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

• Published in: BMC cancer Vol. 22; no. 1; p. 228
• Main Authors: Krens, Stefanie D, van Erp, Nielka P, Groenland, Stefanie L, Moes, Dirk Jan A R, Mulder, Sasja F, Desar, Ingrid M E, van der Hulle, Tom, Steeghs, Neeltje, van Herpen, Carla M L
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02.03.2022; BioMed Central; BMC
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Analysis; Anilides - administration & dosage; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Cabozantinib; Carcinoma, Renal cell; Carcinoma, Renal Cell - drug therapy; Care and treatment; Diagnosis; Dosage and administration; Dose-Response Relationship, Drug; Drug Monitoring - methods; Exposure; Female; Humans; Kidney Neoplasms - drug therapy; Male; Middle Aged; Pharmacokinetics; Progression-Free Survival; Pyridines - administration & dosage; Renal cell carcinoma; Response; Retrospective Studies; Risk factors; Survival; Treatment Outcome; Netherlands; Response; Cabozantinib; Pharmacodynamics; Renal cell carcinoma; Toxicity; Exposure; Pharmacokinetics; Survival
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-022-09338-1

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. Cabozantinib trough concentrations (C ) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C  > 750 ng/mL and median C . In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. 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 C was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C  ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C  ≥ 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). 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.