The role of PD-L1 in EGFR-mutant non-small cell lung cancer

Abstract

Lung cancer remains the leading cause of cancer-related deaths globally. In China, nearly half of non-small cell lung cancer (NSCLC) patients carry epidermal growth factor receptor (EGFR) mutations. EGFR tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the prognosis for patients with EGFR mutations and are considered the preferred treatment for these individuals. Programmed death-ligand 1 (PD-L1) expression levels are now widely used as a biomarker to predict the effectiveness of PD-1/PD-L1 immunotherapy in NSCLC. Additionally, the impact of PD-L1 expression on the efficacy of EGFR-TKIs has garnered considerable attention from researchers. This review explores recent studies on the epidemiology and clinical outcomes associated with PD-L1 in NSCLC patients harboring driver gene mutations.

Introduction

Programmed death-ligand 1 (PD-L1) is a crucial predictive marker for immunotherapy in non-small-cell lung cancer (NSCLC). Multiple studies have demonstrated that PD-L1-positive NSCLC patients benefit from PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy [1–4]. For patients with low or negative PD-L1 expression, the KEYNOTE-189 and KEYNOTE-407 trials revealed that combining chemotherapy with PD-1/PD-L1 inhibitors offers additional survival advantages [2, 3].

However, the situation is more complex in NSCLC patients with epidermal growth factor receptor (EGFR) mutations. EGFR tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced NSCLC patients with EGFR-sensitive mutations, irrespective of PD-L1 expression. Several studies have indicated that EGFR-mutant patients generally do not benefit from immunotherapy [5–7]. Nevertheless, the ORIENT-31 and HARMONi-A studies have shown that immunotherapy can provide significant benefits for NSCLC patients who have developed resistance to EGFR-TKIs [8, 9].

A substantial proportion of EGFR-mutant NSCLC patients also express PD-L1. The effect of PD-L1 expression on the efficacy of EGFR-TKIs has attracted our attention. This article reviews the literature on the role of PD-L1 in EGFR-mutant NSCLC to enhance our understanding of the value of PD-L1 in this patient population.

PD-L1 expression in EGFR-mutant NSCLC

PD-L1 is an immune checkpoint protein expressed on both tumors and tumor-infiltrating immune cells. PD-L1 expression is typically classified as negative (< 1%), low (1–49%), and high (≥ 50%). As shown in Fig. 1, EGFR mutation as well as the use of EGFR-TKIs impacted PD-L1 expression [10–12]. A global EXPRESS study analyzed PD-L1 expression levels in NSCLC patients, using tumor samples from 2368 patients across 18 countries. The study found that 52% of patients had a PD-L1 tumor proportion score (TPS) ≥ 1%, and 22% had a PD-L1 TPS ≥ 50% [10, 12]. A separate study on PD-L1 expression in advanced NSCLC patients in China revealed that 51.8% had a PD-L1 TPS ≥ 1%, and 21.5% had a PD-L1 TPS ≥ 50% [13]. These findings suggest that PD-L1 expression patterns are similar between global and Chinese populations.

Fig. 1.

PD-L1 expression pattern in whole, EGFR-mutated, and TKIs resistant NSCLC patients

Among EGFR-mutant patients, 44% had a PD-L1 TPS ≥ 1%, while 13% had a PD-L1 TPS ≥ 50% [10]. Another study in China showed that 29.5% of NSCLC patients with EGFR mutations had a PD-L1 TPS between 1–49%, and 14.3% (30 out of 210) had a PD-L1 TPS ≥ 50% [13]. These data indicate that high PD-L1 expression is lower in patients with EGFR mutations compared to those with wild-type EGFR. Furthermore, several studies have demonstrated that NSCLC with uncommon EGFR mutations tends to show higher PD-L1 expression compared to those with common EGFR mutations (e.g., 19 DEL and 21 L858R mutations) [14, 15].

