Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).
Bibliographic record
Abstract
3600 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for RAS wild-type (WT) mCRC. Limited data suggest a correlation between Cet clearance and progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts with KRAS WT mCRC who participated in the randomized phase III NCIC CO.20 trial. Methods: Standard Cet doses ± brivanib (Briv) were administered. Intermittent blood samples were obtained, and analyzed by ELISA for Cet. Pop-pK analysis was conducted to estimate Cet clearance. Pts were divided into quartiles according to clearance parameters to evaluate exposure-outcome with overall survival (OS), PFS, response rate (RR), and toxicity. Results: Blood samples were available from 703 pts. Cet clearance was best described as a one-compartment model with a saturable elimination (defined by Vmax and Km). Mean values (± standard deviation) were 5.6 ± 1.4 L for V, 10.5 ± 2.8 mg/h for Vmax, and 403.1 ± 2.0 mg/L for Km. Vmax and Km were significantly associated with OS, but not PFS or RR. Median OS for pts in the highest quartile of Vmax was 7.8 versus (vs.) 11.6 ms for pts in the lowest Vmax quartile (HR 1.12, 95% confidence interval (CI) 1.05-1.20, p< 0.001). In the highest Km quartile, median OS was 11.6 vs. 7.6 ms in the lowest Km quartile (HR 0.89, 95% CI 0.83-0.96, p= 0.001). Pts with the lowest clearance parameters (lowest Vmax and highest Km) had significantly longer OS (11.6 ms) compared to pts with the highest clearance (highest Vmax and lowest Km) (7.6 ms) (HR 0.67, 95% CI 0.53-0.83, p< 0.001). Overall incidences of grade 3/4 toxicity were not associated with Cet clearance. However, pts with the lowest clearance parameters had more frequent grade 3 diarrhea (OR 0.23, p= 0.005). Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with lower Cet clearance have significantly improved OS and increased likelihood of grade 3 diarrhea. Further studies are needed to identify individual patient factors associated with Cet clearance, and to optimize Cet dosing based on individual pk assessments.
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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 | 0.002 |
| 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) | 0.001 | 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".