Penpulimab Plus Anlotinib Shows Promise in Resectable NSCLC Phase II Trial
Key Insights
The ALTER-L043 phase II trial demonstrated that perioperative penpulimab plus anlotinib and chemotherapy achieved a 76.0% major pathological response rate in resectable NSCLC (search) patients, compared to 57.7% with penpulimab plus chemotherapy alone.
All three treatment combinations showed manageable safety profiles with no treatment-related deaths, though immune-related adverse events were more common in the triple combination group (36.7% vs 20.0% vs 23.3%).
The study represents the first randomized analysis of perioperative immunotherapy combined with an antiangiogenic agent in resectable NSCLC (search), with particularly promising results in patients with squamous histology and stage IIIA/IIIB disease.
The ALTER-L043 phase II trial has demonstrated promising efficacy for perioperative penpulimab combined with the antiangiogenic agent anlotinib in patients with resectable non-small cell lung cancer (NSCLC (search)), according to results published in Signal Transduction and Targeted Therapy.
This multicenter, randomized study represents the first analysis of perioperative immune checkpoint inhibitor therapy in combination with an antiangiogenic agent with or without neoadjuvant chemotherapy in resectable NSCLC (search) patients.
Trial Design and Patient Population
The open-label study enrolled 90 patients across six medical centers in China between December 2021 and January 2024. Patients were randomly assigned 1:1:1 to receive neoadjuvant treatment with penpulimab plus anlotinib and chemotherapy (n=30), penpulimab plus chemotherapy (n=30), or penpulimab plus anlotinib (n=30), followed by surgery and adjuvant therapy.
The study population had a median age ranging from 58-66 years across treatment groups, with over 75% of patients having squamous NSCLC (search) histology. This proportion was notably higher than reported in global trials but consistent with Chinese population studies, partly attributed to the exclusion of patients with known EGFR (search) mutations.
Efficacy Outcomes
Major Pathological Response
Among patients who underwent definitive surgery, major pathological response (MPR) occurred in 76.0% (19/25 patients; 95% CI 54.9-90.6%) in the penpulimab plus anlotinib and chemotherapy group, compared to 57.7% (15/26 patients; 95% CI 36.9-76.7%) in the penpulimab plus chemotherapy group and 52.4% (11/21 patients; 95% CI 29.8-74.3%) in the penpulimab plus anlotinib group.
The MPR rate difference was 18.3% (95% CI -7.9 to 42.2; p=0.166) for the triple combination versus penpulimab plus chemotherapy, though this did not reach statistical significance.
Pathological Complete Response
Pathological complete response (pCR) rates were 52.0% (13/25; 95% CI 31.3-72.2%) with the triple combination, 50.0% (13/26; 95% CI 29.9-70.1%) with penpulimab plus chemotherapy, and 38.1% (8/21; 95% CI 18.1-61.6%) with penpulimab plus anlotinib. No significant differences were observed between groups.
Survival Outcomes
The median event-free survival was not reached in any treatment group at the data cutoff. The 12-month event-free survival rates were 94.1% (95% CI 65.0-99.2%), 89.3% (95% CI 63.2-97.2%), and 73.6% (95% CI 49.9-87.3%) for the respective treatment groups.
Overall survival data showed 12-month rates of 100.0%, 94.7%, and 96.7% across the three arms, with only two deaths reported at the time of analysis.
Subgroup Analysis
Particularly promising results were observed in specific patient subgroups. Among patients with squamous NSCLC (search), the triple combination achieved MPR rates of 79.0% compared to 55.0% with penpulimab plus chemotherapy and 50.0% with penpulimab plus anlotinib. Similarly, in patients with stage IIIA/IIIB disease, MPR rates were 82.4%, 55.6%, and 50.0%, respectively.
Safety Profile
Treatment-emergent adverse events of any grade occurred in 86.7%, 96.7%, and 93.3% of patients across the three treatment groups. Grade ≥3 treatment-related adverse events were reported in 26.7%, 20.0%, and 30.0% of patients, respectively.
The most common grade ≥3 treatment-related adverse events included hypertension (6.7% vs 0.0% vs 13.3%), nausea (3.3% vs 3.3% vs 0.0%), and anorexia (3.3% vs 0.0% vs 3.3%).
Immune-related adverse events were more frequent in the triple combination group (36.7%) compared to penpulimab plus chemotherapy (20.0%) or penpulimab plus anlotinib (23.3%), though most events were grade 1-2. No treatment-related deaths were observed across any treatment group.
Mechanistic Insights
The researchers suggest that anlotinib's efficacy may be attributed to its ability to modulate the tumor microenvironment by normalizing tumor vessels and increasing immune effector cell infiltration. Preclinical studies indicate that anlotinib reduces extracellular matrix stiffness and decreases interstitial fluid pressure, potentially facilitating better penetration of immunotherapy and chemotherapy agents.
Study Limitations and Future Directions
The study authors acknowledged several limitations, including the open-label design, limited sample size of approximately 30 patients per group, and relatively short follow-up duration. The median event-free survival and overall survival were not reached at the time of analysis, warranting longer follow-up to determine whether early pathological responses translate into durable survival benefits.
Lead study author Meng Weng from Tianjin Medical University Cancer Institute and Hospital noted that "further data from ongoing and future clinical trials are needed to confirm the clinical benefits of combining perioperative ICI and an anti-angiogenic agent with or without neoadjuvant chemotherapy in this patient population."
The results suggest therapeutic potential for combining perioperative immune checkpoint inhibitors with antiangiogenic agents in resectable NSCLC (search), particularly given the manageable safety profile and promising efficacy signals observed in this exploratory trial.