Cabozantinib real-world effectiveness in the second-line setting of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Zarba Martin , O'Sullivan Dylan , El Hajj Chehade Razane , McKay Rana R. , Pal Sumanta Kumar , Beuselinck Benoit , Donskov Frede , Lalani Aly-Khan A. , Crumbaker Megan , Li Haoran , Alva Ajjai Shivaram , Powles Thomas , Takemura Kosuke , Kollmannsberger Christian K. , Wong Shirley S. , Wood Lori A , de Velasco Guillermo , Cheung Winson Y. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2025

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Background:
Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy.
Methods:
We identified patients with mRCC from the IMDC who were treated with cabozantinib in the second-line (2L) setting from 2010 to 2023. These patients were stratified by IMDC risk groups and first-line (1L) treatment. We analyzed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), overall survival (OS) and performed a multivariable analysis adjusted by IMDC criteria at 2L.
Results:
A total of 603 patients were identified. Baseline characteristics are summarized in the table. For the entire cohort, the ORR was 25.7%, TTNT was 10.1 months (mo), TD was 8.9 mo and mOS was 19 mo. Among patients treated with 1L ipilimumab/nivolumab (n=190), anti-PD1 + TKI (n=148), and TKI alone (n=207), cabozantinib showed an ORR of 27.2%, 26.4%, and 25%, respectively; a median TTNT of 9.9, 10.3, and 9.7 mo; a median TD of 9.4, 8.2, and 8.3 mo. Median OS was 18.6, 17.6, and 21.3 mo, respectively. A multivariable analysis was unable to demonstrate that first-line ORR (CR/PR vs SD vs PD) or TTNT (< 12 vs ≥ 12 mo) predicts for second-line cabozantinib ORR in the overall cohort and by first-line therapy type. Specifically, patients with stable disease or with partial and complete response in 1L were associated with an OR for a response of 0.99 (95% CI 0.52-1.92) or 1.23 (95% CI 0.61-2.49), respectively. Similarly, a first-line TTNT of ≥12 months had an OR for response of 1.04 (95% CI 0.59-1.82).
Conclusions:
This study demonstrates that cabozantinib maintains efficacy comparable to that observed in the METEOR trial in a real-world setting, including in patients with prior immunotherapy combination therapies. Efficacy of 1L treatment does not predict efficacy of 2L cabozantinib.

Baseline characteristics.

Variable
Overall (N = 603)
IO-IO (N = 190)
IO-TKI (N = 148)
TKI Alone (N = 207)
Other (N = 58)
p-value

Non clear cell histology
107 (17.7)
33 (17.4)
26 (17.6)
28 (13.5)
20 (34.5)
0.003

Nephrectomy
416 (69.0)
97 (51.1)
110 (74.3)
166 (80.2)
43 (74.1)
<0.001

1st line IMDC Risk Fav/Int/Poor
83 (13.8)/296 (49.1)/101 (16.7)
10 (5.3)/100 (52.6) /46 (24.2)
37 (25)/62 (41.9) /20 (13.5)
29 (14)/99 (47.8)/27 (13)
7 (12.1)/35 (60.3)/8 (13.8)
<0.001

2nd line IMDC risk Fav/Int/Poor
56 (9.3)/269 (44.6)/108 (17.9)
7 (3.7)/90 (47.4)/45 (23.7)
25 (16.9)/63 (42.6)/24 (16.2)
19 (9.2)/87 (42.0)/32 (15.5)
5 (8.6)/29 (50.0)/7 (12.1)
0.002

Greater than 1 site of Metastasis
473 (78.4)
146 (76.8)
114 (77.0)
161 (77.8)
45 (77.6)
0.722

Brain Metastasis
36 (6.0)
18 (9.5)
5 (3.4)
13 (6.3)
0 (0.0)
0.022

Bone Metastasis
221 (36.7)
74 (38.9)
60 (40.5)
70 (33.8)
17 (29.3)
0.326

Liver Metastasis
106 (17.6)
32 (16.8)
26 (17.6)
39 (18.8)
9 (15.5)
0.926