Exposure–response analyses of cabozantinib in patients with metastatic renal cell cancer

Stefanie D. Krens*, Nielka P. van Erp, Stefanie L. Groenland, Dirk Jan A.R. Moes, Sasja F. Mulder, Ingrid M.E. Desar, Tom van der Hulle, Neeltje Steeghs, Carla M.L. van Herpen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aim: In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure–response relationship in patients with mRCC treated in routine care. Methods: Cabozantinib trough concentrations (Cmin) were collected and average exposure was calculated per individual. Exposure–response analyses were performed using the earlier identified target of Cmin > 750 ng/mL and median Cmin. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. Results: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0–5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median Cmin was 572 ng/mL (IQR: 496–701). Only 17% of patients had an average Cmin ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40–64). No improved PFS was observed for patients with Cmin ≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p =.001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14–0.70, p =.004). Conclusion: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.

Original languageEnglish
Article number228
JournalBMC Cancer
Volume22
Issue number1
DOIs
Publication statusPublished - 2 Mar 2022
Externally publishedYes

Keywords

  • Cabozantinib
  • Exposure
  • Pharmacodynamics
  • Pharmacokinetics
  • Renal cell carcinoma
  • Response
  • Survival
  • Toxicity

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