Pharmacodynamic (PD) and immunophenotyping analyses of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib in a phase Ib study in patients with advanced unresectable solid tumors.
Bibliographic record
Abstract
2612 Background: Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases orchestrate the DNA damage response. A synthetic lethal relationship between ATR and ATM genes in cancer has been described1 and ATMi synergistically potentiate the efficacy of ATRi in vitro and in vivo.2 The combination of tuvusertib + lartesertib was investigated in Part A1 of the open-label, multicenter study DDRiver Solid Tumors 320 in patients with advanced unresectable solid tumors. Here, we report results of the PD and immunophenotyping analyses. Methods: PD analysis comprised γ-H2AX in serial blood samples, stimulated ex vivowith 4-NQO, bleomycin, or controls. Flow cytometry was used to measure target inhibition via γ-H2AX modulation in the CD45+ lymphocytes fraction and to explore the effect of tuvusertib + lartesertib on the immunophenotype (myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells subsets) in serial blood samples. Pharmacokinetic samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method. Time-matched blood samples were collected at baseline, 1, 3, 6, and 24 hours after first tuvusertib and lartesertib administration on days 1 and 8 of cycle 1 for the γ-H2AX analysis, and on days 1 and 15 of cycles 1 and 2 before treatment for immunophenotyping. Results: Immunophenotyping data and γ-H2AX levels were obtained from 41 and 34 patients, respectively. For tuvusertib, complete or almost complete target inhibition was seen at 1–6 hours after treatment, followed by a rebound above baseline after 24 hours, on both days 1 and 8 at doses of 130 and 180 mg once daily (QD). For lartesertib, a variable target inhibition of approximately 50 % on average was seen across all time points at doses of 100, 150 and 200 mg QD. No target inhibition was seen for tuvusertib at 90 mg QD and lartesertib at 50 mg QD (cohort 1). Tuvusertib + lartesertib induced a transient decrease of monocytes and natural killer (NK) cells, with partial or complete recovery to baseline levels during treatment breaks in schedules of 2 weeks on treatment followed by a treatment break of 1 or 2 weeks, respectively. Conclusions: Tuvusertib and lartesertib combination PD outcomes were in line with respective monotherapy observations.3,4 The combination did not cause any consistent change in the levels of immune cell subsets at all dose levels tested, except a mild, transient decrease in monocytes and NK cells, in line with the tuvusertib monotherapy observations. 1. Kantidze et al., Trends Cancer 2018;4(11):755–68. 2. Turchick et al., Mol Cancer Ther 2023;22(7):859–72. 3. Yap et al., Ann Oncol 2022;33(suppl_7):S197–S224. 4. Siu et al., Cancer Res 2023;83(8_Suppl):CT171. Clinical trial information: NCT05396833 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".