Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases.
Bibliographic record
Abstract
513 Background: Modern registry data of MBC (Hurvitz ‘15; Witzel ‘15) suggest that HER2+ pts with CNS metastases (CNS+) have a poor prognosis. CNS disease is also associated with worse PS & QOL scores. Most systemic treatments for MBC have limited brain penetration & clinical trials often exclude CNS+ pts, causing a lack of prospective data on the outcome of CNS+ pts treated (tx) in the post-pertuzumab (P) / T-DM1 era. We report here the efficacy results of CNS+ & CNS- pts tx at the RP2D of TDM1 & ONT-380, a HER2 selective TKI with CNS penetration. Methods: Study ONT-380-004, a Phase 1b study of T-DM1 & escalating doses of ONT-380, enrolled HER2+ MBC pts, including pts with previously tx CNS lesions (stable or progressive) or untreated asymptomatic CNS lesions. We report the efficacy results in all pts tx at the RP2D of ONT-380 (300 mg BID) & TDM1 (3.6 mg/kg IV q 21 days) tx before 6/15/15. Eligibility: HER2+ MBC post taxane/trastuzumab (T); RECIST 1.1 measurable or non-measurable disease. All pts had baseline scans (including brain MRI). Efficacy assessments q6w x 6m, then q9w: OR & PFS by RECIST 1.1; CNS by modified CNS RECIST 1.1. Results: 45 pts were tx at the RP2D including 26 CNS+ (58%), the majority of whom were either progressing post-CNS treatment or had untreated CNS mets. Median age 51 y, 69% ER+, 31% ER-, 47% PS 0, 53% PS 1. Median 2 prior metastatic regimens: 100% taxane/T, 44% prior P, 22% prior lapatinib (L). In evaluable pts, OR was 47% (15/32) & was similar in CNS+ & CNS- pts: 47% (9/19) vs. 46% (6/13). Of the 26 CNS+ pts, 12 had measurable CNS mets, with best CNS response: 2 CRs, 2 PRs, 5 SDs (3/5 SD > 6m), 2 PDs, 1 NE. Median PFS overall was 6.5 m: CNS+ median PFS 6.5 m, & in the subset of CNS+ pts w progressing lesions post-tx or asymptomatic untx metastases, the median PFS was 6.7 m. The median PFS for CNS- was 8.2 m. The safety profile in CNS+ & CNS- pts was similar & unchanged from SABCS ’15; a complete safety update will be presented at ASCO. Conclusions: In a poor-prognosis HER2+ population with many CNS+ pts & with prior exposure to P or L, ONT-380 given in combination with T-DM1 resulted in promising PFS & ORR in both CNS- & CNS+ pts, with evidence of sustained CNS responses. Clinical trial information: NCT02025192.
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 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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".