Abstract CT006: Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects
Bibliographic record
Abstract
Abstract Introduction: ATR kinase is a critical component of DDR machinery and is activated by DNA damage or replication stress. Elimusertib is a selective ATR inhibitor with promising antitumor activity in pts with advanced solid tumors with ataxia telangiectasia mutated (ATM) protein loss and/or ATM putative deleterious alterations (Yap et al. Cancer Discov 2021). We report here the safety and efficacy of elimusertib in expansion cohorts of pts with a range of cancer types and DDR deficiencies and/or ATM loss. We also explored an alternative dose schedule in pts with ATM aberrations. Methods: Pts with advanced solid tumors resistant or refractory to standard treatment were screened for pathogenic DDR defects by next-generation sequencing or ATM protein loss by immunohistochemistry (IHC) analysis of baseline tumor tissue. Pts were assigned to cohorts: colorectal cancer (CRC); castration-resistant prostate cancer (CRPC); HER2− breast cancer (BC); gynecologic (GYN, mainly ovarian and endometrial); and advanced cancers with ATM IHC loss. Pts were treated with elimusertib 40 mg twice daily (BID) 3 days on/4 days off (3 on/4 off). A schedule of 3 on/11 off was also explored by dose escalation in pts with ATM loss or inactivating mutation. Results: 143 pts received ≥1 dose of elimusertib 40 mg BID 3 on/4 off, including 24 CRC, 19 CRPC, 19 BC, 45 GYN, and 36 ATM loss. 56% of pts had ≥4 prior therapy lines. Drug-related grade 3 and 4 treatment-emergent adverse events (TEAEs) were observed in 69% and 15% of pts, respectively, mainly anemia, leukopenia/neutropenia, and thrombocytopenia leading to dose modification but not withdrawal. 32 pts were treated 3 on/11 off with doses from 60 to 120 mg BID. Compared with 3 on/4 off, drug-related grade ≥3 hematologic TEAEs and dose modifications improved at lower doses, with 80 mg 3 on/11 off determined as the recommended dose. In pts receiving elimusertib 3 on/4 off, 5 RECIST partial responses were observed: 1 in ovarian (BRCA1 heterozygous mutation), 1 in BC (BRCA2 mutation), and 3 in ATM IHC loss: 2 CRPC pts both with ATM mutations (1 heterozygous, 1 homozygous), including 1 with FANCA mutation; 1 esophageal with ATM mutation. In pts with ATM IHC loss, objective response rate (ORR) was 9% and disease control rate (DCR) was 65%. A similar ORR was seen on 3 on/11 off in pts with ATM aberrations. In GYN pts, ORR was 2.3% and DCR was 73%. Conclusions: Elimusertib monotherapy demonstrated clinical activity in pts with DDR defects. Overall safety was manageable and hematologic toxicity improved on the 3 on/11 off schedule. Further biomarker analysis is underway to identify potential gene signatures associated with response. Clinical development of elimusertib in combination with checkpoint inhibitors and chemotherapy is ongoing (NCT04095273, NCT04514497). Citation Format: Timothy A. Yap, David S. Tan, Anastasios Stathis, Geoffrey I. Shapiro, Satoru Iwasa, Markus Joerger, Jingsong Zhang, Ruth Plummer, Michael Sawyer, Aaron C. Tan, Vincent Castonguay, Nashat Gabrail, Nobuaki Matsubara, Gary Wilkinson, Matthias Ludwig, Yinghui Zhou, Claudia Merz, Joseph Hreiki, Neelesh Sharma, Johan deBono. Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT006.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.011 | 0.002 |
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".