Perioperative penpulimab-based combination therapy in patients with resectable non-small cell lung cancer (ALTER-L043): an open-label, multicenter, randomized, phase II trial

Abstract Although perioperative immunotherapy combined with neoadjuvant chemotherapy has improved the clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC), the optimal combination strategy remains unknown. This multicenter, open-label, randomized, phase II trial (ALTER-L043; NCT04846634) evaluated the efficacy and safety of perioperative penpulimab plus anlotinib with or without neoadjuvant chemotherapy in patients with resectable NSCLC. Eligible patients were randomly assigned (1:1:1) to receive 3–4 cycles of neoadjuvant penpulimab (200 mg on day 1) plus anlotinib (12 mg on days 1–14) and chemotherapy, penpulimab plus chemotherapy, or penpulimab plus anlotinib, followed by surgery and matching adjuvant therapy. The primary endpoint was the investigator-assessed major pathologic response (MPR) rate. Between December 3, 2021, and January 23, 2024, 90 patients were randomly assigned to the penpulimab plus anlotinib and chemotherapy (n = 30), penpulimab plus chemotherapy (n = 30), or penpulimab plus anlotinib (n = 30) groups. Definitive surgery was performed in 92.6%, 89.7%, and 70.0% of patients, respectively. Among those who underwent surgery, the MPR and pathological complete response rates were 76.0% (95% CI 54.9–90.6) and 52.0% (95% CI 31.3–72.2), respectively, in the penpulimab plus anlotinib and chemotherapy group; 57.7% (95% CI 36.9–76.7) and 50.0% (95% CI 29.9–70.1), respectively, in the penpulimab plus chemotherapy group; and 52.4% (95% CI 29.8–74.3) and 38.1% (95% CI 18.1–61.6), respectively, in the penpulimab plus anlotinib group. Across all treatment phases, the incidences of grade ≥3 treatment-related adverse events were 26.7%, 20.0%, and 30.0%, respectively. Penpulimab plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and a manageable safety profile in patients with resectable NSCLC, suggesting its potential as a viable perioperative treatment option.