Comparison of Proteasome Inhibition Activity between Carfilzomib and Bortezomib in the Phase 3 Endeavor Study
Bibliographic record
Abstract
Introduction: In the randomized phase 3 ENDEAVOR study, treatment with carfilzomib (56 mg/m2) and dexamethasone (Kd56) resulted in a superior progression-free survival (PFS; median 18.7 vs 9.4 months, respectively; hazard ratio (HR), 0.53; 95% confidence interval (CI), 0.44-0.65; one-sided P Methods: Patients in the Kd56 arm received intravenous (IV) carfilzomib as a 30-min infusion on days (D) 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m2 on D1 and 2 of cycle 1 [C1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) was given on D1, 2, 8, 9, 15, 16, 22, and 23. In the Vd arm, bortezomib (1.3 mg/m2; IV or subcutaneous administration) was given on D1, 4, 8, and 11 and dexamethasone (20 mg) was given on D1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Patients in both arms received treatment until withdrawal of consent, progression of disease, or unacceptable toxicity. Population PK and PDn were evaluated as exploratory endpoints. Blood for plasma PK assessments was collected from a subset of 133 Kd56 patients and analyzed by population PK analysis. PDn in the form of proteasome inhibition was measured in whole blood and isolated peripheral blood mononuclear cells (PBMCs) collected from 8 Kd56- and 9 Vd-treated patients at select sites during C1, 2, 3, 5, and 7, using LLVY-AMC as a substrate to measure chymotrypsin-like (CT-L) proteasome activity (Lightcap ES, et al. Clin Chem . 2000;46:673-83). Results: At the 56 mg/m2 dose, carfilzomib was eliminated with a half-life of approximately 1 hr; clearance at 56 mg/m2 was similar to that observed at 27 mg/m2 and 70 mg/m2 and was not impacted by infusion duration (10 min vs 30 min). Treatment with Kd56 resulted in reduction of CT-L activity in whole blood to undetectable levels by 1 hr post-dose on C1D8 (Figure). The extent of proteasome inhibition was greater at all time points for Kd56 vs Vd. Maximal inhibition of the activity of the β5 subunit in whole blood was higher in Kd56-treated pts (100% of C1D1 pre-dose activity) vs Vd-treated pts (74%). Although CT-L activity returned to pre-treatment levels prior to Kd56 dosing on C2D1 and C3D1, activity was reduced to undetectable levels post-dose on these days. Substantial recovery of β5 subunit activity in whole blood was observed in Vd-treated patients at the start of cycles 3, 5, and 7. In contrast, sustained inhibition of >50% was observed in the whole blood of Kd56-treated patients. A limitation of these data is that whole blood is composed primarily of anucleated cells. Prolonged and deeper suppression of proteasome activity by Kd56 compared with Vd demonstrated using whole blood LLVY-AMC methodology was also supported by PBMC assays. Conclusion: Carfilzomib induced a deep and prolonged proteasome inhibition compared with bortezomib. The proteasome inhibition profile of carfilzomib may be consistent with superiority in PFS and OS demonstrated by Kd56 relative to Vd. Figure. Comparison of CT-L proteasome activity between Kd56- and Vd- treated patients in C1, 3, 5, and 7 Disclosures Ludwig: Bristol-Meyers: Speakers Bureau; Celgene: Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Spencer: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kovacsovics: Seattle Genetics: Research Funding; Celgene: Consultancy; Flexus: Research Funding. Minuk: Celgene, Janssen, Amgen, BMS: Other: Personal fees, Research Funding. Kimball: Amgen: Employment, Equity Ownership. Pelham: Amgen Inc.: Employment, Equity Ownership. Ou: Amgen Inc.: Employment, Equity Ownership. Orlowski: BioTheryX: Consultancy, Membership on an entity9s Board of Directors or advisory committees.
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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 | 0.005 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| 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) | 0.002 | 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 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".