PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients

Abstract

Background: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC.

Methods: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive.

Results: PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01).

Conclusions: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Figure 1

Levels of PD-1 expression and patient characteristics. This picture illustrates changes in the levels of PD-1 expression according to clinical (A–C) and biological (D–F) characteristics. Median levels of PD-1 score and interquartile ranges are showed. Median levels of PD-1 expression were higher in male (median score 60 vs 20) than in female (A), in current (median score 60 vs 20) than in never/former smokers (B), in adenocarcinoma (median score 40 vs 0) than in squamous-cell carcinoma histology (C), in EGFR wild type (median score 40 vs 20) than in EGFR mutated (D), in KRAS mutated (median score 60 vs 25) than in KRAS wild type (E) and in ALK wild type (median score 35 vs 15) than in ALK translocated (F) patients.

Figure 2

PD-1 and PD-L1 immunohistochemistry analysis. This figure illustrates four cases of PD-1 IHC analysis (A–D) and four cases of PD-L1 IHC analysis (E–H). Specifically, this picture showed: a PD-1 negative case (A), a PD-1 1+ case in 60% of tumour cells (B), a PD-1 2+ case in 80% of tumour cells (C), a PD-1 3+ case in 95% of tumour cells (D), a PD-L1 negative case (E), a PD-L1 1+ case in 10% of tumour cells (F), a PD-L1 2+ case in 50% of tumour cells (G) and a PD-L1 3+ case in 70% of tumour cells (H). The magnification used for the images was 20 × .

Figure 3

Levels of PD-L1 expression and patient characteristics. This picture illustrates changes in the levels of PD-L1 expression according to clinical (A–C) and biological (D–F) characteristics. Median levels of PD-1 score and interquartile ranges are showed. Median levels of PD-L1 expression were higher in female (median score 80 vs 60) than in male (A), in never/former (median score 60 vs 30) than in current smokers (B), in adenocarcinoma (median score 100 vs 0) than in squamous-cell carcinoma histology (C), in EGFR mutated (median score 120 vs 20) than in EGFR wild type (D), in KRAS wild type (median score 80 vs 55) than in KRAS mutated (E) and in ALK translocated (median score 115 vs 70) than in ALK wild type (F).

Figure 4

Kaplan–Meier curves of time to progression (TTP) (A–C) and overall survival (OS) (B–D) in patients treated with EGFR-TKIs. In the subgroup of patients (N=99) treated with EGFR-TKIs no differences in terms of TTP (7.0 months vs 8.0 months, P=0.97) (A) and OS (17.8 months vs 18.9 months, P=0.82) (B) were identified in PD-1 positive (N=26, 28.0%) vs PD-1 negative (N=67, 72.0%) cases. PD-L1 positive (N=49, 51.6%) patients had a significant longer TTP (11.7 months vs 5.7 months, P<0.0001) (C) and a longer OS (21.9 months vs 12.5 months, P=0.09) (D) than PD-L1 negative (N=46, 48.4%) patients.

Figure 5

Kaplan–Meier curves of time to progression (TTP) (A) and overall survival (OS) (B) in PD-L1 positive vs PD-L1 negative EGFR mutated patients treated with EGFR-TKIs. In EGFR mutated patients (N=54) treated with EGFR-TKIs, PD-L1 positive (N=38, 70.4%) cases had a significantly longer TTP (13.1 months vs 8.5 months, P=0.01) (A) and a non-significantly longer OS (29.5 months vs 21.1 months, P=0.75) (B) than PD-L1 negative (N=16, 29.6%) cases.