Based on the final progression-free survival (PFS) analysis and interim overall survival (OS) analysis, the phase III ETER701 study demonstrated that benmelstobart and anlotinib plus etoposide/carboplatin provide significant improvements in survival compared with etoposide/carboplatin chemotherapy alone among patients with extensive-stage small-cell lung cancer (ES-SCLC). The group of patients treated with benmelstobart and anlotinib plus etoposide/carboplatin had a median OS of 19.3 months that provides a 7.4-month prolongation versus etoposide/carboplatin alone. The median PFS with benmelstobart and anlotinib plus etoposide/carboplatin was 6.9 months, providing a 2.7-month prolongation compared with etoposide/carboplatin alone.
The Kaplan–Meier survival curves displayed early and sustained separation, with a more significant separation favouring benmelstobart and anlotinib plus etoposide/carboplatin as maintenance therapy continued. Sustained responses were also observed with benmelstobart and anlotinib plus etoposide/carboplatin compared with etoposide/carboplatin alone, with a 14.5% increase in objective response rate (81.3% versus 66.8%) and a 2.7-month extension in median duration of response (5.8 versus 3.1 months). The findings are reported by Dr. Ying Cheng of the Jilin Cancer Hospital in Changchun, China, Dr. Runxiang Yang of the Yunnan Cancer Hospital in Kunming, China and colleagues on 11 July 2024 in the Nature Medicine.
The addition of an immune checkpoint inhibitor (ICI) to platinum-based chemotherapy has been associated with prolonged median survival in patients with ES-SCLC, and four randomised, controlled phase III studies (IMpower133, CASPIAN, CAPSTONE-1 and ASTRUM-005) have reported significant improvements in median OS on the order of 2-4 month.
Antiangiogenesis is known to augment the efficacy of ICIs in multiple cancer types. Anlotinib is a multitargeted antiangiogenic agent with a potential synergistic effect with ICI. Anlotinib monotherapy has been approved for third-line treatment of ES-SCLC in China. Benmelstobart is a humanised anti-PD-L1 antibody that has demonstrated preclinical antitumour activity similar to other ICIs. A phase Ib dose-escalation study that investigated the combination of anlotinib and benmelstobart demonstrated a favourable safety profile with four out of six enrolled patients with ES-SCLC attaining a partial response.
This multicentre, double-blind, randomised, placebo-controlled phase III study compared three-drug regimens: benmelstobart and anlotinib plus etoposide/carboplatin in 246 patients, placebo/anlotinib plus etoposide/carboplatin in 245 patients or double placebo/etoposide/carboplatin chemotherapy alone in 247 patients, followed by matching maintenance therapy.
ETER701 was designed to address whether the addition of benmelstobart and anlotinib to chemotherapy shows synergistic benefit in the first-line treatment of patients with ES-SCLC and whether the addition of anlotinib alone to chemotherapy provides clinical benefit. Because no PD1/PD-L1 inhibitors for ES-SCLC were available in China at the approval of the study protocol, etoposide/carboplatin chemotherapy was adopted as the control arm in the ETER701 study.
Two primary endpoints were Independent Review Committee-assessed PFS per RECIST v1.1 and OS. Compared with etoposide/carboplatin alone, median OS was prolonged with benmelstobart and anlotinib plus etoposide/carboplatin, 19.3 versus 11.9 months (hazard ratio [HR] 0.61; p = 0.0002), while improvement of OS was not statistically significant with anlotinib plus etoposide/carboplatin, 13.3 versus 11.9 months (HR 0.86; p = 0.1723).
The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus etoposide/carboplatin, anlotinib plus etoposide/carboplatin, and etoposide/carboplatin alone groups.
This study of immunochemotherapy plus multi-target antiangiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomised studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. The ETER701 study met the primary endpoint at the preplanned interim analysis and confirmed that first-line therapy with benmelstobart and anlotinib plus etoposide/carboplatin significantly improved OS and PFS in patients with ES-SCLC. Anlotinib plus etoposide/carboplatin improved PFS and response rates compared with etoposide/carboplatin alone, but the difference in OS was not significant. The final OS will be confirmed after the prespecified 497 OS events have been reached.
The study was sponsored by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Reference
Cheng Y, Chen J, Zhang W, et al. Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial. Nature Medicine; Published online 11 July 2024. DOI: https://doi.org/10.1038/s41591-024-03132-1