Cancer Res Treat.  2024 Oct;56(4):1084-1095. 10.4143/crt.2024.084.

Adjuvant Pembrolizumab in Patients with Stage IIIA/N2 Non–Small Cell Lung Cancer Completely Resected after Neoadjuvant Concurrent Chemoradiation: A Prospective, Open-Label, Single-Arm, Phase 2 Trial

• Shin J
• Park S
• Kim KH
• Shin EC
• Jung HA
• Cho JH
• Sun JM
• Lee SH
• Choi YS
• Ahn JS
• Kim J
• Park K
• Shim YM
• Kim HK
• Noh JM
• Ahn YC
• Pyo H
• Ahn MJ

• KMID: 2560243
• DOI: http://doi.org/10.4143/crt.2024.084

Abstract

Purpose
Optimal treatment for stage IIIA/N2 non–small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT).
Materials and Methods
In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to 2 years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39⁺PD-1⁺CD8⁺ T cells using fold changes in the percentage of proliferating Ki-67⁺ cells from days 1 to 7 of cycle 1 (Ki-67_D7/D1).
Results
Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), nine (26%), and four (12%) had a tumor proportion score of < 1%, 1%-50%, and ≥ 50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a 5-year DFS rate of 29%. The OS rate was 86% at 2 years and 76% at 5 years. Patients with tumor recurrence within 6 months had a significantly lower Ki-67D7/D1 among CD39⁺PD-1⁺CD8⁺ T cells than those without (p=0.036). No new safety signals were identified.
Conclusion
Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

Keyword

Non-small-cell lung carcinoma; Pembrolizumab; Adjuvant chemotherapy; Chemoradiotherapy

Figure

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  Fig. 1. Clinicopathologic profiles and disease-free survival follow-up of individual patients. Each horizontal color bar indicates each patient’s disease-free survival follow-up period. Patients who had disease recurrence, died without recurrence, and were disease-free and alive at the end of follow-up are denoted with different bar colors. The patient indicated with an asterisk received four doses of pembrolizumab beyond disease recurrence. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; EOT, end of treatment; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score; TRAE, treatment-related adverse event.

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  Fig. 2. Disease-free survival (A) and overall survival (B) in the intention-to-treat population. Rates of disease-free survival and overall survival at 24 and 60 months and their 95% confidence intervals are shown in the inset tables.

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  Fig. 3. Disease-free survival according to the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) (A) and epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) alteration status (B) and overall survival according to the PD-L1 tumor proportion score (C) and EGFR/ALK alteration status (D). Rates of disease-free and overall survival at 24 and 60 months and their 95% confidence intervals (CIs) are shown in the inset tables. HR, hazard ratio.

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  Fig. 4. Early proliferative response of CD39+PD-1+CD8+ T cells after anti–PD-1 therapy as a predictor of durable clinical benefit. (A-C) Ki-67D7/D1 among peripheral blood CD39+PD-1+CD8+ T cells (A), PD-1+CD8+ T cells (B), and CD8+ T cells (C). One patient with durable clinical benefit had a baseline (day 1) percentage of Ki-67+ cells among CD39+PD-1+CD8+ T cells of 0, hence an infinite Ki-67D7/D1 value (shown as a cropped dot in panel A). Error bars indicate standard errors. (D) The rate of recurrence within 6 months after surgery in patients with Ki-67D7/D1 ≥ 2.055 and those with Ki-67D7/D1 < 2.055 among CD39+PD-1+CD8+ T cells. (E, F) Disease-free survival (E) and overall survival (F) according to Ki-67D7/D1 among CD39+PD-1+CD8+ T cells. CI, confidence interval; HR, hazard ratio; PD-1, programmed cell death protein 1.

Reference

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