Abstract P4-14-20: A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC)
Bibliographic record
Abstract
Abstract Background: ONT 380 is a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects. Preclinical studies demonstrate synergism with trastuzumab (T) and chemotherapy, as well as activity in models of HER2+ CNS disease. Based on the potential for increased clinical activity of dual HER2 blockade in the context of a targeted cytotoxic agent, we evaluated the safety, tolerability, and anti-tumor activity of ONT-380 in combination with T-DM1 in patients (pts) with MBC with and without CNS metastases (mets). Methods: 3+3 dose escalation with MTD expansion cohorts in pts with/without CNS mets evaluating ONT-380 (300 or 350 mg PO BID) combined with T-DM1 3.6 mg/kg IV q 21 days. Prior treatment with T and taxane was required; prior lapatinib and asymptomatic brain mets (treated or untreated) were allowed. Assessments included safety, PK, and systemic (RECIST 1.1) and CNS (modified RECIST) tumor response, with brain MRI at baseline and q 6 wks in pts with CNS mets at baseline. DLT was defined as the occurrence of protocol-specified events during the 1st treatment cycle. Results: As of 01 June 2015, 51 pts have been enrolled and have received between 1 and 22 cycles, with safety data available for 43 pts (n=36 at 300 mg BID; n=7 at 350 mg BID). Pts had a median of 2 prior treatments for MBC, including T (n=43); pertuzumab (n=15) and lapatinib (n=7). The MTD for ONT-380 was 300 mg BID with 5/36 pts (14%) with DLT (Gr 3 AST/ALT [n=4]; Gr 2 vomiting/Gr1 diarrhea [n=1]) vs. 3/7 pts (43%) with DLT at 350 mg BID (Gr 3 vomiting [n=1]; Gr 3 hypersensitivity [n=1]; Gr 3 fatigue [n=1]). Overall, the majority of AEs have been Gr 1 or 2. The most common AEs, regardless of relationship, were nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia. Gr 3 AST/ALT elevation has occurred in 7/43 pts (16%), with no events meeting Hy's law, and has been reversible with dose interruption and reduction except in 2 pts found to have progressive liver mets. No Gr 3 diarrhea has occurred at any dose. ONT-380 PK was dose proportional, and no drug-drug interaction was observed with T-DM1. In 33 of 43 pts with data available from at least one follow-up scan to evaluate response, best systemic response regardless of dose was 11 PR, 16 SD, and 6 PD, with clinical benefit rate (CBR= CR, PR, or SD >6 mos) of 19/33 (58%). The most common reason for treatment discontinuation was PD, with 3 pts coming off study for AEs (n=1 each of Gr 3 hypersensitivity, Gr 2 vomiting, Gr 3 AST/ALT). Eight pts to date have been evaluable for CNS response (untreated or progressive CNS mets with ≥1 follow-up MRI), with best CNS response of 1 CNS CR, 2 CNS PR, and 5 CNS SD, with a CNS CBR of 5/8 (63%). All pts with CNS response are still active. Conclusion: Treatment with ONT-380 300 mg BID and T-DM1 3.6 mg/kg has been tolerable. Early evidence of anti-tumor activity has been seen, including clinical benefit in patients with CNS mets. Updated results will be presented. Citation Format: Ferrario C, Hamilton E, Aucoin N, Falkson CI, Khan Q, Krop IE, Welch S, Bedard PL, Conlin A, Chaves J, Vo A, Walker L, Borges V. A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-20.
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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 | 0.000 |
| 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) | 0.004 | 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".