122TiP Phase III study of durvalumab with SBRT for unresected stage I/II, lymph-node negative NSCLC (PACIFIC-4/RTOG 3515)

Abstract

Stereotactic body radiation therapy (SBRT) is a standard treatment for pts 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 pts. Durvalumab (D) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1/CD80. In the placebo (pbo)-controlled phase (ph) 3 PACIFIC trial of pts with stage III UR-NSCLC without progression on/after concurrent chemoradiotherapy, D improved PFS and OS with manageable safety (Antonia et al, 2017; 2018), leading to its approval in stage III UR-NSCLC. Osimertinib (O) is a 3rd-generation, irreversible CNS-active EGFR-TKI that selectively inhibits NSCLC tumors with EGFR-sensitizing mutations (EGFRm). In the recent pbo-controlled ph 3 ADAURA trial, O demonstrated statistically significant and clinically meaningful improvement in DFS (HR, 0.20 [99.12% CI, 0.14–0.30], P<0.001) in pts with resected stage IB-IIIA EGFRm NSCLC (Wu et al, 2020), leading to its approval in an adjuvant setting. Based on data for D and O in the early-stage setting, PACIFIC-4 is designed to assess the efficacy and safety of D combined with SBRT in pts with stage I/II UR-NSCLC and O after SBRT in pts with stage I/II EGFRm UR-NSCLC. PACIFIC-4 (NCT03833154) is an international ph 3 study with 2 independent cohorts. Eligible pts are ≥18 years with stage T1-T3, N0, M0 unresected NSCLC and ECOG PS 0–2. The main cohort of ∼630 pts will be randomized (1:1) in a double-blind manner, stratified by tumor size and location, to receive D (1500 mg IV) or pbo Q4W for up to 26 cycles with concurrent SoC SBRT. The primary endpoint in this cohort is PFS (BICR; RECIST v1.1); other endpoints include OS, health-related QoL and safety. The protocol was amended (v4) to exclude pts with an identified EGFRm from the main cohort and add a separate cohort of ∼60 pts with EGFRm (L858R or Ex19del) who will receive O 80 mg PO QD, following SoC SBRT, for up to 36 months. The primary endpoint in this cohort is 4-year PFS (ICR; RECIST v1.1); secondary endpoints include PFS, OS and safety. Trial recruitment is ongoing. NCT03833154. Medical writing support, under the direction of the authors, was provided by Nina Kratky of Ashfield MedComms (Manchester, UK), an Ashfield Health Company, and was funded by AstraZeneca. AstraZeneca.