PD-L1 expression in NSCLC patients after developing resistance to TKIs remains complex and controversial [16]. Lin et al. reported that gefitinib reduced PD-L1 expression by inhibiting NF-κB signaling [17], while Jiang et al. found that osimertinib inhibited PD-L1 mRNA expression and induced PD-L1 protein degradation [18]. However, Isomoto et al. observed that among 134 EGFR-TKI-resistant patients, the proportion of patients with high PD-L1 expression increased from 14% to 28% following treatment [11]. The discrepancy of PD-L1 expression after osimertinib treatment might cause by several reasons. Firstly, initial osimertinib treatment might cause PD-L1 expression degradation, while sustained osimertinib cause drug resistance and activation of bypass pathway, inducing PD-L1 expression. Secondly, human tumor tissue is a complex environment, in vitro cannot fully simulate TME. PD-L1 is regulation by not only tumor cells by also tumor microenvironment [19]. Overall, changes in PD-L1 expression after EGFR-TKI treatment in NSCLC patients with EGFR mutations present a multifaceted issue, requiring further clinical and laboratory studies for comprehensive understanding.

Correlation between PD-L1 expression and TKI efficacy

PD-L1 is a critical biomarker for immunotherapy, but its significance in patients receiving TKIs (Tyrosine Kinase Inhibitors) remains unclear. A retrospective study analyzed 186 EGFR-mutant lung adenocarcinoma patients treated with gefitinib, erlotinib, or afatinib [20]. The results indicated that patients with high PD-L1 expression had significantly shorter median progression-free survival (PFS) (6.6 vs. 13.0 months, p < 0.0001) and overall survival (OS) (11.5 vs. 32.9 months, p < 0.0001) compared to those with low or negative PD-L1 expression. Additionally, the objective response rate (ORR) was lower in patients with high PD-L1 expression (57% vs. 76%).

Another retrospective study reinforced this finding, showing that high PD-L1 expression was associated with a significantly shorter median PFS in response to EGFR-TKIs (6.0 vs. 9.5 vs. 3.8 months, p < 0.001) [21]. Multiple studies have consistently demonstrated a correlation between high PD-L1 expression and poor response to EGFR-TKIs (Table 1) [10, 22–25].

Table 1.

Literature on the correlation between PD-L1 expression and clinical efficacy of EGFR-TKIs

Study	Numbers	EGFR-TKIs	PD-L1 Antibody	Cutoff	Line of therapy	Clinical outcomes in PD-L1 high expression
D'Incecco 2015	95	Gefitinib, erlotinib	AB58810 (Abcam)	5% staining	≥ 1	Higher ORR and better TTP [32]
Lin 2015	56	Gefitinib, erlotinib	AB58810 (Abcam)	H score:mean	1	Better PFS and higher DCR [13]
Tang 2015	99	Most 1-generation TKIs	E1L3N (CST)	H score: 5	Not mentioned	No impact on ORR and PFS [33]
Soo 2017	90	1st line EGFR TKI	SP142 (Ventana)	H score: 109	1	Poor PFS [34]
Yoneshima 2018	71	Not mentioned	22C3 (Dako)	1% of TPS	1	Poor PFS [35]
				TC3/IC3: > 50%/10%
Su 2018	101	Most 1-generation TKIs	SP142 (Ventana)	TC1-2/IC1-2:5–49%/5–9%	1	Significantly lower ORR and PFS [21]
				TC0/IC0: < 5%/5%
Hsu 2019	123	Gefitinib, erlotinib, afatinib	SP263 (Ventana)	1%, 25%, 50% TPS	1	Shorter PFS and higher primary resistance rate [36]
Yang 2020	153	Gefitinib, erlotinib, afatinib	22C3 (Dako)	1%, 50% TPS	1, > 2	Lower ORR and shorter PFS [37]
Inomata 2020	47	Gefitinib, erlotinib, afatinib, osimertinib	22C3 (Dako)	1% of TPS	1	Poor PFS [22]
Yoon 2020	131	Gefitinib, erlotinib, afatinib	22C3 (Dako)	1%, 50% TPS	1	Poor PFS,OS and lower acquired T790M mutations rate [10]
Brown 2020	54	Osimertinib	SP263 (Ventana)	1%, 25%, 50% TC	1	No difference in ORR and DoR [26]
Liu 2021	186	Gefitinib, erlotinib, afatinib	SP263 (Ventana)	1%, 50% TPS	1	Poor PFS, OS [20]
Shiozawa 2022	158	Osimertinib	Not available	1%, 50% TPS	1	Poor PFS [38]
Yang 2024	134	Osimertinib	SP263 (Ventana)	1%, 50% TC	≥ 2	No difference in ORR, DCR, PFS, and OS [25]

