Design and Rationale for a Phase III, Randomized, Placebo-controlled Trial of Durvalumab With or Without Tremelimumab After Concurrent Chemoradiotherapy for Patients With Limited-stage Small-cell Lung Cancer: The ADRIATIC Study

Abstract

Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with tremelimumab (anticytotoxic T-lymphocyte eassociated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, doubleblind, placebo-controlled, multicenter, global study (ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018.

Efficacy and Safety of First-Line Immunotherapy in Combination with Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

“…However, this study did not discover the improvement of median OS by the combination therapy [ 23 ]. The ADRIATIC study, an ongoing randomized controlled phase 3 trial, compares tremelimumab plus durvalumab with durvalumab in treating limited-stage SCLC patients who have finished concurrent chemoradiotherapy [ 24 ]. We are eagerly waiting for the results of this study.…”

Recent developments in the treatment of small cell lung cancer

“…In the ongoing phase 3 ADRIATIC trial, 600 patients with at least stable disease after concomitant chemoradiotherapy, with or without PCI, will be randomised 1:1:1 to receive durvalumab plus placebo, durvalumab plus tremelimumab, or double placebo for a maximum of 24 months [32]. Primary end-points are PFS and OS for durvalumab, with or without tremelimumab, compared with placebo.…”

Long-Term Survival Data of Patients With Limited-Disease Small-Cell Lung Cancer

“…In patients with ED-SCLC, the combination therapy of immune checkpoint inhibitors and chemotherapy showed a signi cant survival bene t compared with chemotherapy alone [19,20]. Since a randomized phase III study of the addition of durvalumab to concurrent CRT is now ongoing, these data can be helpful as historical data [21].…”