High expression of PD-L1 is associated with shorter survival and resistance to targeted therapies in patients with EGFR-mutant lung adenocarcinoma, according to a new study.

While PD-L1 expression has been shown to be associated with response to immunotherapy, previous reports have yielded conflicting results on whether it is also predictive for EGFR tyrosine kinase inhibitor efficacy.

“While mechanisms of acquired resistance to 1st/2nd generation EGFR TKIs have been well documented, 10% exhibit de novo resistance of which the mechanisms are unclear,” wrote study authors led by Dr Jia Liu, of the Crown Princess Mary Cancer Centre, in Lung Cancer.

The researchers conducted a retrospective, multicentre study of 186 patients with stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation who were treated with first-line TKI. The cohort was mixed between Asian (54%) and non-Asian (46%) ethnicity.

They found that patients with high PD-L1 expression had a shorter median progression-free survival, at 6.6 months, compared with 13.0 months in those with PD-L1-low/negative tumours (p < .0001). Median overall survival was also significantly shorter, at 11.5 months versus 32.9 months (p < .0001).

The objective response rate in patients with PD-L1-high tumours was 57%, compared with 76% in those with PD-L1-low tumours. Those with high expression were more likely to exhibit de novo resistance to EGFR TKI therapy, at 39% compared with 18% in those with PD-L1-low/negative tumours (p = .018).

“I am not surprised that this is true across ethnicity, as I think the most important predictive markers tend to be biological rather than ethnicity,” senior author Dr Steven Kao, of Chris O’Brien Lifehouse, told the limbic.

A multivariate analysis found that along with low ECOG performance status, female gender, and non-exon 19 deletion EGFR alteration, high PD-L1 expression was independently associated with poorer OS. High PD-L1 expression was also independently associated with poorer PFS, along with poorer ECOG status, presence of bone metastases, and non-exon 19 deletion. The authors noted that PD-L1 outperformed those other factors as a predictive biomarker of outcome.

“The findings of this study suggest that the treatment of patients with PD-L1 high EGFR-mutant NSCLC remains an area of unmet need,” the authors wrote.

The findings suggest that EGFR TKIs alone are not sufficient to treat patients in the setting of PD-L1 suppressed immunity, but immune checkpoint inhibitors are also not effective in this setting, suggesting other mechanisms beyond immune suppression. High tumour mutational burden could be driving the high PD-L1 expression, the authors wrote, resulting in activation of alternative oncogenic pathways that then confer resistance to therapy directed at EGFR.

They noted that the retrospective nature of the study may affect the accuracy of PD-L1 expression analysis from archival biopsy samples. “Next-generation sequencing studies are underway to explore the underlying biological drivers of high PD-L1 expression and its relationship to outcome in these patients.”

Dr Kao told the limbic that another next step is to see if patients treated with osimertinib show similar patterns, with high PD-L1 expression associated with poor outcome. “If the same observation was found, PD-L1 status may be a marker for treatment escalation strategy, such as [with] osimertinib plus chemotherapy.”