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

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.