A group of Italian and Swiss researchers have found a correlation between PD-L1 expression and EGFR mutation, as well as between PD-1 expression and KRAS mutations in a cohort of molecularly selected patients with non-small-cell lung cancer (NSCLC). Their findings support a rationale for investigating anti-PD-L1 and anti-PD-1 agents in combination with targeted therapies. The results were presented by Dr Armida D’Incecco of the Department of Medical Oncology, Istituto Toscano Tumori in Livorno, Italy in a proffered papers session at the 4th European Lung Cancer Conference (26-29 March 2014, Geneva, Switzerland).
The programmed death 1 (PD-1) receptor is an inhibitory T cell receptor with two known ligands, programmed death ligand 1 and 2 (PD-L1 and PD-L2). In this study, the researchers evaluated PD-L1 and PD-1 expression in a cohort of 125 NSCLC patients.
PD-L1 and PD-1 Expression Analysis
The cohort included 56 (44.8%) patients with EGFR mutated tumours, 29 (23.2%) KRAS mutated patients, 10 (8.0%) patients with ALK translocation and 30 (24.0%) EGFR/KRAS/ALK wild-type (wt) patients (triple-negative).
PD-L1 and PD-1 expression was assessed by immunohistochemistry, considering as positive a staining intensity ≥ 2 in more than 5% of cells.
PD-L1 was successfully evaluated in 123 samples. PD-L1 positive expression was observed in 68 (54.4%) cases. The researchers found that PD-L1 positivity was significantly associated with presence of EGFR mutations (p < 0.0001), while no association was observed with other biomarkers.
PD-1 was assessed in 122 samples and PD-1 expression was demonstrated in 43 (34.4%) cases. PD-1 positive expression was significantly associated with KRAS mutated status (p = 0.005), while no association was observed with other biomarkers.
Among the 95 patients treated with gefitinib or erlotinib who were evaluable for response analysis, there were 49 patients (51.6%) positive for PD-L1 expression. They achieved a significantly higher response rate (61.2% versus 34.8%, p = 0.010), a significantly longer time to progression (11.7 months versus 5.7 months, p < 0.0001) and longer overall survival (21.9 months versus 12.5 months, p = 0.087) compared to PD-L1 negative patients.
Correlation with EGFR Mutation
In the subset of 55 EGFR mutated patients treated with EGFR tyrosine kinase inhibitors and evaluable for response, those who were PD-L1 positive (70.9%) showed a longer time to progression (13.0 months versus 8.5 months, p = 0.011). The overall survival was 29.5 months in PD-L1 positive compared to 21.0 months in PD-L1 negative patients. However, no differences were identified in PD-1 positive versus PD-1 negative patients.
Although the study sample is small, time to progression was more favourable in PD-L1 positive and EGFR mutated patients treated with EGFR-TKIs than in PD-L1 negative patients (8.5 vs. 13 months, p = 0.01).
© Armida D’Incecco
Although analysis was done in a small subset, the results are interesting and suggest a correlation between PD-L1 expression and EGFR mutation, as well as between PD-1 expression and KRAS mutations, supporting the idea for further investigation of anti-PD-L1 or anti-PD-1 agents in combination with targeted therapies.
PD-1 and PD-L1 expression differ according to clinical and biological characteristics; PD-1 positive patients were generally male, smokers, with adenocarcinoma histology, KRAS mutated; while PD-L1 positive patients were generally female, never/former smokers, with adenocarcinoma histology, EGFR mutated or ALK translocated.
Dr Fred Hirsch, who discussed the study results, believes that PD-L1/PD-1 immunohistochemistry needs validation, as no assay is fully validated yet. In addition, he presented PD-L1 expression and driver mutation “map” in NSCLC - a knowledge derived and modified upon Kowanetz M et al. presentation at 2013 World Conference on Lung Cancer.
In lung adenocarcinoma, approximately 47% of the immune infiltrate is PD-L1. Approximately 70% of these PD-L1 positive tumours are also MET positive, KRAS mutant or EGFR mutant. Further, PD-L1 positive NSCLC also expresses other immune checkpoints such as TIM3, LAG-3, B7-H3, B7-H4, and CTLA-4.
Dr Hirsch concluded that the study of D’Incecco and colleagues opens an interesting hypothesis if PD-L1 and PD-1 expressing tumours are two different diseases.
Reference
Abstract 38O: PD-L1 and PD-1 expression in molecularly selected non-small-cell lung cancer (NSCLC) patients.
All authors have declared no conflicts of interest.
The European Lung Cancer Conference (ELCC) is organised by the European Society for Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC). During the four-day programme, attendees benefit from educational and scientific updates provided by thoracic oncology specialists on different multidisciplinary topics important for research and clinical practice in the field of lung cancer.