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The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFRand ALKwild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y).

EGFRC797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts.

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552.

IMPORTANCE: The use of adjuvant chemotherapy for stage IB-IIIA resected non–small cell lung cancer (NSCLC) has limited benefit for improving cure rates. The proportion of epidermal growth factor receptor (EGFR) alterations among patients with resected NSCLC is comparable to that observed in patients with advanced disease, and the use of EGFR tyrosine kinase inhibitors (TKIs) has been demonstrated to prolong disease-free survival (DFS). With recent approval of osimertinib in this context, a focus on the rapidly evolving scenario and future perspective in clinical practice is needed and was the aim of the current review. OBSERVATIONS: Randomized phase 3 clinical trials demonstrated DFS benefit with adjuvant EGFR TKI therapy in patients with resected EGFR mutation–positive NSCLC. The most recent trial (ADAURA) assessed 3-year adjuvant osimertinib and showed consistent DFS benefit and a significant role of the intervention in preventing the occurrence of brain metastasis. However, the role of adjuvant chemotherapy, the appropriate duration of treatment, the management of disease relapse, and the effective cure rate remain undetermined. A deeper investigation on molecular biomarkers, covariant patterns, and dynamic monitoring of postsurgical circulating DNA would be helpful for the implementation of future strategies to further improve survival rates after adjuvant therapy for EGFR mutation–positive NSCLC. CONCLUSIONS AND RELEVANCE: Adjuvant osimertinib revolutionized the treatment algorithm for patients with stage IB-IIIA resected EGFR mutation–positive NSCLC. Further evidence driven by clinical issues will be key for further optimization of the goals of adjuvant treatment in these patients.

Most published guidelines for genomic biomarker testing in NSCLC reflect the disease epidemiology and treatments readily available in Europe and North America. Nevertheless, 60% of annual global NSCLC cases occur in Asia, where patient characteristics, tumor molecular profiles, and treatments vary greatly from the Western world. For example, mutations in the EGFRoccur at a higher prevalence in Asia than in other world regions. Although medical associations such as the International Association for the Study of Lung Cancer, European Society for Medical Oncology, and American Society of Clinical Oncology have described principles for tumor genomic biomarker testing in NSCLC, there is a need for recommendations specific for Asia.

IMPORTANCE: Immune-related adverse events (irAEs) arising from immune checkpoint inhibitor (ICI) cancer therapy may potentially predict improved outcomes. OBJECTIVE: To evaluate the association between irAEs and atezolizumab efficacy in patients with advanced non–small cell lung cancer (NSCLC) using pooled data from 3 phase 3 ICI studies. DESIGN, SETTING, AND PARTICIPANTS: IMpower130, IMpower132, and IMpower150 were phase 3, multicenter, open-label, randomized clinical trials to evaluate the efficacy and safety of chemoimmunotherapy combinations involving atezolizumab. Participants were chemotherapy-naive adults with stage IV nonsquamous NSCLC. These post hoc analyses were conducted during February 2022. INTERVENTIONS: Eligible patients were randomly assigned 2:1 to receive atezolizumab with carboplatin plus nab-paclitaxel, or chemotherapy alone (IMpower130); 1:1 to receive atezolizumab with carboplatin or cisplatin plus pemetrexed, or chemotherapy alone (IMpower132); and 1:1:1 to receive atezolizumab plus bevacizumab plus carboplatin and paclitaxel, atezolizumab plus carboplatin and paclitaxel, or bevacizumab plus carboplatin and paclitaxel (IMpower150). MAIN OUTCOMES AND MEASURES: Pooled data from IMpower130 (cutoff: March 15, 2018), IMpower132 (cutoff: May 22, 2018), and IMpower150 (cutoff: September 13, 2019) were analyzed by treatment (atezolizumab-containing vs control), irAE status (with vs without), and highest irAE grade (1-2 vs 3-5). To account for immortal bias, a time-dependent Cox model and landmark analyses of irAE occurrence at 1, 3, 6, and 12 months from baseline were used to estimate the hazard ratio (HR) of overall survival (OS). RESULTS: Of 2503 randomized patients, 1577 were in the atezolizumab-containing arm and 926 were in the control arm. The mean (SD) age of patients was 63.1 (9.4) years and 63.0 (9.3) years, and 950 (60.2%) and 569 (61.4%) were male, respectively, in the atezolizumab arm and the control arm. Baseline characteristics were generally balanced between patients with irAEs (atezolizumab, n = 753; control, n = 289) and without (atezolizumab, n = 824; control, n = 637). In the atezolizumab arm, OS HRs (95% CI) in patients with grade 1 to 2 irAEs and grade 3 to 5 irAEs (each vs those without irAEs) in the 1-, 3-, 6-, and 12-month subgroups were 0.78 (0.65-0.94) and 1.25 (0.90-1.72), 0.74 (0.63-0.87) and 1.23 (0.93-1.64), 0.77 (0.65-0.90) and 1.1 (0.81-1.42), and 0.72 (0.59-0.89) and 0.87 (0.61-1.25), respectively. CONCLUSIONS AND RELEVANCE: In this pooled analysis of 3 randomized clinical trials, longer OS was observed in patients with vs without mild to moderate irAEs in both arms and across landmarks. These findings further support the use of first-line atezolizumab-containing regimens for advanced nonsquamous NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02367781, NCT02657434, and NCT02366143

