193P - Translational, PK, PD, and immunophenotyping analyses of tuvusertib + niraparib in a phase Ib open-label multicenter dose-escalation study in patients with advanced solid tumors (DDRiver Solid Tumors 301)

Background

Ataxia telangiectasia and Rad3 (ATR) and poly-ADP ribose polymerase (PARP) kinases are essential components of the DNA damage response. Combining the ATR inhibitor tuvusertib and PARP inhibitor niraparib may synergistically enhance synthetic lethality and increase cancer cell death. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) is assessing this combination; acceptable tolerability and preliminary efficacy have been observed (Yap, et al. ASCO 2024). Here, we report tuvusertib pharmacokinetics, changes in levels of ɣ-H2AX (a pharmacodynamic biomarker of ATR inhibition) and immunocyte subsets, and a retrospective analysis of molecular response (MR).

Methods

Patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment were enrolled. Intermittent tuvusertib (90–180 mg once-daily [QD]) and continuous or intermittent niraparib (100–200 mg QD) schedules were explored. MR was defined as >50% reduction in circulating tumor DNA (ctDNA), according to changes from baseline in somatic single nucleotide variant (SNV) allele frequencies or tumor-specific DNA-methylation levels.

Results

Tuvusertib exposure increased in a dose-related manner when combined with niraparib and was consistent with monotherapy observations. Tuvusertib + niraparib reduced ɣ-H2AX at 3 hours post-dose across all dose schedules (n=29); no trends were observed in changes in immunocyte subsets (n=43). MRs were observed in 50.0% of evaluable patients by both methylation-based and SNV-based ctDNA assay. MRs were more frequent at tuvusertib doses of ≥130 mg, compared with doses <130 mg. Alterations in BRCA1 were associated with greater reductions in ctDNA during treatment, compared with wild-type BRCA1 (p=0.017).

Conclusions

Target modulation across all tuvusertib + niraparib dose schedules was observed. No detrimental effect was seen on the immune system. MRs were observed in >50% of patients, with the strongest effects in patients with BRCA1-mutated tumors. MRs were more frequent at tuvusertib doses of ≥130 mg. Further clinical investigation of this combination in ovarian cancer is ongoing.

Clinical trial identification

NCT04170153.

Editorial acknowledgement

Medical writing services were provided by Melody Watson of Bioscript Group, Macclesfield, UK, and funded by Merck.

Legal entity responsible for the study

Merck.

Funding

Merck (CrossRef Funder ID: 10.13039/100009945).

