Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).
Bibliographic record
Abstract
699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.
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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 | 0.000 | 0.001 |
| 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".