Correlation between Classic Driver Oncogene Mutations in EGFR, ALK, or ROS1 and 22C3-PD-L1 ≥50% Expression in Lung Adenocarcinoma

Abstract

Introduction: Targeted somatic genomic analysis (EGFR, anaplastic lymphoma receptor tyrosine kinase gene [ALK], and ROS1) and programmed death ligand 1 (PD-L1) tumor proportion score (TPS) determined by immunohistochemistry (IHC) are used for selection of first-line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported.

Methods: We retrospectively probed the first 71 pairs of patients with lung adenocarcinoma from our institution. They were analyzed for PD-L1 by IHC using the clone 22C3 pharmDx kit (Agilent Technologies, Santa Clara, CA) and evaluated for co-occurrence of genomic aberrations and clinicopathologic characteristics.

Results: Surgical resection specimens, small biopsy (transbronchial or core needle) samples, and cytologic cell blocks (needle aspirates or pleural fluid) were tested. A PD-L1 TPS of at least ≥50% was seen in 29.6% of tumors. Of 19 tumors with EGFR mutations, ALK fluorescence in situ hybridization positivity, or ROS1 fluorescence in situ hybridization positivity, 18 had a PD-L1 TPS less than 50% versus only one tumor with a PD-L1 TPS of at least 50% (p = 0.0073). Tumors with a PD-L1 TPS of at least 50% were significantly associated with smoking status compared with tumors with a PD-L1 TPS less than 50% but were not associated with patient sex, ethnicity, tumor stage, biopsy site, or biopsy type/preparation.

Conclusions: PD-L1 IHC can be performed on routine clinical lung cancer specimens. A TPS of at least 50% seldom overlaps with presence of driver oncogenes with approved targeted therapies. Three biomarker-specified groups of advanced lung adenocarcinomas can now be defined, each paired with a specific palliative first-line systemic therapy of proven clinical benefit: (1) EGFR/ALK/ROS1-affected adenocarcinoma paired with a matched tyrosine kinase inhibitor (∼20% of cases), (2) PD-L1-enriched adenocarcinoma (TPS ≥50%) paired with anti-PD-1 pembrolizumab (∼30% of cases), and (3) biomarker-negative (i.e., EGFR/ALK/ROS1/PD-L1-negative) adenocarcinoma paired with platinum doublet chemotherapy with or without bevacizumab (∼50% of cases).

Keywords: ALK; EGFR; Lung cancer; PD-1; PD-L1; Pembrolizumab.

Figure 1. PD-L1 tumor proportion score (TPS) immunohistochemistry (IHC) results in 71 lung adenocarcinomas

A. Pie chart of PD-L1 IHC TPS. B. Representative Hematoxylin and Eosin (H&E) and PD-L1 IHC using clone 22C3 in different tumor materials: 1) cytology cell blocks from pleural fluid, 2) cytology cell blocks from lymph node aspirates, 3) small core biopsies, and 4) surgical resection specimens. TBNA, transbronchial needle aspirate; TPS, tumor proportion score.

Figure 2. Co-occurrence of genomic aberrations in EGFR, ALK, ROS1 and PD-L1 IHC TPS

A. Graphic pie chart representation of the frequency of driver oncogene mutations (EGFR, or ALK, or ROS1) with approved therapies in tumors with PD-L1 tumor proportion score (TPS) of <50%. B. Graphic pie chart representation of the reported frequency of driver oncogene mutations (EGFR, or ALK, or ROS1) with approved therapies in tumors with PD-L1 TPS of ≥50%. * all tumors were tested for aberrations on EGFR, or ALK, or ROS1 (as detailed on the Methods) and only tumors without positive results are included in this group.