After a median follow-up of 18·3 months, the third-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, lorlatinib, improved progression-free survival in patients with treatment-naive, ALK-positive non-small-cell lung cancer in the phase 3 CROWN study. Here we report updated efficacy data, including intracranial activity, from an unplanned analysis after 3 years of follow-up.

Lung cancer is the most prevalent malignant tumour in the Asia–Pacific region. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers. Among these, the rate of EGFRmutations in Asian patients with lung adenocarcinoma is 40–60%. Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) have improved the clinical management of NSCLC with EGFRmutations, but resistance to these drugs remains a significant challenge. Despite numerous ongoing studies, there is no standardized consensus on managing resistance to third-generation EGFR-TKIs. This consensus integrates international guidelines on EGFR-TKI management, findings from clinical studies, and experiences from the Asia–Pacific region in addressing post-resistance. Detailed recommendations are provided for classification and progression patterns, clinical testing, and post-resistance treatment strategies related to third-generation EGFR-TKI resistance. The aim of these recommendations is to offer reference opinions for the standardized management of patients exhibiting resistance to third-generation EGFR-TKIs in clinical practice.

IMPORTANCE: Molecular testing in non–small cell lung cancer (NSCLC) is commonly limited by inadequate tumor sample. Plasma cell-free DNA (cfDNA) genotyping as a complementary test is specific but only moderately sensitive. Genotyping of cfDNA in pleural and pericardial effusion (PE-cfDNA) can further optimize molecular diagnostic yield and reduce the need for repeated biopsies. OBJECTIVE: To prospectively validate droplet digital polymerase chain reaction (ddPCR) for detection of sensitizing EGFR variants and acquired Thr790Met variant (T790M) from PE-cfDNA in patients with NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This prospective diagnostic validation study was conducted between September 6, 2016, and January 21, 2021 at 2 major Hong Kong cancer centers. Patients with advanced NSCLC with both wild-type and variant EGFR status and exudative PE who underwent thoracocentesis or pericardiocentesis were randomly enrolled. Patients were either EGFR-tyrosine kinase inhibitor (TKI) naive (cohort 1) or EGFR-TKI treated but osimertinib naive (cohort 2). Enrolled patients underwent pleural- or pericardial-fluid and blood sampling for ddPCR EGFR testing. EGFR status results with ddPCR testing of PE-cfDNA and blood were compared with EGFR status in matched tumor biopsy or PE cell block samples. MAIN OUTCOMES AND MEASURES: Specificity, sensitivity, and concordance of PE-cfDNA for detection of sensitizing EGFR variants and acquired T790M variation. RESULTS: Among 171 patients (54% female) enrolled, there were 104 in cohort 1 and 67 in cohort 2. In cohort 1, 37% (38/102) were EGFR-variant positive; PE-cfDNA showed 97% sensitivity (95% CI, 92%-100%), 97% specificity (95% CI, 93%-100%), and 97% concordance (ĸ = 0.94, P < .001) for the detection of sensitizing EGFR variants. It was more sensitive than plasma in detecting sensitizing EGFR variants (97% vs 74%, P < .001). In cohort 2, 38% (15 of 40) were positive for the EGFR T790M variant; PE-cfDNA showed 87% sensitivity (95% CI, 69%-100%), 60% specificity (95% CI, 41%-79%), and 70% concordance (ĸ = 0.42, P = .004) for acquired T790M. The EGFR T790M variant was detected in 51% of PE-cfDNA vs 25% of PE cell block samples. CONCLUSIONS AND RELEVANCE: In this diagnostic study, EGFR variants could be accurately detected from PE-cfDNA in patients with NSCLC. More EGFR T790M was detected in PE-cfDNA than in guideline-recommended PE cell block preparations. These results suggest that PE-cfDNA can complement plasma and tumor genotyping for detecting EGFR variants in patients with advanced NSCLC.