Disclosure

A.W. Tolcher: Financial Interests, Personal, Other, Consultant: AbbVie, Aclaris Therapeutics, Affinia Therapeutics, Agenus, Asana Biosciences, Ascentage, Astex Pharmaceuticals, AxImmune, Bayer, Blu Print Oncology, Daiichi Sankyo, Exelixis, Gilde Healthcare Partners, HBM Partners, IDEA Pharma, Ikena Oncology, Immuneering, Immunomet Therapeutics, Impact Therapeutics, Karma Oncology, Karma Oncology, Kirilys Therapeutics, Lengo Therapeutics, Link Immunotherapeutics, Medicxi, Mekanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Nerviano Medical Sciences, Novo Nordisk, Nurix Therapeutics, Ocellaris Pharma, Eli Lilly, Partner Therapeutics, Pfizer, Pierre Fabre, Pyramid Biosciences, Qualigen Therapeutics, Roche, RYVU Therapeutics, Seattle Genetics, Singzyme, SK Life Science, SOTIO Biotechnology, Senti Biosciences, Sun Pharma Advanced Research Company (SPARC), Theratechnologies, Transcenta Therapeutics, Transgene, Trillium Therapeutics, Venus Oncology, Verastem Oncology; Financial Interests, Personal, Advisory Board: Adagene, Bioinvent, Boehringer Ingelheim, Bright Peak Therapeutics, Cullinan Oncology, Elucida Oncology, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Immunome, Jazz Pharmaceuticals, Mirati, NBE Therapeutics, Nested Therapeutics, Pheon Therapeutics, PYXIS Oncology, Roche, Spirea Limited, Vincerx, VRISE Therapeutics, Zentalis Pharmaceuticals, ZielBio. T.A. Yap: Financial Interests, Personal, Full or part-time Employment, Vice President, Head of Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): University of Texas MD Anderson Cancer Center; Financial Interests, Personal, Other, Consultant: AbbVie, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Astex, AstraZeneca, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, BioCity Pharma, Blueprint, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clovis, Cybrexa, Daiichi Sankyo, Dark Blue Therapeutics, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Entos, F-Star, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, MSD, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Prolynx, Radiopharma Theranostics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi Inc, Xinthera, Zai Labs, ZielBio; Financial Interests, Personal, Research Funding: Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, BMS, Boundless Bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Forbius, F-Star, GSK, Genentech, Haihe, Ideaya ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, MSD, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivace, Zenith; Financial Interests, Research Funding: Insilico Medicine; Financial Interests, Personal, Stocks or ownership: Seagen. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Fabre, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Personal, Royalties: Clovis Oncology; Financial Interests, Personal, Other, Honorarium: Sotio, Alligator Biosciences, GSK. D. Sommerhalder: Financial Interests, Personal, Full or part-time Employment: Texas Oncology; Financial Interests, Personal, Stocks/Shares: Texas Oncology, NEXT Oncology; Financial Interests, Personal, Other, Honoraria: Syneos; Financial Interests, Personal, Other, Consulting fees: Guidepoint; Financial Interests, Personal, Advisory Board: Revolution Medicines; Financial Interests, Personal, Research Funding: AbbVie, ADC Therapeutics, Ascentage Pharma Group, Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Bioscience, BioNTech, Bristol Myers Squibb, Fate Therapeutics, Gilead Sciences, GSK, Haihe Pharmaceutical, Iconovir Bio, Immuneering, Impact Therapeutics, Kura Oncology, MediLink Therapeutics, Mirati Therapeutics, Monopteros Therapeutics, Navire Pharma Inc, Nimbus Saturn Inc, NGM Biopharmaceuticals, OncoResponse Inc, Parthenon, Pfizer, Revolution Medicines, Symphogen, Tachyon Therapeutics, Teon Therapeutics, Vincerx Pharma, Vividion Therapeutics, ZielBio Inc.. J. Rodon: Financial Interests, Personal, Other, Non-financial support and reasonable reimbursement for travel: European Society for Medical Oncology, Loxo Oncology; Financial Interests, Personal, Other, consulting and travel fees: Ellipses Pharma, Molecular Partners, IONCTURA, Sardona, Mekanistic, Amgen, Merus, MonteRosa, Aadi, Bridgebio; Financial Interests, Personal, Other, Consulting fees: Bridgebio, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, Guidepoint; Financial Interests, Personal, Research Funding: Blueprint Medicines, MSD, Hummingbird, AstraZeneca, Yingli, Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Personal, Other, serving as investigator in clinical trials: Cancer Core Europe, Symphogen, BioAlta, Pfizer, Kelun-Biotech, GSK, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bicycle Therapeutics, AadiBioscience, ForeBio, Loxo Oncology, Hutchinson MediPharma, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, MonteRosa, Kinnate, Yingli, Debio, BioTheryX, Storm Therapeutics, Beigene, MapKure, Relay, Novartis, FusionPharma, C4 Therapeutics, Scorpion Therapeutics, Incyte, Fog Pharmaceuticals, Tyra, Nuvectis Pharma; Financial Interests, Personal, Other, serving as investigator in clinical trials serving as investigator in clinical trials: Merus. N. Wohlfeil: Financial Interests, Personal, Full or part-time Employment: Merck KGaA, Darmstadt, Germany. D. Wang, J. Kaur Mukker: Financial Interests, Personal, Full or part-time Employment: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. G. Sessa, A. Manginelli: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Janssen, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Personal, Research Grant: Bayer, Cellcentric, Daiichi Sankyo, Genentech/Roche, Genmab, GSK, Harpoon, Janssen, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics. All other authors have declared no conflicts of interest.