Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Lung cancer is the world’s leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts. Genomic and transcriptomic analysis of lung adenocarcinoma (LUAD) in Asia indicates that Asian LUADs have fewer mutations, lower driver prevalence and fewer copy number alterations than European LUADs.

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Genomic landscape of lung adenocarcinoma in East Asians

Radiomics and its emerging role in lung cancer research, imaging biomarkers and clinical management: State of the art

Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.

Methionine is a metabolic dependency of tumor-initiating cells.

Importance The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non–small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition Objectives To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors Data Sources The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, includingtumor vaccine,cellular immunotherapy,immune checkpoint inhibitor,cytotoxic T-lymphocyte-associated protein 4,programmed death-ligand 1,programmed death receptor 1, andnon-small cell lung carcinoma Systematic reviews, meta-analyses, references, and conference proceedings were manually searched Study Selection English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC Data Extraction and Synthesis Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS Dichotomous data, such as object response rate data, were analyzed using the risk ratio Mantel-Haenszel random-effects model was usedI2was used to assess the heterogeneity between trials; anI2value exceeding 50% indicated the existence of substantial heterogeneity Analyses took place from February 1, 2018, to August 31, 2018 Main Outcomes and Measures Primary outcomes were OS and PFS Results In total, 14 395 patients (9500 [660%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 652 [99] years; 1063 [580%] men) were included in the individual patient–level study Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 076; 95% CI, 071-082;P  Conclusions and Relevance Immunotherapies showed promising clinical outcomes for patients with NSCLC Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients’ survival and response to precision immunotherapy The further combination of CD8+T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis The predictive value of that combination needs to be prospectively validated in large-scale studies

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Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non–Small Cell Lung Cancer: A Meta-analysis and Individual Patient–Level Analysis

Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(16)30123-1.pdf

Novel therapeutic targets on the horizon for lung cancer.

Nasopharyngeal carcinoma (NPC) is a unique disease endemic in Asia. It is etiologically linked to the Epstein-Barr virus and is both radio- and chemo-sensitive. While radiotherapy (RT) remains the primary treatment modality with high cure rates for early stage disease, systemic treatment forms an important integral component in the treatment of NPC, both in the non-metastatic as well as palliative setting. Presently, standard therapy in locally advanced NPC comprises conventional cytotoxic chemotherapy administered concurrently during RT. The role of induction chemotherapy and adjuvant chemotherapy remain to be well-defined. Further research strategies in non-metastatic disease will require better identification of patients with high risk disease, and determining the optimal sequence and combination of chemotherapeutic regimens. In metastatic disease, whilst chemotherapy remains the mainstay of care, resistance inevitably develops. Development of molecularly targeted therapies has not yielded much success to date, and further research has been focused on development of EBV-targeted strategies such as vaccination or administration of cytotoxic T-cells directed towards EBV, as well as evaluation of immune checkpoint inhibition approaches.

/pdf/advances-in-systemic-treatment-for-nasopharyngeal-carcinoma-10uii1bfz6.pdf

Advances in systemic treatment for nasopharyngeal carcinoma

Afatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control. We performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models. Out of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3–19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15–0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34–1.80). In patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.

/pdf/influence-of-afatinib-dose-on-outcomes-of-advanced-egfr-1ev7vjrqpd.pdf

Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases

Real world data on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) use in advanced/metastatic non-small cell lung cancer (NSCLC) with EGFR mutations in Singapore

266O Combination ipilimumab and nivolumab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): Updated efficacy and safety analysis of NCT03097939

Wan-Ling Tan

Papers

Novel therapeutic targets on the horizon for lung cancer.

Advances in systemic treatment for nasopharyngeal carcinoma

Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases

Real world data on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) use in advanced/metastatic non-small cell lung cancer (NSCLC) with EGFR mutations in Singapore

266O Combination ipilimumab and nivolumab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): Updated efficacy and safety analysis of NCT03097939