Assessing the Influence of Subsequent Immunotherapy on Overall Survival in Patients with Unresectable Stage III Non-Small Cell Lung Cancer from the PACIFIC Study

Abstract

Background: Historically, the standard of care for patients with unresectable, Stage III non-small cell lung cancer had been concurrent chemoradiotherapy. However, outcomes had been poor, with approximately 15% to 32% of patients alive at 5 years. In the placebo-controlled Phase III A PACIFIC trial, consolidation treatment with durvalumab after concurrent chemoradiotherapy significantly improved overall survival (OS) and progression-free survival in patients with unresectable, Stage III non-small cell lung cancer, establishing this regimen as a new standard of care in this setting. In the PACIFIC trial, crossover between treatment arms (durvalumab or placebo) was not permitted. However, after discontinuation from study treatment, patients from both arms of PACIFIC could switch to subsequent anticancer therapy, including durvalumab and other immunotherapies, which is known to influence standard intention-to-treat analysis of OS, potentially underestimating the effect of an experimental drug. Moreover, the introduction of immunotherapies has demonstrated marked improvements in the postprogression, metastatic non-small cell lung cancer setting.

Objective: To examine the influence of subsequent immunotherapy on OS in the PACIFIC trial.

Methods: Both a Rank Preserving Structural Failure Time Model (RPSFTM) and modified 2-stage method were used. RPSFTM assumes that a patient's survival time with no immunotherapy (counterfactual survival time) is equal to the observed time influenced by immunotherapy, multiplied by an acceleration factor, plus the time not influenced. The modified 2-stage method estimates the effect of immunotherapy by comparing postsubsequent-treatment-initiation survival times between patients with and without subsequent immunotherapy. In both models, OS was adjusted to reflect a hypothetical scenario in which no patients received subsequent immunotherapy. RPSFTM was also used for scenarios in which subsequent immunotherapy was received by increasing proportions of placebo patients but none of the durvalumab patients.

Results: In the intention-to-treat analysis (3-year follow-up), durvalumab improved OS versus placebo (stratified hazard ratio = 0.69; 95% CI, 0.55-0.86). Overall, 10% and 27% of durvalumab and placebo patients, respectively, received subsequent immunotherapy. With subsequent immunotherapy removed from both arms, estimated hazard ratio was 0.66 (95% CI, 0.53-0.84) with RPSFTM and 0.68 (95% CI, 0.54-0.85) with the modified 2-stage method. With subsequent immunotherapy removed from the durvalumab arm only (RPSFTM), estimated hazard ratio increased as the proportion of placebo patients receiving subsequent immunotherapy increased, up to 0.75 (95% CI, 0.60-0.94) maximum (assuming all placebo patients with subsequent treatment received immunotherapy).

Conclusions: Results were consistent with the intention-to-treat analysis, supporting the conclusion that durvalumab after chemoradiotherapy provides substantial OS benefit in patients with Stage III, unresectable non-small cell lung cancer. ClinicalTrials.gov identifier: NCT02125461 (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

Keywords: Durvalumab; Modified 2-stage method; Overall survival; PACIFIC; Rank Preserving Structural Failure Time Model.

© 2021 The Author(s).

Figures

Figure 1

Modified 2-stage method (M2SM): Procedure for transforming the postsecondary-baseline survival times of patients in the placebo arm who received subsequent immunotherapy into what their survival times would have been if they had not received immunotherapy (this same procedure can be applied to patients in the durvalumab arm). AFT = Accelerated failure time.

Figure 2

Rank Preserving Structural Failure Time Model (RPSFTM): Observed and adjusted Kaplan-Meier curves for overall survival (OS) when no subsequent immunotherapy is received in either treatment arm (based on the log-rank test). HR = hazard ratio; ITT = intention to treat; NR = not reached.

Figure 3

Rank Preserving Structural Failure Time Model (RPSFTM): Observed and adjusted Kaplan–Meier curves for overall survival (OS), assuming that patients in the placebo arm received subsequent immunotherapy as prescribed in the trial, and that patients in the durvalumab arm received no subsequent immunotherapy (based on the log-rank test). HR = hazard ratio; ITT = intention to treat; NR = not reached.

Figure 4

Modified 2-stage method: Observed and adjusted Kaplan-Meier curves for overall survival (OS) when no subsequent immunotherapy is received in either treatment arm. HR = hazard ratio; ITT = intention to treat; NR = not reached.