Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB).
Bibliographic record
Abstract
1005 Background: Tucatinib (TUC) is an investigational, highly selective HER2 kinase inhibitor. HER2CLIMB (NCT02614794) showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression free survival (PFS) in all pts, prolongation of PFS in pts with brain metastases (BM), and objective response rate (ORR) when TUC was added to trastuzumab (T) and capecitabine (C). Primary methods and outcomes have been reported previously (Murthy NEJM 2019). We report the results of exploratory efficacy analyses in pts with BM. Methods: All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB had a baseline brain MRI. Pts with BM were eligible and classified as untreated, treated stable, or treated and progressing. Pts were randomized 2:1 to receive TUC or placebo, in combination with T and C. Efficacy analyses in pts with BM at baseline were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS (progression in the brain or death) and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR (ORR-IC) and IC duration of response (DOR-IC) were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy after local treatment until second progression, and time from randomization to second progression or death was evaluated. Results: Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P < 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3). In pts with isolated brain progression who continued study therapy after local treatment (n = 30), risk of second progression or death was reduced by 67% (HR: 0.33; 95% CI: 0.11, 1.02), and median PFS from randomization was 15.9 mo vs 9.7 mo, favoring the TUC arm. Conclusions: In pts with heavily previously treated HER2+ MBC with BM, TUC in combination with T and C doubled the ORR-IC, reduced risk of IC progression or death by two thirds and reduced risk of death by nearly half. If approved, TUC in combination with T and C has the potential to become a new standard of care in pts with HER2+ MBC with and without BM. Clinical trial information: NCT02614794 .
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".