Toripalimab plus anlotinib maintenance shows promise in ES-SCLC after first-line chemo

PURPOSE: To evaluate the efficacy, safety and underlying mechanisms of toripalimab combined with anlotinib as maintenance therapy in patients with extensive-stage small cell lung cancer (ES-SCLC) who achieved disease control after first-line platinum-etoposide chemotherapy. EXPERIMENTAL: Design: A multi-center, single-arm, open-label phase II trial (NCT04363255) enrolled 20 patients with ES-SCLC. Participants received maintenance therapy with toripalimab (240mgevery3weeks) plus anlotinib (12mgorallyondays1-14ofeach21-daycycle) until disease progression or unacceptable toxicity. Preclinical studies were conducted using SCLC cell lines to investigate the effects of anlotinib on PD-L1 expression, immune checkpoint regulation and neuroendocrine (NE) differentiation. RESULTS: The combination therapy resulted in a median progression-free survival (mPFS) of 13.6 months from initial treatment and 8.18 months during the maintenance phase. Median overall survival (mOS) reached 23.05 months. Preclinical studies demonstrated that anlotinib promoted dose-dependent PD-L1 upregulation through de novo protein synthesis and enhanced surface expression. Transcriptomic analyses revealed broad immunomodulatory effects, including activation of Notch signaling and upregulation of multiple immune checkpoints. Anlotinib also altered gene expression programs associated with NE differentiation and epithelial-mesenchymal transition (EMT). These findings were accompanied clinical observation, reduced post-treatment levels of serum NE markers (NSE and ProGRP) were significantly correlated with improved survival. The combination exhibited a manageable safety profile. CONCLUSIONS: Toripalimab plus anlotinib is associates with promising efficacy and acceptable safety as maintenance therapy in ES-SCLC. The therapeutic effect may be mediated through coordinated immunomodulation and anlotinib-induced changes in differentiation-related pathway, providing a mechanistic rationale for the observed clinical benefits. These results warrant further validation in randomized controlled trials.