The correlation between programmed death-ligand 1 expression and driver gene mutations in NSCLC

Abstract

ObjectivesThis study aimed to evaluate the correlation between positive PD-L1 expression and driver gene mutations in NSCLC and to seek preliminary evidence in favor of the strategy of PD-L1 inhibitors plus targeted agents.ResultsThe overall analyses revealed that positive PD-L1 expression had a significant relationship with KRAS status (RR = 1.26; 95% CI, 1.06−1.50, P = 0.010), but no correlation with clinical characteristics (gender, smoking status, histological types), driver gene status (EGFR, ALK) and overall survival (OS): male versus female (RR = 1.16; 95% CI, 0.95−1.42; P = 0.15), never smoking versus former/current smoking (RR = 0.79; 95% CI, 0.56−1.11; P = 0.17), adenocarcinoma versus non-adenocarcinoma (RR = 0.94; 95% CI, 0.63−1.41; P = 0.77), EGFR mutation versus EGFR wild type (RR = 0.74; 95% CI, 0.52−1.06; P = 0.10), ALK positive versus ALK negative (RR = 1.02; 95% CI, 0.75−1.38; P = 0.91), OS of positive PD-L1 expression versus that of negative PD-L1 expression (HR = 1.31, 95% CI, 0.90−1.90; P = 0.15), respectively. Noteworthily, subgroup analyses exhibited that in Chinese cohort studies, positive PD-L1 expression was significantly correlated with OS (HR = 1.75, 95% CI, 1.36−2.24, P < 0.0001); and in the studies using PD-L1 monoclonal antibodies (McAbs), positive PD-L1 expression was significantly correlated with KRAS mutation (RR = 1.32, 95% CI, 1.06−1.65, P = 0.01) and EGFR mutation (RR = 0.51, 95% CI, 0.28−0.93, P = 0.03).Materials and MethodsAfter thoroughly searching PubMed, EMBASE and Cochrane Library databases, 11 relevant studies incorporating 3128 cases were identified. The pooled data were analyzed via Review manager 5.3 software.ConclusionsPD-L1 inhibitors probably was a potential promising option to manage advanced NSCLC harboring KRAS mutation.

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

“…Over the next 6-18 months the NSCLC tumors evolve so that they become resistant to the kinase inhibitory drugs. It is known from in vitro studies that ERBB1 inhibitors reduce the expression of immunotherapy biomarkers such as PD-L1 in NSCLC cells and tumors from kinase inhibitor resistant patients express low levels of PD-L1 and PD-L2 [ 43 , 44 , 45 – 46 ]. In NSCLC, low levels of immunotherapy biomarkers correlate with a poor anti-tumor response to anti-PD-1 and anti-CTLA4 inhibitory antibodies.…”

Association between certain non–small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death‐ligand 1 inhibition

“…For example, NSCLC patients with ALK+ responded well to pemetrexed‐based therapy, obtaining prolonged progression‐free survival . For advanced NSCLC patients with KRAS mutations, who were considered chemo‐resistant, PD‐(L)1 inhibitors were available and platinum‐based chemotherapy were added . BRAF mutation in Chinese NSCLC patients was rare, with patients not responding well to chemotherapy, and limited data available.…”

“…Anti PD‐(L)1 was optional and taxanes might be the most sensitive chemo agents. For EGFR‐mutant patients, PD‐(L)1 inhibitors were not recommended, while patient with KARS, BRAF and MET mutations benefit more from immune checkpoint inhibitors than EGFR, ALK and RET patients . With the common practice of gene mutation detection, there will be more evidence from qualified clinical studies to support these results.…”

The MYC oncogene is a global regulator of the immune response

“…Multiple oncogenes have been shown to regulate the expression of immune checkpoints, including EGFR, KRAS, BRAF, b-catenin, and STAT3, as can tumor suppressive gene products, such as PTEN [82][83][84][85][86][87][88][89] (Table 1; Figure 2). NF-kB signaling, which can drive many inflammatory-based cancers, also may regulate PD-L1.…”