Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer.

Inhibitors of the programmed cell death 1 (PD-1) pathway show the potential to substantially increase the efficacy of therapy for various malignancies, including non-small cell lung cancer (NSCLC). At the same time, substantial effort has been invested in finding biomarkers predicting which patients will respond best to this immune checkpoint inhibition. PD-L1 expression in tumor cells and the tumor microenvironment, genetic alterations and mutational load in tumor cells, and pre-existing immunity and its enhancement during treatment through tumor-infiltrating immune cells have been associated with outcomes of immune checkpoint inhibition. Here, we review the reported predictive biomarkers of response to PD-1 pathway immune checkpoint inhibitors in NSCLC, mainly focusing on results obtained with clinical trials.

Shien K ，Papadimitrakopoulou VA ，Wistuba II 《-》

Durvalumab in non-small-cell lung cancer patients: current developments.

Mezquita L ，Planchard D 《-》

[Efficacy of PD-1/PD-L1 immune checkpoint inhibitors and PD-L1 testing in thoracic cancers].

Tumoral immune environment is a major component of cancer. Its composition and its organization represent a reproducible characteristic of tumors and a validated prognostic factor. In non-small cell lung cancer (NSCLC), cytotoxic T CD8+ lymphocyte density, associated with a Th1 environment and tertiary lymphoid structures impacts survival. Tumor cell-immune cell interaction is targeted by PD1/PD-L1 inhibitors. In advanced NSCLC, PD1/PD-L1 inhibitors are more effective than second-line chemotherapy. Pembrolizumab outperforms first-line chemotherapy in NSCLC strongly positive for PD-L1. PD1/PD-L1 inhibitors are currently tested in mesothelioma and thymic tumors. PD-L1 expression evaluated with immunochemistry is the most studied predictive biomarker of PD1/PD-L1 inhibitor efficacy. Tumor and immune cell expression of PD-L1 is still difficult to evaluate because of intra-tumoral heterogeneity and expression modulation by the microenvironment. Four commercial diagnostic antibodies are in development, with differences concerning recognized epitopes, methodology of evaluation of PD-L1 expression, positivity threshold, kit and platforms used. Clinical trials in NSCLC have shown that patients with tumors strongly positive for PD-L1 derived the best clinical benefit with PD1/PD-L1 inhibitors whereas clinical benefit is less common in tumors negative for PD-L1. PD-L1 expression is not a perfect biomarker since some PD-L1 negative NSCLC respond to PD1/PD-L1 inhibitors and some PD-L1 positive NSCLC do not. PD-L1 testing is likely to be implemented in daily practice for selection of advanced NSCLC that will be treated with pembrolizumab, underscoring the relevance of ongoing harmonization studies of the use of the different antibodies available for PD-L1 testing.

Duruisseaux M ，Rouquette I ，Adam J ，Cortot A ，Cazes A ，Gibault L ，Damotte D ，Lantuejoul S ... -  《ANNALES DE PATHOLOGIE》

Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: A meta-analysis.

Programmed death-ligand-1 (PD-L1) is a well-known predictive biomarker in non-small cell lung cancer (NSCLC) patients, however, its accuracy remains controversial. Here, we investigated the correlation between PD-L1 expression level and efficacy of its inhibitors, and hence assessed the predictive effect of PD-L1 expression. Studies that evaluated the efficacy of programmed death-1 (PD-1)/ PD-L1 inhibitors in advanced NSCLC patients according to tumor PD-L1 expression levels were searched for on Medline, Cochrane Library, and Embase. The pooled risk ratio (RR) and 95% confidence intervals (95% CIs) were calculated for the objective response rate (ORR) with overall survival (OS) and progression-free survival (PFS) were measured in terms of hazard ratio (HR) and the corresponding 95% CIs. 1432 NSCLC patients from six randomized controlled trials (RCTs) were included and three PD-1/PD-L1 inhibitors (atezolizumab, nivolumab, and pembrolizumab) were used to treat the patients. A significantly higher ORR was observed in the high PD-L1 expression group compared to the low expression group (0.35 [95% CI, 0.30-0.40] vs 0.11 [95% CI, 0.09-0.14]). The results of the subgroup analysis, grouped by the type of drugs and antibodies which assess immune checkpoint inhibitors were identical with the pooled result. However, our study showed that PD-L1 expression was neither prognostic nor predictive of overall survival (OS) or progression-free survival (PFS) in patients treated with PD-1/PD-L1 inhibitors compared to chemotherapy. PD-L1 can be a predictive biomarker for ORR. Nevertheless, PD-L1 expression is not a good predictive tool for OS and PFS.

Zhang B ，Liu Y ，Zhou S ，Jiang H ，Zhu K ，Wang R ... -  《-》

The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity.

Immune checkpoint inhibitors against PD-1/PD-L1 yield improved survival rates of KRAS-mutant NSCLC patients, who conferred a poor prognosis without effective targeted therapy until now. Yet, the underlying association between KRAS mutations and immune responses remains unclear. We performed an integrated analysis of the data from publicly available repositories and from clinical center cohorts to explore the association between KRAS mutation status and tumor immunity-associated features, including PD-L1 expression, CD8+ tumor-infiltrating lymphocytes (TILs) and tumor mutational burden (TMB). Our results revealed that KRAS mutations are correlated with an inflammatory tumor microenvironment and tumor immunogenicity, resulting in superior patient response to PD-1/PD-L1 inhibitors. Meanwhile, three-pool analysis further confirmed that KRAS-mutant NSCLC patients show remarkable clinical benefit from anti-PD-1/PD-L1 immunotherapy. In addition, a KRAS-mutant lung adenocarcinoma mouse model was established to estimate the relative efficacy of anti-PD-L1 monoclonal antibody monotherapy or combination treatment with docetaxel versus docetaxel alone. Most surprisingly, we found that PD-L1 blockade combined with docetaxel did not promote an anti-tumor response. These findings uncover that PD-1/PD-L1 blockade monotherapy may be the optimal therapeutic schedule in NSCLC patients harboring KRAS mutations.

Liu C ，Zheng S ，Jin R ，Wang X ，Wang F ，Zang R ，Xu H ，Lu Z ，Huang J ，Lei Y ，Mao S ，Wang Y ，Feng X ，Sun N ，Wang Y ，He J ... -  《-》