Study Identifies Potential Biomarker of Response to Neoadjuvant Pembrolizumab in Early-Stage NSCLC

Perioperative pembrolizumab showed a “promising” major pathologic response rate and survival outcomes in patients with early-stage non–small cell lung cancer (NSCLC), according to a recent study that suggests there may be a biomarker of major pathologic response in this setting.

Cameron Wood, MD, of the Bon Secours Richmond Health System, and colleagues conducted the study and published their findings in the Journal for ImmunoTherapy of Cancer.

The single-arm phase 2 study evaluated the safety, efficacy, and immunologic effects of perioperative pembrolizumab among patients with untreated, clinical stage IB to IIIA NSCLC. Patients received 2 doses of pembrolizumab 200 mg, followed by surgery, standard adjuvant chemotherapy, and 4 doses of adjuvant pembrolizumab.

The primary objective of the study was to determine the surgical feasibility rate with this approach. Secondary objectives included pathologic response rate, treatment-related adverse events, efficacy data, and exploratory analysis of biomarkers.

The investigators reported that 30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. With a median follow-up of 59 months after surgical resection for those 25 patients, 7 patients had disease progression and 6 died. The researchers determined that the 5-year progression-free survival (PFS) rate from the time of surgery was 72% (56.4%-91.9%). The overall survival (OS) rate from time of surgery was 75.8% (60.7%-94.7%).

A major pathologic response occurred in 7 tumors (28%), including 2 complete responses (4%). Among all patients who received pembrolizumab, treatment-related adverse events of grade 3 or higher were reported in 4 patients who received neoadjuvant therapy and in 4 who received adjuvant therapy, but no grade 5 events occurred.

The researchers also reported that plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels “increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment.” They found there was a significant postoperative difference in the mean plasma PCSK9 levels when patients with a major pathologic response were compared with all other patients.

The study authors explained in associated article commentary why it was important to evaluate this biomarker and the implications of these findings.

“Studying biomarkers before and after neoadjuvant PD-1 inhibition for early-stage non-small cell lung cancer (NSCLC) contributes important insights into factors associated with response to PD-1 checkpoint-based therapies,” Dr. Wood and colleagues wrote. “One such potential biomarker, PCSK9, is a member of the subtilisin-like proprotein convertase family which has roles both in cholesterol metabolism and affecting the tumor immune microenvironment.”

Based on the study findings, Dr. Wood and colleagues concluded that this treatment strategy “was safe and effective with promising major pathological response rate (MPR), progression-free survival, and overall survival,” and that PCSK9 “may be a biomarker associated with MPR after neoadjuvant pembrolizumab.” The study investigators also outlined current related research and future directions.

“At this time, two clinical trials (NCT 05144529, NCT 05553834) are underway at our institution investigating combination of anti-PCSK9 therapy with ICI [immune checkpoint inhibitor] therapy in the first-line metastatic, and second-line metastatic setting to test the hypothesis that PCSK9 inhibition can overcome PD1 checkpoint immune resistance,” Dr. Wood and colleagues wrote in the associated article commentary.

Reference

Wood C, Lyniv L, Isaacs JM, et al. Perioperative pembrolizumab in early-stage non-small cell lung cancer (NSCLC): safety, efficacy, and exploratory biomarker analysis. J Immunother Cancer 2025;13(2):e010395. doi:10.1136/jitc-2024-010395