Unanchored simulated treatment comparison on survival outcomes using parametric and Royston-Parmar models with application to lenvatinib plus pembrolizumab in renal cell carcinoma

Background
Population-adjusted indirect comparison using parametric Simulated Treatment Comparison (STC) has had limited application to survival outcomes in unanchored settings. Matching-Adjusted Indirect Comparison (MAIC) is commonly used but does not account for violation of proportional hazards or enable extrapolations of survival. We developed and applied a novel methodology for STC in unanchored settings. We compared overall survival (OS) and progression-free survival (PFS) of lenvatinib plus pembrolizumab (LEN + PEM) against nivolumab plus ipilimumab (NIVO + IPI), pembrolizumab plus axitinib (PEM + AXI), avelumab plus axitinib (AVE + AXI), and nivolumab plus cabozontanib (NIVO + CABO) in patients with advanced renal cell carcinoma (RCC). Unanchored comparison was necessitated as the control groups differed in their use of PD-1/PD-L1 rescue therapy.

Methods
We fit covariate-adjusted survival models to individual patient data from phase 3 trial of LEN + PEM, including standard parametric distributions and Royston-Parmar spline models with up to 3 knots. We used these models to predict OS and PFS in the population of comparator treatments. The base case model was selected by minimum Akaike Information Criterion (AIC). Treatment effects were measured using difference in restricted mean survival time (RMST), over shortest follow-up of input trials, and hazard ratios at 6, 12, 18, and 24 months.

Results
The survival model with the lowest AIC was 1-knot spline odds for OS and log-logistic for PFS. Difference in RMST OS was 6.90 months (95% CI: 1.95, 11.36), 5.31 (3.58, 7.28), 5.99 (1.82, 9.42), and 11.59 (8.41, 15.38) versus NIVO + IPI (over 64.8 months follow-up), AVE + AXI (46.7 months), PEM + AXI (64.8 months), NIVO + CABO (53.0 months), respectively. Difference in RMST PFS was 4.50 months (95% CI: 0.92, 8.26), 8.23 (5.60, 10.57), 5.38 (2.06, 9.09), and 4.58 (0.09, 9.44) versus NIVO + IPI (over 57.8 months), AVE + AXI (44.9 months), PEM + AXI (57.8 months), NIVO + CABO (23.8 months), respectively. Hazard ratios indicated strong evidence of greater OS and PFS on LEN + PEM at most timepoints.

Conclusions
We developed and applied a novel methodology for comparing survival outcomes in unanchored settings using STC. Pending investigation with a simulation study or further examples, this methodology could be used for clinical decision-making and, if long-term data are available, inform economic models designed to extrapolate outcomes for the evaluation of lifetime cost-effectiveness.

Trial registration
NCT02811861 (registered: 23/06/2016).