537P - Exposure-response analysis of cabozantinib in patients with metastatic renal cell cancer treated in routine care

Background

In the registration trial, cabozantinib (cabo) exposure ≥750 μg/L correlated to improved tumor size reduction, response rate and progression-free survival (PFS) in metastatic renal cell cancer (mRCC) patients (pts). Because pts in routine care differ from pts in clinical trials, we explored the cabo exposure-response (E-R) relationship in mRCC pts treated in routine care.

Methods

Clinical data and cabo trough concentrations levels (C_min) were collected from all mRCC pts treated with cabo with ≥1 measured C_min at steady state in three Dutch hospitals. Based on C_min and reported cabo treatment details, the average exposure over the duration of treatment (ODT) was calculated for each patient. E-R analyses were performed using the C_min threshold of >750 μg/L and median C_min ODT for PFS. In addition, we explored the effect of dose reductions on PFS.

Results

In total 59 pts were included: 10% were favourable, 61% intermediate and 17% 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 pts. Dose reductions were needed in 58% of pts. Forty one pts discontinued cabo of whom 29 were due to progressive disease. Median C_min ODT was 572 μg/L (IQR 496-701). Only 17% of pts had a C_min ODT ≥750 μg/L. Median PFS was 52 wks (95%CI 40-64). No improved PFS was observed for pts with a C_min ODT ≥750 μg/L vs. <750 μg/L (19 vs. 52 wks, p=.2). A trend for longer PFS was observed for pts with a C_min ODT <572 μg/L vs. those with ≥572 μg/L (65 vs. 42 wks, p=.055). A prolonged PFS was observed in pts who received a dose reduction vs. those who did not (65 vs. 31 wks, 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 0.15-0.70, p=.004).

Conclusions

This exploratory study in routine care mRCC pts showed that the average cabo exposure was below the target of 750 μg/L in 83% of pts. No improved PFS was observed for pts with an exposure above the target of 750 μg/L or above the median exposure of 572 μg/L. Interestingly, a significantly longer PFS was observed for pts who received a dose reduction.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Radboud University Medical Center.

Funding

Has not received any funding.

Disclosure

N.P. van Erp: Other, Institutional, Research Grant: Novartis; Other, Institutional, Research Grant: Astellas; Other, Institutional, Research Grant: Janssen-Cliag; Other, Institutional, Research Grant: Pfizer; Other, Institutional, Advisory Board: Pfizer; Other, Institutional, Other, Honoraria: Bayer; Other, Institutional, Other, Honoraria: Sanofi. I.M.E. Desar: Other, Institutional, Research Grant: Novartis. S.F. Mulder: Other, Institutional, Other, Honoraria: Pfizer; Other, Institutional, Other, Honoraria: Roche; Other, Institutional, Other, Honoraria: Merck Sharp an Dohme; Other, Institutional, Other, Honoraria: Bristol Meyers Squibb. N. Steeghs: Other, Institutional, Other, Honoraria: Boehringer Ingelheim; Other, Institutional, Research Grant: AstraZeneca/MedImmune; Other, Institutional, Research Grant: Bayer; Other, Institutional, Research Grant: Bristol Meyers Squibb; Other, Institutional, Research Grant: Novartis; Other, Institutional, Research Grant: GlaxoSmithKline; Other, Institutional, Research Grant: Roche; Other, Institutional, Research Grant: Boehringer Ingelheim; Other, Institutional, Research Grant: Blueprint Medicines; Other, Institutional, Research Grant: AB Science; Other, Institutional, Research Grant: Deciphera; Other, Institutional, Research Grant: Genetech; Other, Institutional, Research Grant: Merck Sharp and Dohme; Other, Institutional, Research Grant: Amgen; Other, Institutional, Research Grant: Merus; Other, Institutional, Research Grant: Lilly; Other, Institutional, Research Grant: Incyte. C.M. Van Herpen: Other, Institutional, Research Grant: AstraZeneca; Other, Institutional, Research Grant: Bristol Meyers Squibb; Other, Institutional, Research Grant: Merck Sharp and Dohme; Other, Institutional, Research Grant: Merck; Other, Institutional, Research Grant: Ipsen; Other, Institutional, Research Grant: Sanofi; Other, Institutional, Research Grant: Novartis; Other, Institutional, Advisory Board: Bayer; Other, Institutional, Advisory Board: Bristol Meyers Squibb; Other, Institutional, Advisory Board: Ipsen; Other, Institutional, Advisory Board: Merck Sharp and Dohme; Other, Institutional, Advisory Board: Regeneron. All other authors have declared no conflicts of interest.