A Randomized Non-Comparative Phase II Study of Anti-Programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as Second-Line Therapy in Patients With Small Cell Lung Cancer: Results From the IFCT-1603 Trial

Abstract

Introduction: This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum-etoposide chemotherapy. Methods: Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O'Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders. Results: Overall, 73 patients were randomized (atezolizumab n ¼ 49; chemotherapy n ¼ 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0-6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8-33.1). Among eligible chemotherapy patients (n ¼ 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2-1.5) with atezolizumab and 4.3 months (95% CI: 1.5-5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratio atezolizumab : 0.84, 95% CI: 0.45-1.58; p ¼ 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone). Conclusions: Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed.

Immunotherapeutic approaches for small-cell lung cancer

“…Overall, 64% of the patients had platinum-sensitive disease (defined as disease progression ≥90 days after completion of induction chemotherapy). Results from this trial, published in January 2019, revealed no significant difference in median OS (9.5 months versus 8.7 months; HR 0.84, 95% CI 0.45-1.58; P = 0.60) 45 . Furthermore, median PFS was statistically inferior in patients who received atezolizumab (1.4 months versus 4.3 months in patients receiving chemotherapy; adjusted HR 2.26, 95% CI 1.3-3.9; P = 0.004).…”

Prognostic and Clinicopathological Value of Programmed Cell Death Ligand1 Expression in Patients With Small Cell Lung Cancer: A Meta-Analysis

“…In addition, ∼65% of new patients are at an extensive stage when diagnosed, and <5% of those patients survive for 2 years (23,24). Several ongoing phase I, II, and III clinical trials have revealed the primary results of PD-1 inhibitors for SCLC (25,26). In the present meta-analysis, nine relevant studies were included to explore the prognostic impact of PD-L1 expression on SCLC.…”

Atezolizumab in combination with carboplatin and etoposide for heavily treated small cell lung cancer

“…The additive effect of atezolizumab in the current case is better understood, as CE readministration immediately before the current treatment resulted in PD. Atezolizumab monotherapy in patients treated with first‐line platinum‐etoposide chemotherapy has previously demonstrated efficacy (IFCT‐1603 trial), in which the response rate and median PFS were 2.3% and 1.4 months, respectively 8 . Although the IFCT‐1603 trial resulted in a negative result, Kaplan‐Meier estimates of both PFS and OS in the atezolizumab group exhibited a tail plateau, suggesting that there is a selected population who may benefit from SCLC second‐line atezolizumab monotherapy.…”