Pharmacokinetic (PK) and pharmacodynamic (PD) findings from a phase 1b study of ATR inhibitor tuvusertib + anti-PD-L1 avelumab in patients with advanced unresectable solid tumors.
Bibliographic record
Abstract
2614 Background: Ataxia telangiectasia and Rad3-related protein (ATR) kinase is critical in the DNA damage response, and its inhibition modulates antitumor immunity. The combination of ATR inhibitor (ATRi) + immune checkpoint inhibitor (ICI) has shown activity in patients with ICI-resistant tumors and may have the potential to overcome ICI resistance and induce antitumor immune responses. Methods: Part B1 of the open-label, multicenter study DDRiver Solid Tumors 320 investigated safety, tolerability, PK, and PD, including effects on immune cells, of ATRi tuvusertib in combination with the ICI avelumab (anti-PD-L1) in patients with advanced unresectable solid tumors. Flow cytometry was used to analyze tuvusertib target inhibition via γ-H2AX modulation in the CD45+ fraction of ex-vivo stimulated peripheral blood mononuclear cells, and to explore the effect on the peripheral immunophenotype. Tuvusertib PK samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method. Results: 22 patients were enrolled and treated with tuvusertib 180 mg once daily on a schedule of 2 weeks (w) on treatment followed by a treatment break of 1 or 2 w, and avelumab 800 mg once every 2 weeks (Q2W). The 2 w on/1 w off schedule, corresponding to the recommended dose for expansion (RDE) for tuvusertib monotherapy, was chosen for further exploration. At this schedule, 2 of 9 patients evaluable for dose-limiting toxicity (DLT) experienced DLTs: Grade 3 ALT and Grade 3 AST increase (n=1), and Grade 3 anemia requiring transfusion (n=1). A patient with chordoma experienced a RECIST v1.1 partial response. Preliminary PK data for tuvusertib suggested rapid absorption with median Tmax range of ~2–3 h and mean elimination half-life range of ~2.93 to 4.23 h, with ~2-fold accumulation of steady-state area-under-the-curve following multiple doses. Exposure of tuvusertib in combination with avelumab was consistent with tuvusertib monotherapy exposure (1). PD showed complete or almost complete target inhibition at 1–6 h after tuvusertib 180 mg followed by rebound above baseline after 24 h on days 1 and 8 of cycle 1. No clear trend of variation in absolute counts of myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cell subtypes was detected. Conclusions: Tuvusertib and avelumab were combined at established monotherapy doses with no new safety findings. Tuvusertib PD and exposure data were in line with monotherapy observations. The combination did not cause any consistent change of the immunophenotype. Given the accumulating evidence of ATRi as an immunosensitiser (2), further evaluation of this combination in patients with ICI-resistant advanced solid tumors is warranted. 1. Yap T et al., Ann Oncol 2022;33(suppl_7):S197–S224. 2. Besse B et al., JTO 2022;17(suppl_9):S41–S42. 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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".