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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.

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC. Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma.

Background 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. Methods 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. Results 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). Conclusion 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.

The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined. To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence. This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021. Adjuvant treatment was administered per investigator's discretion. The main outcome was 2-year disease-free survival (DFS). A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification. This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.

Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET, and fusions involving ALK and RET. We term these “non-smoking-related oncogenes” (NSROs). In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers, and the clonal architecture and genomic landscape of these tumors remain unknown. We investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. NSRO-driven NSCLCs in smokers and non-smokers have similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle, suggesting that smoking still affects tumor phenotype independently of genomic alterations. This study highlights the lack of genomic scars caused by smoking in NSCLCs driven by non-smoking-related oncogenes regardless of smoking history. The impact of smoking on these tumors is mainly non-genomic. The transcriptomic features of NSCLCs associated with smoking may help in the development of therapeutic approaches.

Background: Unlike smoking-related non-small cell lung cancers (NSCLCs), oncogene-driven NSCLCs (including those driven by epidermal growth factor receptor, EGFR) are characterized by low mutational burdens and complex genomic landscapes. However, the clonal architecture and genomic landscape of the oncogene-driven NSCLCs in smokers remain unknown. Here, we investigate the impact of tobacco smoking on genomic and transcriptomic alterations in the context of oncogene-driven NSCLC. Methods: Patients undergoing resection for NSCLC at the National Cancer Centre Singapore were enrolled in this study. Resected tumors were divided into multiple regions, which then underwent whole-exome sequencing and bulk RNA sequencing. We investigated tumor mutational burden, intra-tumor heterogeneity, tumor phylogeny, mutational signatures, and transcriptomes across the regions of each tumor. Results: We studied a total of 173 tumor sectors from 48 patients. Tumors were classified into three groups: \"oncogene-driven non-smoking\" (n=25, 52%), \"oncogene-driven smoking\" (n=12, 25%) and \"typical smoking\" (n=11, 23%). Oncogene-driven smoking versus non-smoking tumors did not differ significantly in terms of tumor mutational burden, intra-tumor heterogeneity, and driver mutation composition. Surprisingly, the mutational signature caused by tobacco smoking was essentially absent in oncogene-driven smoking tumors, despite prominent smoking histories. Compared to oncogene-driven non-smoking tumors, oncogene-driven smoking tumors had higher activity in pathways related to regulation of cell cycle, especially mitotic exit. Conclusions: Oncogene-driven tumors in smokers shared similar clonal architecture and genomic features with archetypical oncogene-driven tumors in non-smokers. Oncogene-driven tumors in smokers had low tumor mutational burden and high intra-tumor heterogeneity and the mutational signature of smoking was largely absent. However, among oncogene-driven tumors, the differences in transcriptomic pathway activities between smokers and non-smokers suggest that smoking may foster a tumor phenotype distinct from that in non-smokers.Competing Interest StatementG. Lai reports receiving personal fees from Astra Zeneca and grants from Merck, Astra Zeneca, Pfizer, Bristol-Myers-Squibb, Amgen and Roche outside the submitted work and sponsorship from DKSH. A.C. Tan reports receiving personal fees from ASLAN Pharmaceuticals, and Illumina, consultation fees from Pfizer, Amgen, Bayer, and honoraria from Amgen, Thermo Fisher Scientific, Janssen, Pfizer, Juniper Biologics, and Guardant Health. S.P. Saw reports receiving personal fees from MSD, consultation fees from Pfizer, and Bayer, and grants from Astra Zeneca, and Guardant Health. R. Kanesvaran reports receiving honoraria and consultation fees from MSD , BMS, Astellas, Novartis, Pfizer, Merck, J&J, and AstraZeneca. D.W.T. Lim reports receiving grant support from AstraZeneca, honoraria from Novartis, Merck, Amgen, personal fee from AstraZeneca, Ipsen, Boehringer Ingelheim, Bristol-Myers-Squibb, and DKSH. B.H. Ong reports receiving personal fees from AstraZeneca, Medtronic, Stryker, and MSD. All remaining authors have declared no conflicts of interest.Footnotes* https://github.com/Rozen-Lab/oncogene-NSCLC/

Topological transitions between considerably different phases typically require harsh conditions to collectively break chemical bonds and overcome the stress caused to the original structure by altering its correlated bond environment. In this work we present a case system that can achieve rapid rearrangement of the whole lattice of a metal–organic framework through a domino alteration of the bond connectivity under mild conditions. The system transforms from a disordered metal–organic framework with low porosity to a highly porous and crystalline isomer within 40 s following activation (solvent exchange and desolvation), resulting in a substantial increase in surface area from 725 to 2,749 m2 g–1. Spectroscopic measurements show that this counter-intuitive lattice rearrangement involves a metastable intermediate that results from solvent removal on coordinatively unsaturated metal sites. This disordered–crystalline switch between two topological distinct metal–organic frameworks is shown to be reversible over four cycles through activation and reimmersion in polar solvents.

The rapid global spread of the coronavirus disease (COVID-19) has inflicted significant health and socioeconomic burden on affected countries. As positive cases continued to rise in Malaysia, public health laboratories experienced an overwhelming demand for COVID-19 screening. The confirmation of positive cases of COVID-19 has solely been based on the detection of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) using real-time reverse transcription polymerase chain reaction (qRT-PCR). In efforts to increase the cost-effectiveness and efficiency of COVID-19 screening, we evaluated the feasibility of pooling clinical Nasopharyngeal/Oropharyngeal (NP/OP) swab specimens during nucleic acid extraction without a reduction in sensitivity of qRT-PCR. Pools of 10 specimens were extracted and subsequently tested by qRT-PCR according to the WHO-Charité protocol. We demonstrated that the sample pooling method showed no loss of sensitivity. The effectiveness of the pooled testing strategy was evaluated on both retrospective and prospective samples, and the results showed a similar detection sensitivity compared to testing individual sample alone. This study demonstrates the feasibility of using a pooled testing strategy to increase testing capacity and conserve resources, especially when there is a high demand for disease testing.

In Taiwan's Central Range mountains, fundamental constraints on depositional ages and the timing of deformation and metamorphism remain a problematic issue preventing a consensual chronology of orogenic events to be established. In this contribution, we report detrital zircon U-Pb detrital ages for the Chulai Formation, the easternmost strip of metamorphic sediments depositionally overlying the metamorphic, high-pressure Yuli belt. We demonstrate that the maximum depositional age of this unit is 11.2 ± 0.2 Ma (Upper Miocene, Tortonian), making it the youngest pervasively deformed and metamorphosed unit of the Central Range. Detrital zircon ages suggest an almost exclusively continental origin of the sediments similar to the Yuli belt's matrix detrital age zircon spectra. Sedimentary relationships and structural considerations indicate that the Chulai Formation underwent essentially the same deformation history as the underlying Yuli belt, and thus the maximum depositional age of 11.2 ± 0.2 Ma is interpreted as the upper limit for the start of pervasive deformation of the eastern Central Range geological units. When considering the existing geochronological constraints on the metamorphism, we argue that the timing for the Cenozoic metamorphism of the Taiwan orogen is likely to be ~6 - 8 Ma.