Image registration is a fundamental medical image analysis task, and a wide variety of approaches have been proposed. However, only a few studies have comprehensively compared medical image registration approaches on a wide range of clinically relevant tasks. This limits the development of registration methods, the adoption of research advances into practice, and a fair benchmark across competing approaches. The Learn2Reg challenge addresses these limitations by providing a multi-task medical image registration data set for comprehensive characterisation of deformable registration algorithms. A continuous evaluation will be possible at https://learn2reg.grand-challenge.org. Learn2Reg covers a wide range of anatomies (brain, abdomen, and thorax), modalities (ultrasound, CT, MR), availability of annotations, as well as intra- and inter-patient registration evaluation. We established an easily accessible framework for training and validation of 3D registration methods, which enabled the compilation of results of over 65 individual method submissions from more than 20 unique teams. We used a complementary set of metrics, including robustness, accuracy, plausibility, and runtime, enabling unique insight into the current state-of-the-art of medical image registration. This paper describes datasets, tasks, evaluation methods and results of the challenge, as well as results of further analysis of transferability to new datasets, the importance of label supervision, and resulting bias. While no single approach worked best across all tasks, many methodological aspects could be identified that push the performance of medical image registration to new state-of-the-art performance. Furthermore, we demystified the common belief that conventional registration methods have to be much slower than deep-learning-based methods

NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC).

Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors.

In the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)—an open-label, global, multicohort trial—evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N= 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P= 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.

Background: Single-agent doxorubicin has been widely used to treat unresectable hepatocellular carcinoma (HCC), but the response rate is low (

IMPORTANCE: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non–small cell lung cancer (NSCLC). OBJECTIVE: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC. INTERVENTIONS: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily. MAIN OUTCOMES AND MEASURES: The primary end point was blinded independent review committee–assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory–confirmed ALK-positive NSCLC. RESULTS: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02767804

First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.

The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.

The first-line treatment of choice for patients with EGFRmutation-positive NSCLC is an EGFR tyrosine kinase inhibitor (TKI), of which five as follows are predominantly available in practice: gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. Most prospective clinical trial data with these agents are limited to patients with the common activating and sensitizing EGFRmutations as follows: exon 19 deletions and exon 21 L858R point mutations. However, 10% to 20% of patients with NSCLC harbor uncommon EGFRmutations that have variable sensitivity to different EGFR TKIs. Owing to their molecular structures, afatinib, dacomitinib, and osimertinib have broader inhibitory profiles than the first-generation agents, gefitinib and erlotinib. Nevertheless, the paucity of prospective clinical data, the wide heterogeneity of uncommon mutations, and the existence of compound mutations in up to 25% of the cases complicate treatment decisions in this patient subgroup. Here, we collate the latest preclinical and clinical data regarding the activity of different TKIs against major uncommon EGFRmutations including compound mutations, but excluding exon 20 insertions which are generally insensitive to TKIs. On the basis of these data, we offer suggestions regarding treatment strategies for uncommon EGFRmutations. Moving forward, it will be important to include uncommon EGFRmutations in the first-line molecular analysis of all patients with adenocarcinoma of the lung, as this will help optimize patient outcomes according to their precise genotype.

We retrospectively examined progression-free survival (PFS) and response by ALKfluorescence in situ hybridization (FISH) status in patients with advanced ALKimmunohistochemistry (IHC)-positive NSCLC in the ALEX study.

Objective To assess the cost-effectiveness of acupuncture in the management of chemotherapy-induced peripheral neuropathy (CIPN) in Hong Kong.Methods A within trial cost-utility analysis with the primary endpoint for the economic evaluation being the Quality Adjusted Life Year (QALY) and associated Incremental Cost Effectiveness Ratio (ICER) over 14 weeks of treatment. A secondary cost-effectiveness analysis was undertaken with the endpoint being change in pain as measured on the Brief Pain Inventory (BPI).Results Eighty-seven patients were randomised to acupuncture or usual care. Acupuncture resulted in significant improvements in pain intensity (8- and 14-week mean changes compared to usual care of −1.8 and −1.8, respectively), pain interference (8- and 14-week mean changes compared to usual care of −1.5 and −0.9, respectively) and indicators of quality of life and neurotoxicity-related symptoms. However, in the economic evaluation there was little difference in QALYs between the two arms (mean change 0.209 and 0.200 in the acupuncture and usual care arms, respectively). Also, costs yielded deterministic ICERs of HK$616,965.62, HK$824,083.44 and HK$540,727.56 per QALY gained from the health care provider perspective, the societal perspective and the patient perspective, respectively. These costs are significantly higher than the cost-effectiveness threshold of HK$180,450 that was used for the base case analysis.Conclusion While acupuncture can improve symptoms and quality of life indicators related to CIPN, it is unlikely to be a cost-effective treatment for CIPN-related pain in health care systems with limited resources.Trial registration number NCT02553863 (ClinicalTrials.gov) post-results.

Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR–Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3–74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0–0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR–Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.

Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFR-positive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3).

The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)–naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results.

Stage III NSCLC represents a heterogeneous disease for which optimal treatment continues to pose a clinical challenge. Recent changes in the American Joint Commission on Cancer staging to the eighth edition has led to a shift in TNM stage grouping and redefined the subcategories (IIIA–C) in stage III NSCLC for better prognostication. Although concurrent chemoradiotherapy has remained standard-of-care for stage III NSCLC for almost 2 decades, contemporary considerations include the impact of different molecular subsets of NSCLC, and the roles of tyrosine kinase inhibitors post-definitive therapy and of immune checkpoint inhibitors following chemoradiotherapy. With rapid evolution of diagnostic algorithms and expanding treatment options, the need for interdisciplinary input involving multiple specialists (medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists and thoracic surgeons) has become increasingly important. The unique demographics of Asian NSCLC pose further challenges when applying clinical trial data into clinical practice. This includes differences in smoking rates, prevalence of oncogenic driver mutations, and access to health care resources including molecular testing, prompting the need for critical review of existing data and identification of current gaps. In this expert consensus statement by the Asian Thoracic Oncology Research Group, an interdisciplinary group of experts representing Hong Kong, Korea, Japan, Taiwan, Singapore, Thailand, Malaysia, and Mainland China was convened. Standard clinical practices for stage III NSCLC across different Asian countries were discussed from initial diagnosis and staging through to multi-modality approaches including surgery, chemotherapy, radiation, targeted therapies, and immunotherapy.

Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear.

At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p< 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALKvariant, after an additional 10 months’ follow-up (cutoff December 1, 2017).

Patients with pulmonary large-cell carcinoma (LCC) have poor prognosis and limited treatment options. The identification of clinically actionable molecular alterations helps to guide personalized cancer treatment decisions.

Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated NSCLC.

The germline human leukocyte antigen (HLA) status has been found to be associated with immunotherapy outcomes in patients with NSCLC, but its correlation to immunotherapy-induced pneumonitis and prognostic impact in the Asian population remains largely unknown.

SMARCA4 mutation has emerged as a marker of poor prognosis in lung cancer and has potential predictive value in cancer treatment, but recommendations for which patients require its investigation are lacking. We comprehensively studied SMARCA4alterations and the clinicopathological significance in a large cohort of immunohistochemically-subtyped non-small cell lung cancer (NSCLC). A total of 1416 patients was studied for the presence of SMARCA4 deficiency by immunohistochemistry (IHC). Thereafter, comprehensive sequencing of tumours was performed for 397 of these patients to study the mutational spectrum of SWI/SNF and SMARCA4aberrations. IHC evidence of SMARCA4 deficiency was found in 2.9% of NSCLC. Of the sequenced tumours, 38.3% showed aberration in SWI/SNF complex, and 9.3% had SMARCA4mutations. Strikingly, SMARCA4aberrations were much more prevalent in large cell carcinoma (LCC) than other histological tumour subtypes. SMARCA4-deficient and SMARCA4-mutated tumours accounted for 40.5% and 51.4% of all LCC, respectively. Multivariable analyses confirmed SMARCA4mutation was an independent prognostic factor in lung cancer. The immunophenotype of a subset of these tumours frequently showed TTF1 negativity and HepPAR1 positivity. SMARCA4mutation or its deficiency was associated with positive smoking history and poor prognosis. It also demonstrated mutual exclusion with EGFRmutation. Taken together, the high incidence of SMARCA4aberrations in LCC may indicate its diagnostic and prognostic value. Our study established the necessity of SMARCA4 IHC in the identification of SMARCA4-aberrant tumours, and this may be of particular importance in LCC and tumours without known driver events.

Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly fragmented and possess information related to their tissues of origin. Pathologies causing death of cells from particular tissues result in perturbations in the relative distribution of DNA from the affected tissues. Such tissue-of-origin analysis is particularly useful in the development of liquid biopsies for cancer. It is therefore of value to accurately determine the relative contributions of the tissues to the plasma DNA pool in a simultaneous manner. In this work, we report that in open chromatin regions, cfDNA molecules show characteristic fragmentation patterns reflected by sequencing coverage imbalance and differentially phased fragment end signals. The latter refers to differences in the read densities of sequences corresponding to the orientation of the upstream and downstream ends of cfDNA molecules in relation to the reference genome. Such cfDNA fragmentation patterns preferentially occur in tissue-specific open chromatin regions where the corresponding tissues contributed DNA into the plasma. Quantitative analyses of such signals allow measurement of the relative contributions of various tissues toward the plasma DNA pool. These findings were validated by plasma DNA sequencing data obtained from pregnant women, organ transplantation recipients, and cancer patients. Orientation-aware plasma DNA fragmentation analysis therefore has potential diagnostic applications in noninvasive prenatal testing, organ transplantation monitoring, and cancer liquid biopsy.

The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population.

In ret proto-oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized.

Immune checkpoint blockade targeting the PD-1/PD-L1 axis has recently demonstrated efficacy and promise in cancer treatment. Appropriate biomarker selection is therefore essential for improving treatment efficacy. However, the establishment of PD-L1 assay in pathology laboratories is complicated by the presence of multiple testing platforms using different scoring systems. Here we assessed the PD-L1 expression in 713 consecutive non-small cell lung carcinomas by four commercially available PD-L1 immunohistochemical assays, namely, 22C3, 28-8, SP142 and SP263. The analytical performances of the four assays and diagnostic performances across clinically relevant cutoffs were evaluated. The prevalence of PD-L1 (22C3) expression was 21% with a ≥50% cutoff and 56% with a ≥1% cutoff. High PD-L1 expression (using a ≥50% cutoff) was significantly associated with male sex (P= 0.001), ever smoking history (P< 0.001), squamous cell carcinoma (P= 0.001), large cell carcinoma (P< 0.001), lymphoepithelioma-like carcinoma (P= 0.006), sarcomatoid carcinoma (P< 0.001), mutant KRAS (P= 0.005) and wild-type EGFR (P= 0.003). Elevated PD-L1 expression was also significantly associated with shorter survival in patients with adenocarcinoma (log-rank P= 0.026) and remained an independent prognostic factor by multivariable analysis. Among the four assays, 22C3, 28-8 and SP263 were highly concordant for tumor cell scoring. With a cutoff of ≥50% (i.e., the threshold for first-line patient selection), inter-rater agreement was high among the three assays with percentage agreement >97%. In conclusion, three PD-L1 assays showed good analytical performance and a high agreement with each other, but not all cases were correctly classified using the same clinical cutoff. Further studies comparing the predictive value of these assays are required to address the interchangeability of these assays for clinical use.

The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests — such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements — are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC.

Although programmed death-ligand 1–programmed death 1 (PD-L1–PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.

Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant NCLC.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.04.030 Byline: Juan C. Garzon (a), Fernand M. Lai (b), Tony S.K. Mok (c), Anthony V. Manlulu (a), Calvin S.H. Ng (a), Tak Wai Lee (a), Anthony P.C. Yim (a) Author Affiliation: (a) Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China. (b) Department of Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China. (c) Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China. Article History: Received 7 April 2005; Accepted 18 April 2005

IMPORTANCE: Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non–small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics. OBJECTIVE: To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics. DATA SOURCES: This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017. STUDY SELECTION: Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients’ clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017. DATA EXTRACTION AND SYNTHESIS: Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method. RESULTS: In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta-analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P &lt; .001). They prolonged overall survival in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P &lt; .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P = .54; interaction, P = .005), and they prolonged overall survival in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24). The relative treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (&lt;65 years [HR, 0.71] vs ≥65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), or sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82). CONCLUSION AND RELEVANCE: Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second-line therapy in NSCLC. The finding of no overall survival benefit for patients with EGFR mutant tumors suggests that checkpoint inhibitors should be considered only after other effective therapies have been exhausted. The findings of this meta-analysis could also assist in the design and interpretation of future trials and in economic analyses.

The extent to which intratumoral heterogeneity of programmed death ligand 1 (PD-L1) expression causes discordance of PD-L1 expression between paired samples remains unclear. Here, PD-L1 status was compared between whole sections from NSCLCs and the corresponding tissue microarrays (TMAs) serving as surrogate biopsy specimens.