DNA Damage Response (DDR) Basket of Baskets (D-BOB) Trial: Phase 1/2 Study of the ATR inhibitor (ATRi) berzosertib and PD-L1 inhibitor avelumab in patients (pts) with advanced solid tumors with DDR molecular alterations
European Journal of Cancer(2022)
Abstract
Background: ATR is a central kinase involved in the DDR and replication stress response (RSR) and innate immune activation. This is the first report of the investigator-initiated phase 1/2 D-BOB trial (NCT04266912), funded by EMD Serono (CrossRef Funder ID: 10.13039/100004755). Materials and Methods: Pts with advanced cancers and actionable variants in ≥1 DDR gene (ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, MRE11A, MSH2, NBN, PALB2, RAD51, RAD51C/D, SMARCB1, VHL) were enrolled. Prior immunotherapy (IO), but not ATRi, was allowed. Dose escalation was conducted using Bayesian optimal interval design (dose level (DL) 1: berzosertib 240 mg/m2; DL2: berzosertib 480 mg/m2 weekly, plus avelumab 800 mg 2-weekly), followed by dose-expansion of pts with ATM mutated cancers. Primary objectives were safety and recommended phase 2 doses (RP2D). Secondary objectives were antitumor activity. Exploratory objectives assessed biomarkers of response/resistance through serial tumor and blood sampling for tumor whole exome, RNA sequencing and RPPA, RSR scores, immune biomarkers and ctDNA NGS. Results: 17 pts (7:10 M:F; mean age 56y (37–80y); ECOG PS 0:1 1:16) with advanced breast (n = 3), colorectal (n = 3), pancreas (n = 3), prostate (n = 2) and other (n = 6) cancers were enrolled. Pts had actionable germline/ somatic DDR mutations in ATM (n = 7), ARID1A (n = 5), ATRX (n = 3), BRCA1/2 (n = 3), CHEK2 (n = 2), CDK12 (n = 1), MSH2 (n = 1), PALB2 (n = 1), RAD51 (n = 1). 6/17 pts had prior PARP inhibitors; 6/17 had prior IO. 13/ 17 pts were treated in dose-escalation (DL 1: 7/13, DL 2: 6/13), 4/17 pts in dose-expansion. Common all-grade toxicities were chills (2/17), diarrhea (2/ 17), rash (2/17), thrombocytopenia (2/17). 2/17 pts had grade ≥3 transaminitis related to avelumab, 1 was a DLT. 2 RECIST 1.1 responses were observed (1 CR, 1 PR). 2 further pts had SD as best response, including a germline ATM-mutated pancreatic cancer pt treated at DL1 for 6 months and an ATM-mutated colorectal cancer pt treated at DL2. A RAD51/ATRX co-mutated PD-L1+ vaginal cancer pt treated at DL1 had a CR for 84+ weeks; a MSH2 mutated colorectal cancer pt treated at DL1 had PR (−30%) for 91+ weeks. In total, 19 tumor and 52 ctDNA samples were obtained longitudinally for ongoing analyses. Conclusions: The berzosertib plus avelumab combination was well tolerated with preliminary efficacy in genomically-selected cancers. RP2D was berzosertib 480 mg/m2 weekly plus avelumab 800 mg 2-weekly. DDR-aberrant doublet cohorts and triplet cohorts with peposertib (DNA-PK inhibitor) are planned. Conflict of interest: Ownership: T.A.Y holds stocks in Seagen. Advisory Board: T.A.Y has received fees for consulting from AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio. Board of Directors: N/A. Corporate-sponsored Research: T.A.Y has received research support (paid to his institution) from Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, Artios, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith. Other Substantive Relationships: N/A.
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Key words
atr inhibitor,advanced solid tumors,ddr,d-bob
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