Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), <i>PIK3CA</i>-mutated (mut) advanced breast cancer (ABC): Baseline biomarker analysis and progression-free survival (PFS) by duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy in the BYLieve study.
Bibliographic record
Abstract
1018 Background: ALP (PI3K-α selective inhibitor and degrader) + fulvestrant (FUL) is approved for pts with HR+, HER2– ABC and a tumor mutation in PIK3CA (̃ 40% of these pts). Primary analyses from the Phase 2 BYLieve study demonstrated efficacy and safety of ALP + ET in pts with PIK3CA-mut, HR+, HER2– ABC in the post-CDK4/6i setting. Post hoc analyses, including pts with disease progression within 6 mo of CDK4/6i + ET treatment (Tx), confirmed ALP benefit regardless of duration of prior CDK4/6i. Here we assess baseline biomarkers in circulating tumor DNA (ctDNA) by duration of prior CDK4/6i Tx and PFS in pts from BYLieve Cohorts A and B. Methods: In the BYLieve study, pts with PIK3CA-mut, HR+, HER2– ABC had CDK4/6i + aromatase inhibitor (Cohort A) or + FUL (Cohort B) as immediate prior Tx to receiving ALP + FUL and ALP + letrozole (LET), respectively. At data cutoff dates, pts had ≥ 18-mo follow-up in Cohort A and ≥ 6-mo in Cohort B. In each cohort, pts were grouped based on duration of prior CDK4/6i Tx (≤ 6 mo or >6 mo). Alterations were detected on ctDNA using next-generation sequencing (PanCancer V2 Panel). PFS was assessed in each cohort and by duration of prior CDK4/6i Tx. Results: Of 127 and 126 pts enrolled in Cohorts A and B, respectively, 98 (≤ 6-mo: 24; >6-mo: 74) and 94 (≤ 6-mo: 28; >6-mo: 66) were included in this analysis based on availability of ctDNA samples, data on duration of prior CDK4/6i, and centrally confirmed PIK3CA-mut disease. In this population, median (m) PFS (95% CI) was 8.2 mo (5.6 - 9.5) and 5.6 mo (3.7 - 7.1) in Cohorts A and B, respectively. In Cohort A, mPFS (95% CI) was 12.0 mo (5.5-non estimable) and 6.2 mo (5.4 - 8.5) in the ≤ 6-mo and >6-mo groups, respectively. The OncoPrint genomic profiles showed that pts in the ≤ 6-mo vs >6-mo group had a lower median ctDNA fraction and fewer detected gene alterations, including in genes associated with ET and/or CDK4/6i resistance, and fewer chromosomes 8/11 amplifications (linked to early relapse). In Cohort B, mPFS was 5.9 mo (3.5 - 11.0) and 5.6 mo (3.7 - 7.1) in the ≤ 6-mo and >6-mo groups, respectively. Both groups had high median ctDNA fractions and complex tumor mutation profiles reflecting more extensive treatment history. Conclusions: Lower median ctDNA fraction and lower mutational complexity observed in Cohort A ≤ 6-mo vs >6-mo group was associated with numerically longer mPFS, potentially indicating increased dependence on the mutant PI3K-α. In Cohort B, both ≤ 6-mo and >6-mo groups had high median ctDNA fractions and similar tumor mutation profiles. Additional ctDNA and tissue analyses are needed to elucidate the correlation between ALP + ET efficacy and treatment timing and baseline genomic complexity.
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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 | 0.005 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| 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".