Cabozantinib real-world effectiveness in the first-through fourth-line settings for the treatment of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Chun Loo Gan,Bernadett Szabados,Sumanta K Pal,Flora Yan,Ben Tran,Ulka N Vaishampayan,Georg A Bjarnason,Mathushan Subasri,Frede Donskov,Toni K Choueiri,Nityam Rathi,Shaan Dudani,Nazlı Dizman ,Jae‐Lyun Lee ,Aaron Richard Hansen ,Benoît Beuselinck ,Aly-Khan A Lalani ,Guillermo Velasco ,J.c Wells ,Daniel Y.c Heng

doi:10.1002/cam4.3717

Abstract

BackgroundCabozantinib is approved for metastatic renal cell carcinoma (mRCC) based on the METEOR and CABOSUN trials. However, real‐world effectiveness and dosing patterns of cabozantinib are not well characterized.MethodsPatients with mRCC treated with cabozantinib between 2011 and 2019 were identified and stratified using the International mRCC Database Consortium (IMDC) risk groups. First‐ (1L), second‐ (2L), third‐ (3L), and fourth‐line (4L) overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were analyzed. Dose reduction rates and their association with TTF and OS were determined.ResultsA total of 413 patients were identified. The ORRs across 1L to 4L were 32%, 26%, 25%, and 29%, respectively, and the median TTF rates were 8.3, 7.3, 7.0, and 8.0 months, respectively. The median OS (mOS) rates in 1L to 4L were 30.7, 17.8, 12.6, and 14.9 months, respectively. For patients treated with 1L PD(L)1 combination agent (n = 31), 2L cabozantinib had ORR of 22%, median TTF of 5.4 months, and mOS of 17.4 months. About 50% (129/258) of patients required dose reductions. The TTF and mOS were significantly longer for patients who required dose reduction vs. patients who did not, with an adjusted hazard ratio of 0.37 (95% CI 0.202–0.672, p < 0.01) and 0.46 (95% CI 0.215–0.980, p = 0.04), respectively. Limitations include the retrospective study design and the lack of central radiology review.ConclusionThe ORR and TTF of cabozantinib were maintained from the 1L to 4L settings. Dose reductions due to toxicity were associated with improved TTF and OS. Cabozantinib has clinical activity after 1L Immuno‐oncology combination agents.

Highlights

The sequencing of therapies in metastatic renal cell carcinoma has become increasingly topical and relevant
The randomized phase III METEOR study demonstrated that cabozantinib has superior progression free survival (PFS), overall survival (OS), and overall response rate (ORR) compared to everolimus in patients who progressed after previous vascular endothelial growth factor receptor (VEGFR)-targeted therapy, leading to its approval by the U.S Food and Drug Administration in 2016.2 In the following year, cabozantinib was further approved for use in the first-line setting for patients with International mRCC Database Consortium (IMDC) intermediate-/poor-risk disease
This was based on the randomized phase II CABOSUN trial, which demonstrated a significant improvement in PFS and ORR over the standard-of-care sunitinib for IMDC intermediate-/poor-risk patients.[3]

Summary

Introduction

The sequencing of therapies in metastatic renal cell carcinoma (mRCC) has become increasingly topical and relevant. Cabozantinib is an oral tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR), MET, and AXL.[1] The randomized phase III METEOR study demonstrated that cabozantinib has superior progression free survival (PFS), overall survival (OS), and overall response rate (ORR) compared to everolimus in patients who progressed after previous VEGFR-targeted therapy, leading to its approval by the U.S Food and Drug Administration in 2016.2 In the following year, cabozantinib was further approved for use in the first-line setting for patients with IMDC intermediate-/poor-risk disease. Cabozantinib has clinical activity after 1L Immuno-oncology combination agents

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Discussion

Conclusion