Phase 3 study of durvalumab with SBRT for unresected stage I/II, lymph-node negative NSCLC (PACIFIC-4/RTOG3515).
Authors: Robinson Clifford Grant , Xing Ligang , Tanaka Hiroshi , Tasaka Sadatomo , Badiyan Shahed N , Nasrallah Haitam , Biswas Tithi , Shtivelband Mikhail , Schuette Wolfgang , Shi Anhui , Hepner Adriana , Barrett Karen , Rigas James R. , Jiang Haiyi , Lin Steven H. 
Published: June 2023

TPS8607 Background: Stereotactic body radiation therapy (SBRT) is a standard treatment for patients with unresectable (UR) stage I/II, lymph-node negative NSCLC, with excellent safety and high rates of primary tumor control. Despite predominant regional and distant failure that increases with tumor size, no adjuvant therapy is approved for these patients. Durvalumab is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1/CD80. In the placebo-controlled, phase 3 PACIFIC trial of patients with stage III UR-NSCLC without disease progression on/after concurrent chemoradiotherapy, durvalumab improved progression-free survival (PFS) and overall survival (OS) with manageable safety (Antonia, et al. 2017; 2018), leading to its approval in stage III UR-NSCLC. Osimertinib is a 3rd-generation, irreversible CNS-active EGFR tyrosine kinase inhibitor that selectively inhibits NSCLC tumors with EGFR-sensitizing mutations (EGFRm). In the recent placebo-controlled, phase 3 ADAURA trial, osimertinib demonstrated statistically significant and clinically meaningful improvement in disease-free survival (DFS) (HR, 0.20 [99.12% CI, 0.14–0.30], P < 0.001) in patients with resected stage IB-IIIA EGFRm NSCLC (Wu, et al. 2020), leading to its approval in an adjuvant setting. Based on data for durvalumab and osimertinib in the early-stage setting, PACIFIC-4 is designed to assess the efficacy and safety of durvalumab combined with SBRT in patients with stage I/II UR-NSCLC and osimertinib after SBRT in patients with stage I/II EGFRm UR-NSCLC. Methods: PACIFIC-4 (NCT03833154) is an international, phase 3 study with two independent cohorts. Eligible patients are ≥18 years of age with stage T1-T3, N0, M0 unresected NSCLC and ECOG PS 0–2. The main cohort of approximately 630 patients will be randomized (1:1) in a double-blind manner, stratified by tumor size and location, to receive durvalumab (1500 mg IV) or placebo every 4 weeks for up to 26 cycles with concurrent standard of care (SoC) SBRT. The primary endpoint in this cohort is PFS (RECIST v1.1) by blinded independent central review; other endpoints include OS, health-related quality of life, and safety. The protocol was amended (v4) to exclude patients with an identified EGFRm from the main cohort and add a separate cohort of approximately 60 patients with EGFRm (L858R or Ex19del) who will receive osimertinib 80 mg PO QD, following SoC SBRT, for up to 36 months. The primary endpoint in this cohort is 4-year PFS (RECIST v1.1) by independent central review; secondary endpoints include PFS, OS, and safety. Trial recruitment is ongoing. Previously presented at the European Lung Cancer Congress (ELCC) 2022, FPN (Final Publication Number): 122TiP, Clifford Robinson et al. – Reused with permission. Clinical trial information: NCT03833154 .