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

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.