Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study) Journal Article
| Authors: | Fontana, E.; Rosen, E.; Lee, E. K.; Højgaard, M.; Mettu, N. B.; Lheureux, S.; Carneiro, B. A.; Cote, G. M.; Carter, L.; Plummer, R.; Mahalingam, D.; Fretland, A. J.; Schonhoft, J. D.; Silverman, I. M.; Wainszelbaum, M.; Xu, Y.; Ulanet, D.; Koehler, M.; Yap, T. A. |
| Article Title: | Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study) |
| Abstract: | 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. © 2024 The Author(s). |
| Keywords: | adult; cancer survival; controlled study; treatment response; aged; aged, 80 and over; middle aged; major clinical study; clinical trial; constipation; drug tolerability; fatigue; neutropenia; advanced cancer; area under the curve; diarrhea; dose response; drug dose reduction; drug efficacy; drug safety; monotherapy; side effect; solid tumor; treatment duration; pancreas cancer; endometrium cancer; neoplasm; neoplasms; melanoma; progression free survival; ovary cancer; phase 2 clinical trial; breast cancer; anemia; protein kinase inhibitor; leukopenia; nausea; thrombocytopenia; vomiting; cohort analysis; antineoplastic activity; dose-response relationship, drug; tumor marker; drug dose escalation; dyspnea; prostate cancer; protein kinase inhibitors; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; maculopapular rash; blood; head and neck cancer; dosage schedule comparison; multicenter study; long term care; soft tissue sarcoma; atm protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; optimal drug dose; maximum plasma concentration; time to maximum plasma concentration; drug half life; kidney cancer; drug therapy; drug dose regimen; erythrocyte transfusion; atr protein, human; dose calculation; bile duct cancer; dysgeusia; gastrointestinal cancer; non small cell lung cancer; post hoc analysis; molecularly targeted therapy; phase 2 clinical trial (topic); decreased appetite; phase 1 clinical trial (topic); clinical outcome; drug intermittent therapy; overall response rate; response evaluation criteria in solid tumors; very elderly; humans; human; male; female; article; circulating tumor dna; ataxia telangiectasia mutated proteins; biomarkers, tumor; camonsertib |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 116 |
| Issue: | 9 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2024-09-01 |
| Start Page: | 1439 |
| End Page: | 1449 |
| Language: | English |
| DOI: | 10.1093/jnci/djae098 |
| PUBMED: | 38710487 |
| PROVIDER: | scopus |
| PMCID: | PMC11378309 |
| DOI/URL: | |
| Notes: | Source: Scopus |
