20 Evaluating intermediate endpoints for overall survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors: an IMDC study
Authors: Saliby Renee Maria , Xie Wanling , Wells Connor J , Saad Eddy , Eid Marc , Semaan Karl , Labaki Chris , Ferrier Evan , Zarba Martin , Ebrahimi Hedyeh , Ravi Praful , Suarez Cristina , Morales Jose Ruiz , McKay Rana R , Powles Thomas , Wood Lori , Lalani Aly-Khan A , Pal Sumanta K , de Velasco Guillermo , Takemura Kosuke , Agarwal Neeraj , Braun David A , Heng Daniel Y , Choueiri Toni K 
Published: August 2024

Abstract

Background
In Phase 3 trials, the assessment for primary endpoint of overall survival (OS) necessitates extended follow-up periods, a larger pool of events, and higher associated costs. Hence, we sought to determine whether shorter intermediate (IEs) such as Objective Response (OR), Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients receiving immune checkpoint (ICI)-based therapy.

Methods
We included all International mRCC Database Consortium (IMDC) patients who received contemporary first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last follow-up. OR included investigators-assessed complete or partial response per RECIST1.1 criteria. First, we assessed the endpoint correlations across all follow-up times of individual patient data using Kendall’s Tau (KT) correlation by a Clayton copula. A KT &gt;0.49 indicates a strong correlation (Wicklin R., 2023). Then we evaluated associations of OS with TTF and TTNT status at the 6-month landmark using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by ICI type and years of ICI start. The KT correlation was estimated by the R GJRM package (https://www.r-project.org/). All other statistical analyses were done with SAS 9.4 software (SAS Institute, Cary, NC).

Results
The cohort consisted of 1667 patients with a median follow-up of 15.4 months (IQR: 7.1-28.6). For the 6-month landmark analysis in OS, patients who died or had less than 6 months of follow-up were excluded, affecting 278 for OR, 373 for TTF, and 380 for TTNT. Median age at 1L start was 63 years (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. A total of 1132 patients received dual ICI, while 535 received an ICI+TKI combination.
Over the entire follow-up of individual patient data, the Kendall’s Tau correlation was 0.49 (95%CI: 0.45-0.52) for TTF with OS and 0.67 (95%CI: 0.64-0.69) for TTNT with OS. The Kendall’s Tau correlations between endpoints were also similar in subgroup analyses by IMDC risk group and type of regimen and the strongest in the ICI+TKI subgroup with a Kendall’s Tau correlation of 0.73(0.66-0.78).
On the 6-month OS landmark analysis (Table), patients who discontinued their 1L regimen had poor OS (adjusted HR: 2.77 (95%CI: 2.16-3.55)). Additionally, those who transitioned to a 2L therapy within the first 6 months showed worse OS, reflected by an HR of 2.82 (2.22-3.59). Patients who did not have an objective response also had worse OS (adjusted HR: 2.74 (95%CI: 2.15-3.49)). On the other hand, patients with an objective response had an 18-month OS rate (equivalent of 12-month OS post the 6-month landmark) of 91% (95%CI: 88%-93%) vs 74% (95%CI: 70%-78%) for those with no response at 6 months.
Table. Landmark analysis of OS from 6 months of post therapy initiation, according to OR, TTF and TTNT event status at 6 months, in whole cohort and by IMDC and treatment groups.

Conclusions
Our study explored TTF, TTNT and OR as clinical IEs for OS. TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating treatment efficacy in ICI-based regimens.