Predictive value of oncogenic driver subtype, programmed death-1 ligand (PD-L1) score, and smoking status on the efficacy of PD-1/PD-L1 inhibitors in patients with oncogene-driven non-small cell lung cancer.

This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death-1 ligand (PD-L1) status, and smoking status for predicting which patients with oncogene-driven non-small cell lung cancer (NSCLC) would benefit from treatment with programmed death-1 (PD-1)/PD-L1 inhibitors. The clinical features, PD-L1 tumor proportion scores, and PD-1/PD-L1 inhibitor (PDi) outcomes (objective response rate and progression-free survival) of patients who had advanced NSCLC with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations or common, actionable oncogenic drivers were captured. In total, 189 oncogene-positive patients were analyzed. Of these, 104 received a PDi, and 108 had undergone prior PD-L1 testing. The frequency of PD-L1 positivity (≥1%) was higher in patients who had KRAS mutations (P = .031), smokers (P = .006), and non-Asian patients (P = .002). Multivariable analysis indicated that smoking status (P < .001) was the only factor associated significantly with KRAS mutation. The objective response rate to PDi treatment was 16.9% (11 of 65 patients) among smokers (17.3% in the KRAS-mutant and 15.4% in the non-KRAS-mutant smoker subgroups), which was significantly higher than the 0% rate (0 of 26 patients; P = .019) among never-smokers. In subgroup analyses, progression-free survival was influenced by KRAS mutation status (median, 4.57 vs 1.63 months; P = .004), smoking status (4.07 vs 1.73 months; P = .004), PD-L1 positivity (3.8 vs 1.2 months; P = .040), and non-Asian race (3.0 vs 1.97 months; P = .046). In multivariable analysis, only smoking status (P = .008) remained a significant predictor when a PD-L1 level ≥1% was used. However, both smoking status (P = .001) and PD-L1 status (P = .028) were independent predictors when a PD-L1 level ≥50% was used. Among associated clinical features among patients who have NSCLC with oncogenic drivers, smoking status potentially was the most important, easily available predictor of single PDi efficacy.

Ng TL ，Liu Y ，Dimou A ，Patil T ，Aisner DL ，Dong Z ，Jiang T ，Su C ，Wu C ，Ren S ，Zhou C ，Camidge DR ... -  《-》

Correlation between Programmed Death Ligand-1(PD-L1) Expression and Driver Gene Mutations in Non-Small Cell Lung Carcinoma- Adenocarcinoma Phenotype.

Pandey RK ，Shukla S ，Husain N ，Islam MH ，Hadi R ，Kant Tripathi S ，Singhal A ... -  《-》

Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer.

Objective: The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics, as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer (NSCLC). Methods: We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC patients. Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+ tumor-infiltrating lymphocytes (TILs). Immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT algorithm. Results: Based on East Asian NSCLC patients, TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy, epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged tumors yielded inferior responses; however, although Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors responded better, the difference was not statistically significant (EGFR: P = 0.037; ALK: P < 0.001; KRAS: P = 0.701). Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneities correlated with oncogenic patterns. The results showed remarkably higher PD-L1- and TIL-positive KRAS-mutant tumors, suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance. However, the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors, suggesting an uninflamed phenotype with immunological ignorance. Notably, similar to triple wild-type NSCLC tumors, EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype, suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy (P < 0.05). Furthermore, the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterized by an enriched resting memory CD4+ T cell population (P < 0.001), as well as a lack of CD8+ T cells (P < 0.01), and activated memory CD4+ T cells (P = 0.001). Conclusions: Our study highlighted the complex relationships between immune heterogeneity and immunotherapeutic responses in East Asian NSCLC patients regarding oncogenic dependence.

Jin R ，Liu C ，Zheng S ，Wang X ，Feng X ，Li H ，Sun N ，He J ... -  《Cancer Biology & Medicine》

Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC).

KRAS mutation is the most frequent molecular alteration found in advanced NSCLC; it is associated with a poor prognosis without available targeted therapy. Treatment options for NSCLC have been recently enriched by the development of immune checkpoint inhibitors (ICIs), and data about its efficacy in patients with KRAS-mutant NSCLC are discordant. This study assessed the routine efficacy of ICIs in advanced KRAS-mutant NSCLC. In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and with available molecular analysis between April 2013 and June 2017. Analysis of programmed death ligand 1 (PD-L1) expression was performed if exploitable tumor material was available. A total of 282 patients with ICI-treated (in the first line or more) advanced NSCLC (all histological subgroups) who were treated with ICIs (anti-programmed death 1, anti-PD-L1, or anti-cytotoxic T-lymphocyte associated protein 4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations, and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression of 1% or more and 50%, respectively (49.5% and 21.2%, respectively, in the case of the 85 patients with KRAS-mutant NSCLC). No significant difference was seen in terms of objective response rates, progression-free survival, or overall survival between KRAS-mutant NSCLC and other NSCLC. No significant differences in overall survival or progression-free survival were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRAS-mutant NSCLC, unlike in non-KRAS-mutant NSCLC, the efficacy of ICIs is consistently higher, even though not statistically significant, for patients with PD-L1 expression in 1% or more of tumor cells than for those with PD-L1 expression in less than 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥50%). For patients with KRAS-mutant NSCLC (all mutational subtypes), the efficacy of ICI is similar to that for patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICIs in KRAS-mutant NSCLC than it is in other types of NSCLC.

Jeanson A ，Tomasini P ，Souquet-Bressand M ，Brandone N ，Boucekine M ，Grangeon M ，Chaleat S ，Khobta N ，Milia J ，Mhanna L ，Greillier L ，Biemar J ，Nanni I ，Ouafik L ，Garcia S ，Mazières J ，Barlesi F ，Mascaux C ... -  《-》

Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.

This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1). Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007). We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC. Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.

Shi Y ，Lei Y ，Liu L ，Zhang S ，Wang W ，Zhao J ，Zhao S ，Dong X ，Yao M ，Wang K ，Zhou Q ... -  《Cancer Medicine》