TY - JOUR
T1 - Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study)
AU - Fontana, Elisa
AU - Rosen, Ezra
AU - Lee, Elizabeth K
AU - Højgaard, Martin
AU - Mettu, Niharika B
AU - Lheureux, Stephanie
AU - Carneiro, Benedito A
AU - Cote, Gregory M
AU - Carter, Louise
AU - Plummer, Ruth
AU - Mahalingam, Devalingam
AU - Fretland, Adrian J
AU - Schonhoft, Joseph D
AU - Silverman, Ian M
AU - Wainszelbaum, Marisa
AU - Xu, Yi
AU - Ulanet, Danielle
AU - Koehler, Maria
AU - Yap, Timothy A
N1 - © The Author(s) 2024. Published by Oxford University Press.
PY - 2024/9/1
Y1 - 2024/9/1
N2 - BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects.METHODS: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate.RESULTS: The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity.CONCLUSION: The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy.CLINICAL TRIAL ID: NCT04497116.
AB - BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects.METHODS: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate.RESULTS: The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity.CONCLUSION: The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy.CLINICAL TRIAL ID: NCT04497116.
KW - Humans
KW - Female
KW - Male
KW - Middle Aged
KW - Neoplasms/drug therapy
KW - Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors
KW - Aged
KW - Adult
KW - Biomarkers, Tumor/blood
KW - Protein Kinase Inhibitors/administration & dosage
KW - Dose-Response Relationship, Drug
KW - Aged, 80 and over
U2 - 10.1093/jnci/djae098
DO - 10.1093/jnci/djae098
M3 - Article
C2 - 38710487
SN - 0027-8874
VL - 116
SP - 1439
EP - 1449
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 9
ER -
