Abstract A050: ARRY-380, an oral HER2 inhibitor: Final phase 1 results and conclusions
Bibliographic record
Abstract
Abstract Background: Overexpression of HER2 occurs in ~25% of breast cancers. Despite the treatment successes achieved to date, improved clinical outcomes remain needed, including prevention and treatment of CNS metastases. Small-molecule HER2 inhibitors may have the advantage of being able to treat CNS and systemic disease simultaneously, particularly if used in combination with antibody-based therapy. However, currently available small molecules also target EGFR, with associated use limiting toxicities. Therefore, a specific small-molecule inhibitor of HER2 is needed. ARRY-380 is an oral, potent, reversible, ATP competitive, small molecule inhibitor of HER2. In cell-based assays, ARRY-380 was ~500-fold selective for HER2 versus EGFR. In multiple preclinical models, ARRY-380 demonstrated significant single agent and combination activity. In models of CNS disease, ARRY-380 was highly active as a single agent and demonstrated superior activity compared to lapatinib or neratinib. Thus, ARRY-380 was evaluated in a first in human clinical study. Methods: A Phase 1 clinical study of ARRY-380 was conducted in patients with advanced solid tumors that are believed to express HER2, with both dose-escalation (25 to 800 mg BID) and MTD expansion components. ARRY-380 was administered BID in 28 day cycles. Safety was assessed by AEs, clinical laboratory test results, physical examinations, vital signs and ECGs. Tumor response was assessed by RECIST every 2 cycles. Serial PK assessments were conducted in Cycle 1 on Days 1 and 3 and at steady state on Day 15. Results: A total of 50 patients were enrolled (33 dose-escalation and 17 expansion). These results focus on the 31 patients treated at doses ≥ MTD: 27 at the MTD of 600/650 mg BID and 4 at 800 mg BID. All 31 patients had HER2+ metastatic breast cancer (MBC) that had progressed on a prior trastuzumab containing regimen and 94% had received prior lapatinib, many who progressed on treatment. Dose limiting toxicity consisting of reversible Grade (G) 3 AST (n=1) and AST/ALT elevations (n=1) occurred in 2 of 4 patients treated at 800 mg BID, with an onset that occurred within 1 week, resolved within 2 weeks, and patients resumed treatment at a lower dose. Overall, ARRY-380 demonstrated an acceptable safety profile at the MTD. The most common treatment-related AEs were nausea, diarrhea, fatigue, vomiting, liver enzyme elevations and rash, and were primarily G1 with a low incidence of G2 (gastrointestinal events [n=2], fatigue [n=3], liver enzyme elevations [n=2]) or G3 (rash [n=1], liver enzyme elevations [n=1]) events. There were no treatment-related cardiac events, serious AEs or G4 AEs. ARRY-380 Cmax and AUC increased with increasing dose, with a Tmax of 2 hours and a t1/2 of 5 hours. Twenty-two HER2+ MBC patients with measurable disease were treated with ARRY-380 at doses ≥ 600 mg BID. In this heavily pretreated population, there was a clinical benefit rate (PR [n=3] plus SD for at least 6 months [n=3]) of 27%. Notably, 2 patients with PRs on ARRY-380 had confirmed progressions while on prior lapatinib- and trastuzumab-containing regimens. Conclusions: ARRY-380 has demonstrated an acceptable safety and PK profile at the MTD. As predicted for a HER2-selective agent that does not inhibit EGFR, there was a very low incidence of Grade 2/3 rash and diarrhea. ARRY-380 has shown promising signs of antitumor activity in a heavily pretreated HER2+ MBC population. These safety and preliminary efficacy data support the continued clinical development of ARRY-380 at the recommended dose of 600 mg BID. Citation Format: Virginia F. Borges, Steven K.L Chia, Susan D'Aloisio, Gina Fernetich, Bessie Sajan, Tessa McSpadden, Renae Chavira, Emma Barrett, Kari Guthrie, Jennifer Garrus, Tara Baetz, Stacy Moulder. ARRY-380, an oral HER2 inhibitor: Final phase 1 results and conclusions. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A050.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".