Evaluation of circulating kidney injury marker-1 (KIM-1) as a prognostic and predictive biomarker in advanced renal cell carcinoma (aRCC): Post-hoc analysis of CheckMate 214.
Wenxin Xu, Sai Vikram Vemula, Robert J. Motzer, Aparna Chhibber, Deepthi Chowbene, Nahuel Perrot, Xiaowen Liu, Joseph V. Bonventre, Toni K. Choueiri, David F. McDermott, Saurabh Gupta, Rupal S. Bhatt
Abstract
437 Background: CheckMate 214 established nivolumab and ipilimumab (NIVO+IPI) as a first line standard of care regimen with superior survival and durable response versus sunitinib (SUN) in advanced RCC. Previous studies have shown that high levels of circulating KIM-1 are associated with worse prognosis and reduction in KIM-1 levels is associated with benefit from adjuvant immunotherapy. In this post-hoc analysis we evaluated whether KIM-1 levels at baseline and after 1 cycle of NIVO+IPI or SUN are associated with treatment outcomes in CheckMate 214. Methods: Patients with advanced RCC were randomized to NIVO+IPI or SUN as previously described. Serum KIM-1 was measured at baseline and 3 wks after first treatment dose using an enzyme based electrochemiluminescence assay. The association between KIM-1 levels and clinical outcomes was evaluated using Kaplan-Meier and Cox proportional hazards analyses. Results: We analyzed serum from 821 patients (75% of the CM 214 ITT population). Median KIM-1 at baseline was 660.4 pg/mL. Across both arms, higher KIM-1 levels were associated with shorter overall survival (OS) independent of IMDC risk group, nephrectomy status, and tumor burden. Benefit for NIVO+IPI versus SUN was seen across KIM-1 tertiles. Decrease in KIM-1 from baseline to C2D1 was strongly associated with progression free survival (PFS) and OS among patients treated with NIVO+IPI (Median PFS 70.8 months vs 4.2 months for patients with >30% decrease vs >30% increase in KIM-1, with median OS 85.4 vs 26.6 months, overall response rate (ORR) 69.3 % vs 13.9%), but not in patients treated with SUN. Conclusions: In CheckMate 214, increased levels of baseline circulating KIM-1 were associated with worse clinical outcomes both in NIVO+IPI and SUN arms. The extent of reduction in serum KIM-1 just 3 wks after single cycle of NIVO+IPI was associated with long term efficacy of this IO doublet. Circulating KIM-1 may be a useful minimally invasive biomarker for monitoring patients on RCC immunotherapy. KIM-1 change at 3 weeks (prior to second dose of NIVO+IPI) and association with outcomes (NIVO+IPI arm). 3 week KIM-1 change N (%) ORR, % (95% CI) mPFS, months (95% CI) mOS, months (95% CI) >30% Decrease 140 (31.7) 69.29 (60.94-76.80) 70.80 (17.84- NA) 85.36 (63.08- NA) >10-30% Decrease 87 (19.7) 36.78 (26.69-47.80) 11.43 (6.28-18.20) 66.14 (40.44-80.10) <10% Change 86 (19.5) 30.23 (20.79-41.08) 15.41 (10.32-20.73) 52.70 (30.26-70.67) >10-30% Increase 56 (12.7) 23.21 (12.98-36.42) 7.13 (4.17-16.79) 40.34 (23.82-58.41) >30% Increase 72 (16.3) 13.89 (6.87-24.06) 4.17 (3.02-8.08) 26.61 (18.79-38.44)