PMID- 29667066 OWN - NLM STAT- MEDLINE DCOM- 20190605 LR - 20240318 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 81 IP - 6 DP - 2018 Jun TI - Population exposure-response analysis of cabozantinib efficacy and safety endpoints in patients with renal cell carcinoma. PG - 1061-1070 LID - 10.1007/s00280-018-3579-7 [doi] AB - BACKGROUND: In the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure. OBJECTIVES AND METHODS: Exposure-response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints. RESULTS: Compared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (- 11.9 vs - 9.1 and - 4.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (grade >/= 1), fatigue/asthenia (grade >/= 3), diarrhea (grade >/= 3), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose. CONCLUSION: ER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs. FAU - Lacy, Steven AU - Lacy S AUID- ORCID: 0000-0002-1657-7600 AD - Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA. slacy@exelixis.com. FAU - Nielsen, Jace AU - Nielsen J AD - Ann Arbor Pharmacometrics Group, Inc., Ann Arbor, MI, USA. FAU - Yang, Bei AU - Yang B AD - Ann Arbor Pharmacometrics Group, Inc., Ann Arbor, MI, USA. FAU - Miles, Dale AU - Miles D AD - Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA. FAU - Nguyen, Linh AU - Nguyen L AD - Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA. FAU - Hutmacher, Matt AU - Hutmacher M AD - Ann Arbor Pharmacometrics Group, Inc., Ann Arbor, MI, USA. LA - eng PT - Clinical Trial, Phase III PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180417 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Anilides) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 1C39JW444G (cabozantinib) SB - IM MH - Anilides/*administration & dosage/adverse effects MH - Carcinoma, Renal Cell/*drug therapy MH - Disease-Free Survival MH - Dose-Response Relationship, Drug MH - Humans MH - Kidney Neoplasms/*drug therapy MH - *Models, Biological MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects MH - Pyridines/*administration & dosage/adverse effects MH - Survival Rate MH - Treatment Outcome PMC - PMC5973957 OTO - NOTNLM OT - Cabozantinib OT - Exposure-response modeling OT - Renal cell carcinoma COIS- CONFLICT OF INTEREST: Steven Lacy and Linh Nguyen are stockholders and current employees of Exelixis, Inc. Dale Miles was an employee of Exelixis, Inc. when this work was performed and is currently employed by Genentech, Inc. Jace Nielsen, Bei Yang, and Matt Hutmacher are employees of Ann Arbor Pharmacometrics Group (A2PG), Inc. who designed and conducted the ER modeling reported in this manuscript and was funded by Exelixis, Inc. Bei Yang is currently employed by Luoxin Biotechnology (Shanghai) Co., Ltd. The authors contributed significantly to the design, conduct, analyses, and interpretation of the data, and were involved in the preparation, review, and approval of this manuscript. ETHICAL APPROVAL: The clinical studies were conducted in accordance with the World Medical Association Declaration of Helsinki, the International Conference on Harmonisation Tripartite Guideline for Good Clinical Practice, and all applicable local regulations. Study protocols and informed consent documents were reviewed and approved by the Institutional Review Board (IRB) of participating institutions, and informed consent was obtained from all participants before any study-specified procedures were undertaken. EDAT- 2018/04/19 06:00 MHDA- 2019/06/06 06:00 PMCR- 2018/04/17 CRDT- 2018/04/19 06:00 PHST- 2017/11/07 00:00 [received] PHST- 2018/04/02 00:00 [accepted] PHST- 2018/04/19 06:00 [pubmed] PHST- 2019/06/06 06:00 [medline] PHST- 2018/04/19 06:00 [entrez] PHST- 2018/04/17 00:00 [pmc-release] AID - 10.1007/s00280-018-3579-7 [pii] AID - 3579 [pii] AID - 10.1007/s00280-018-3579-7 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2018 Jun;81(6):1061-1070. doi: 10.1007/s00280-018-3579-7. Epub 2018 Apr 17.