular Template, Monte Rosa Therapeutics, Nektar, Neon Therapeutics, Novartis, Novocure, Peloton Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Seagen, Shenzhen Chipscreen Biosciences, Stemline Therapeutics, Synthekine, Taiho, Tango Therapeutics, Tarveda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Zai Laboratory; Financial Interests, Institutional, Speaker, Consultant, Advisor: AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Evidera, GSK, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Novocure, Pfizer, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi. J. Lin: Financial Interests, Personal and Institutional, Full or part-time Employment: Daiichi Sankyo Inc.; Financial Interests, Personal and Institutional, Stocks/Shares: Daiichi Sankyo Inc. M. Kundu: Financial Interests, Institutional, Full or part-time Employment: Daiichi Sankyo Inc.; Financial Interests, Institutional, Sponsor/Funding: Daiichi Sankyo Inc. A. Bensmaine: Other, Personal, Full or part-time Employment: Daiichi Sankyo; Other, Personal, Stocks/Shares: Daiichi Sankyo. Y. Myobatake: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan-Florentine, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics. All other authors have declared no conflicts of interest.