Penpulimab Regimens Show Promise in Resectable NSCLC Trial

Perioperative penpulimab-kcqx plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and a manageable safety profile among patients with resectable non–small cell lung cancer (NSCLC), according to data from the phase 2 ALTER-L043 trial (NCT04846634) published in Signal Transduction and Targeted Therapy.¹

Data showed a major pathological response (MPR) in 76.0% (n = 19/25; 95% CI, 54.9%-90.6%) of patients who received penpulimab plus anlotinib and chemotherapy, 57.7% (n = 15/26; 95% CI, 36.9%-76.7%) of those who received penpulimab plus chemotherapy, and 52.4% (95% CI, 29.8%-74.3%) of those who received penpulimab plus anlotinib. The MPR appeared to improve with penpulimab plus anlotinib and chemotherapy across different patient subgroups, including those with squamous histology and those with stage IIIA or IIIB disease. Additionally, the pathologic complete response (pCR) rates in each respective group were 52.0% (n = 13/25; 95% CI, 31.3%-72.2%), 50.0% (n = 13/26; 95% CI, 29.9%-70.1%), and 38.1% (n = 8/21; 95% CI, 18.1%-61.6%), with no significant differences in outcomes noted across treatment arms.

The objective response rate (ORR) was 77.8% (n = 21/27; 95% CI, 57.7%-91.4%) in the penpulimab plus anlotinib and chemotherapy arm, 58.6% (n = 17/29; 95% CI, 38.9%-76.5%) in the penpulimab plus chemotherapy arm, and 63.3% (n = 19/30; 95% CI, 43.9%-80.1%) in the penpulimab plus anlotinib arm. The median event-free survival (EFS) was not reached (NR) in any group, and the 12-month 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%), respectively. Data showed that the median overall survival (OS) was NR in all groups, with 12-month OS rates of 100.0% (95% CI, 100.0%-100.0%), 94.7% (95% CI, 68.1%-99.2%), and 96.7% (95% CI, 78.6%-99.5%) in each arm.

“[P]erioperative penpulimab plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and manageable safety profiles in patients with resectable NSCLC. Although a numerically higher MPR rate was observed with perioperative penpulimab plus anlotinib combined with neoadjuvant chemotherapy, this finding should be interpreted cautiously given the exploratory nature of this trial,” lead study author Meng Weng, from the Department of Lung Cancer at Tianjin Medical University Cancer Institute and Hospital in Tianjin, China, wrote with coauthors in the publication.¹ “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.”

In the open-label, multicenter, phase 2 ALTER-L043 trial, patients were randomly assigned 1:1:1 to receive neoadjuvant penpulimab at 200 mg intravenously on day 1 every 3 weeks plus anlotinib at 12 mg orally once daily on days 1 to 14 every 3 weeks and chemotherapy (n = 30), penpulimab plus chemotherapy (n = 30), or penpulimab plus anlotinib (n = 30) before surgery and adjuvant penpulimab with or without anlotinib. Neoadjuvant chemotherapy consisted of intravenous pemetrexed at 500 mg/m² for those with nonsquamous histology and paclitaxel at 175 mg/m² for squamous disease combined with carboplatin area under the curve 5 or cisplatin at 75 mg/m² on day 1 of a 3-week cycle.

The trial’s primary end point was MPR per investigator assessment, defined as the rate of patients with 10% or less residual viable tumor cells in the primary resected tumor. Secondary end points included investigator-assessed pCR, ORR, EFS, OS, and safety.

Patients 18 to 70 years old with early stage IIB to IIIB operable NSCLC; no EGFR, ALK, or ROS1 alterations in the primary tumor or lymph node metastases; and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial.² Having no prior surgery, chemotherapy, radiotherapy, or biotherapy was another requirement for study entry.

The median age was 66 years (range, 46-69) in the penpulimab plus anlotinib and chemotherapy group, 58 years (range, 52-70) in the penpulimab plus chemotherapy group, and 62 years (range, 53-71) in the penpulimab plus anlotinib group. Across each respective group, most patients were male (92.6%, 96.6%, 93.3%) and had formerly smoked (74.1%, 69.0%, 73.3%). Additionally, most had an ECOG performance status of 0 (51.9%, 58.6%, 63.3%), squamous histology (77.8%, 75.9%, 86.7%), and stage IIB disease (40.7%, 65.5%, 46.7%).

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 86.7% of the penpulimab plus anlotinib and chemotherapy group, 96.7% of the penpulimab plus chemotherapy group, and 93.3% of the penpulimab plus anlotinib group. Additionally, 26.7%, 20.0%, and 30.0% of patients in each arm had grade 3 or higher treatment-related AEs (TRAEs), the most common of which included hypertension (6.7%, 0.0%, 13.3%), nausea (3.3%, 3.3%, 0.0%), and anorexia (3.3%, 0.0%, 3.3%).

References

1. Wang M, Liu W, Guo H, et al. Perioperative penpulimab-based combination therapy in patients with resectable non-small cell lung cancer (ALTER-L043): an open-label, multicenter, randomized, phase II trial. Signal Transduct Target Ther. 2026;11(21). doi:10.1038/s41392-025-02544-w
2. Penpulimab-based combination neoadjuvant/​adjuvant therapy for patients with resectable locally advanced non-small cell lung cancer: a phase II clinical study (ALTER-L043) (ALTER-L043). ClinicalTrials.gov. Updated April 15, 2021. Accessed January 16, 2026. https://tinyurl.com/4dsxjmba