IHC, Immunohistochemistry; H score, histological score; TPS, tumour proportion score; TC, Tumor cell; ORR, objective response rate; TTP, time to progression; PFS, progression-free survival; DCR, disease-control rate; OS, overall survival; PD-L1, programmed death ligand-1

However, some studies present contradictory findings. For example, Lin et al. reported that PD-L1 expression was correlated with longer PFS and OS in advanced lung adenocarcinoma patients with EGFR mutations following EGFR-TKI treatment [13]. Similarly, the FLAURA study showed no significant difference in PFS between PD-L1 positive (≥ 1%) and PD-L1 negative patients [26].

These inconsistencies could be attributed to several factors. First, different studies employed various PD-L1 antibodies and cutoff values. Notably, studies utilizing the approved 22C3, SP142, and SP263 antibodies generally support the association between high PD-L1 expression and poor TKI efficacy in NSCLC. Second, first- and second-generation TKIs yielded consistent results regarding poor outcomes in patients with high PD-L1 expression, whereas osimertinib showed mixed results. For instance, the FLAURA study found similar efficacy for osimertinib in PD-L1 positive and negative patients, albeit with a small sample size. Conversely, a larger retrospective study demonstrated poor efficacy of osimertinib in PD-L1 positive NSCLC patients [27]. Third, PD-L1 is a dynamic biomarker, influenced by prior treatments. For patients previously treated with EGFR-TKIs, PD-L1 expression levels may fluctuate [11, 18].

Taken together, most studies suggest that high PD-L1 expression negatively impacts the efficacy of EGFR-TKIs, especially first- and second-generation EGFR-TKIs.

Possible mechanism between PD-L1 and EGFR-TKIs resistance

Li et al. demonstrated that PD-L1 promotes cell proliferation by regulating the cell cycle and inhibiting apoptosis [28]. The study also revealed that PD-L1 induces autophagy through the mitogen-activated protein kinase (MAPK) signaling pathway, leading to primary resistance to gefitinib. Chen et al. found that EGFR mutations induce PD-L1 expression via the p-ERK1/2/p–c-Jun pathway, and increased PD-L1 expression leads to T-cell apoptosis through the PD-L1/PD-1 axis [29]. Additionally, another EGFR-TKI resistance mechanism, MET activation, was shown to promote PD-L1 expression [30]. Despite these findings, the precise mechanisms by which PD-L1 regulates resistance to EGFR-TKIs remain unclear.

In EGFR-TKI naïve patients, high PD-L1 expression correlates with activation of alternative oncogenic which confers primary resistance [31]. While in patients with acquired T790M resistance, PD-L1 expression was often the consequence of acquired resistance, which had limited impact on subsequent EGFR-TKIs.

Conclusion

PD-L1 expression levels can serve as a biomarker for predicting and evaluating the efficacy of EGFR-TKIs in NSCLC patients with EGFR mutations. Studies indicate that high PD-L1 expression is associated with a poor prognosis in patients receiving EGFR-TKI treatment.

Author contributions

Writing of the original draft and editing: WTG, and LCZ; methodology and data acquisition: LLW; data analyses and interpretation: LCZ and YYZ; study concept and design, project administration: LCZ; manuscript revision: WTG and LLW. All the authors have read and approved the final manuscript.

Funding

This study was supported by grants from the Youth Science and Technology Innovation Training Project of Hangzhou Cancer Hospital (HZCH2021QN01) and National Natural Science Foundation of China (82373889). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.