6 Durable response to immunotherapy-based regimens for IMDC favorable risk patients with metastatic clear cell renal cell carcinoma: a pooled analysis of four published randomized control phase 3 trials
Authors: Jang Albert , Margevicius Seunghee , Fu Pingfu , Zhong Mr Jeffrey , Kumar Ms Hamsa , Calaway Adam , Shoag Jonathan , Bukavina Laura , Jia Angela , Mendiratta Prateek , Rao Santosh , Sheng Iris , Brown Jason , Garcia Jorge , Barata Pedro 
Published: August 2024

Abstract

Background
An immune checkpoint inhibitor (ICI) backbone of either ICI doublet (ipilimumab-nivolumab [ipi-nivo]) or tyrosine kinase inhibitor (TKI) with ICI (such as axitinib-pembrolizumab [axi-pembro], cabozantinib-nivolumab [cabo-nivo], or lenvatinib-pembrolizumab [len-pembro]) is the current standard of care for previously untreated, metastatic clear cell renal cell carcinoma (mccRCC). The phase 3 trials that evaluated these four regimens were compared to sunitinib, with no direct head-to-head clinical trial data available. With at least 4-year follow up data available, we compared the long-term responders of the IMDC favorable risk patients enrolled in the four phase 3 trials (CheckMate 214, KEYNOTE-426, CheckMate 9ER, and CLEAR).

Methods
Pseudo individual patient data (IPD) was obtained from the Kaplan-Meier (K-M) curves using the graph digitizer software IPDfromKM R package to extract coordinates of points on the curves and applied the numerical algorithm to reconstruct survival results. The hazard ratios (HRs) of the favorable risk group for both progression-free survival (PFS) and overall survival (OS) comparing the experimental arms to sunitinib were extracted. Responses were measured at 24 (durable response [DR]) and 36 months (extreme durable response [EDR]) and long-term OS as OS ≥48 months. K-M method using the extracted IPD was used to estimate the survival rates at 24-month PFS, 36-month PFS, and 48-month OS. Then, we compared the survival rates at each time point using the generalized linear model for the survival rates at fixed time points obtained from the K-M method.

Results
Len-pembro was associated with the highest DR (57.2%) and EDR (44.5%), while ipi-nivo had the lowest DR (36.0%), and cabo-nivo had the lowest EDR (18.8%). There was no difference in 48 month-OS among regimens (p=0.11), ranging between 58.3% (cabo-nivo) and 70.6% (len-pembro). Comparing the sunitinib control arms among the four studies, a numerically higher PFS at 24 months (59%) and 36 months (40%) was observed in the CheckMate 214 trial compared to the ICI-TKI trials (25-35% and 15-20%, respectively). The 48-month OS for the sunitinib arms ranged from 55-70%, and no differences were observed among trials (p=0.55).
Comparisons of survival rates for the immunotherapy arm on fixed time-points for IMDC favorable risk subset of patients

Conclusions
ICI-based regimens provided durable responses to a significant number of patients with favorable risk mccRCC. While TKI-ICI were associated with higher DR and EDR, no differences in OS at 48 months were observed compared to ipi-nivo or sunitinib for favorable risk disease. Longer follow-up is necessary to evaluate long-term outcomes given the favorable prognosis of these patients. We acknowledge the limitations and caveats of cross-trial comparisons.