Abstract P058: Anti-tumor activity of ATR inhibitor BAY 1895344 in patient-derived xenograft (PDX) models with DNA damage response (DDR) pathway alterations
Bibliographic record
Abstract
Abstract Introduction: The ATR (ataxia-telangiectasia and Rad3 related protein) kinase inhibitor BAY 1895344 is currently in clinical development for the treatment of advanced solid tumors and has demonstrated promising antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein. There is further need to identify robust predictive biomarkers to optimize patient selection for ATR inhibitors. For that purpose, we tested the antitumor activity of BAY 1895344 in patient-derived xenograft (PDX) models that are characterized by a variety of DDR alterations. Methods: PDX models were characterized by genomic sequencing and ATM loss by immunohistochemistry (IHC). PDX models with deleterious ATM, BRCA1 or BRCA2 mutations or loss derived from a variety of histologies were tested. BAY1895344 treatment was tested with two monotherapy regimens 20 mg/kg and 40 mg/kg PO BID both 3 days on/4 days off. For in vivo studies, the percent tumor volume change per time point was calculated as a relative level of tumor growth change from baseline: , where is the tumor volume at time and is the tumor volume at baseline. T/C ratio was defined as the ratio of tumor volume change in treated vs control group. An event in each animal was defined as a doubling of tumor volume from initial tumor volume. Event free survival was analyzed by Kaplan-Meier survival analysis. Results: Seventeen PDX models from sixteen patients were treated with BAY 1895344. The PDX models spanned multiple tumor types: breast, colon, pancreas, and cholangiocarcinoma. BAY 1895344 has shown potent and dose-dependent antitumor activity. Strongest activity was observed with BAY 1895344 at 40 mg/kg PO BID applied for 3 days on and 4 days off treatment, achieving a regression or T/C ratio <0.4 in 6 of 17 models. Eleven models showed statistically significant prolongation of event-free survival. BAY 1895344 had anti-tumor activity in PDX models with ATM loss as well as BRCA alterations. Notably BAY 1895344 had antitumor activity in an ATM-deleted PDX model with acquired PARP inhibitor resistance generated in the lab as well as a PDX model generated from a BRCA-mutant patient with clinically acquired PARP resistance. Conclusion: ATR inhibition via treatment with BAY 1895344 shows potent antitumor activity as monotherapy in selected models that are characterized by certain DDR alterations and even those that have developed resistance to PARP inhibition. Further analyses are ongoing to define predictors of sensitivity to BAY 1895344 as well as pharmacodynamic markers of efficacy/response as a single agent or in rational combinations Citation Format: Christian X. Cruz Pico, Dali Li, Christopher D. Lanier, Kurt Evans, Maria G. Raso, Timothy DiPeri, Yasmeen Rizvi, Min Jin Ha, Huiqin Chen, Ming Zhao, Argun Akcakanat, Xiaofeng Zheng, Gokce Toruner, Erkan Yuca, Stephen Scott, Antje M. Wengner, Timothy A. Yap, Funda Meric-Bernstam. Anti-tumor activity of ATR inhibitor BAY 1895344 in patient-derived xenograft (PDX) models with DNA damage response (DDR) pathway alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P058.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".