Impact of subsequent post-discontinuation immunotherapy on overall survival in patients with unresectable, stage III NSCLC from PACIFIC

Abstract

Background: In cancer trials, pts often receive subsequent lines of anticancer Tx following progression, which, in standard ITT analyses, can lead to bias and underestimation of OS Tx effect. In the phase 3 PACIFIC trial of durvalumab vs. placebo in Stage III NSCLC pts without progression after CRT, both primary endpoints PFS and OS were met, significantly improved with durvalumab. However, after discontinuation, many pts received further anticancer Tx (41% and 54% in the durvalumab and placebo groups), including immunotherapies (IMTs), which may have influenced OS. Using the Rank Preserving Structural Failure Time (RPSFT) model, we quantified the specific impact of subsequent IMT on OS in PACIFIC. Methods: RPSFT modeling is commonly used for analysis of trials with crossover. By assuming a similar effect for Tx in different sequences, RPSFT is capable to pinpoint the most likely effect size based on observed data. Here, we adapted RPSFT to isolate the likely effect of subsequent IMT by assuming similar mortality risk reduction for nivolumab, pembrolizumab, and durvalumab. RPSFT analyses were applied to quantify health outcomes for two hypothetical scenarios: (1) no subsequent IMT was received by pts in either arm, and (2) among placebo pts who received subsequent Tx (54%), all received IMT as first subsequent Tx, and durvalumab pts received no subsequent IMT, to test if delaying IMT was detrimental. Results: Among pts randomized to durvalumab and placebo, 8% (38/476) and 22% (53/237), respectively, received subsequent IMT. Within the ITT population, the HR for OS with durvalumab vs. placebo was 0.68 (95% CI, 0.53-0.87), with respective median OS not reached (NR) and 28.7 months. For scenario 1, there was minimal change in OS, with an estimated HR of 0.67 (95% CI, 0.52-0.86) and identical median OS estimates. For scenario 2, the estimated HR was 0.79 (95% CI: 0.62-1.00), with median OS NR and 32.2 months, respectively. Conclusions: After removing the effects of subsequent IMT, the OS benefit with durvalumab was still evident compared with the ITT analysis. In addition, early Tx with durvalumab after CRT appeared to be associated with improved OS compared with starting IMT after progression.