Abstract P3-11-01: An updated systematic review and meta-analysis of the safety and efficacy of phosphoinositide 3-kinase inhibitors (PI3Ki) in advanced breast cancer
Bibliographic record
Abstract
Abstract Background In advanced breast cancer (ABC), the addition of pan-PI3Ki to the standard of care (SOC) treatment improves tumor response rate and progression free survival (PFS). Yet, further development of these drugs has been limited by their safety profile. Instead, selective PI3Ki were assessed and the Food and Drug Administration has recently approved the use of a selective PI3Ki based on a phase 3 randomized trial. Therefore, we updated our systematic review and meta-analysis to evaluate whether there is a difference in the efficacy and/or safety of pan versus selective PI3Ki in ABC. Methods The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials and Embase, were searched for relevant publications reporting randomized controlled trials between January 2000 and June 2019. Pooled hazard ratios (HR) for progression-free survival (PFS), and pooled odds ratios (OR) for objective response rate (ORR), disease control rate (DCR) and toxicity were computed and weighted using Mantel-Haenszel method and generic inverse variance. Subgroup analyses compared patients with and without PI3K pathway activation. Results Seven studies comprising 3,597 patients were included (5 studies with pan-PI3Ki and 2 studies with selective PI3Ki). Pan and selective PI3Ki decreased the risk of progression by 21% and 32% compared to SOC: HR: 0.79, 95%CI 0.0.71-0.88 and 0.68, 95%CI 0.57-0.81 respectively, p for test for subgroup differences: 0.16. An improvement in ORR was more pronounced with the use of selective versus pan PI3Ki: OR 2.67, 95%CI 1.78-4.00 and OR 1.31, 95%CI 1.01-1.71 respectively, p for test for subgroup differences: 0.004 and DCR was only improved with selective PI3Ki: OR 1.85 95%CI 1.37-2.51. A statistically significant increase in the toxicity of any grade and of grade 3 and higher was observed with pan and selective PI3Ki: 1) for any grade toxicity: OR 5.51, 95%CI 3.05-9.96, and OR 3.77, 95%CI 2.16-6.58 respectively, p for test for subgroup differences 0.16; 2) for grade 3 or higher toxicity: OR 1.91, 95%CI 1.76-2.08 and OR 2.41, 95%CI 2.07-2.82 respectively; p for test for subgroup difference 0.01. In subgroup analyses, the PFS improvement was more pronounced in the PI3K mutant subgroup: HR 0.72, 95%CI 0.63-81 for the PI3K mutant subgroup and HR 0.83, 95%CI 0.73-0.96 for the PI3K wild-type subgroup, p for test for subgroup differences 0.11. Conclusion While selective PI3Ki have a better effect on ORR, DCR and PFS in patients with ABC compared to pan PI3Ki; their toxicity profile is still clinically substantial. Rigorous safety monitoring and early medical intervention are needed to reduce treatment discontinuation, optimize efficacy and render these drugs more clinically usable. Citation Format: Jacques Raphael, Syed Hussaini, Kathleen I Pritchard, Prakesh Shah, Phillip Blanchette, Ricardo Fernandes, Danielle Desautels. An updated systematic review and meta-analysis of the safety and efficacy of phosphoinositide 3-kinase inhibitors (PI3Ki) in advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-01.
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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 | 0.015 | 0.035 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.022 | 0.039 |
| Bibliometrics | 0.009 | 0.010 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.004 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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".