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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.CROWN is an ongoing, international, randomised, open-label phase 3 trial done in 104 centres in 23 countries worldwide. Eligible participants were aged 18 years and older or aged 20 years and older (depending on local regulations) with advanced, ALK-positive non-small-cell lung cancer, had received no previous systemic treatment for metastatic disease, had at least one extracranial measurable target lesion (according to the Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1), and had an Eastern Cooperative Oncology Group performance status score of 0-2. Patients were randomly assigned (1:1) to oral lorlatinib 100 mg daily or oral crizotinib 250 mg twice daily in 28-day cycles. Randomisation was stratified by the presence or absence of brain metastasis, and by ethnicity. Since the primary endpoint of the study had been met at the planned interim analysis, no further formal analysis of progression-free survival was planned, per protocol. The current unplanned analysis was done to further characterise tumour-related endpoints with a longer follow-up and is presented descriptively. For the planned study, the primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, intracranial duration of response, and safety. Efficacy endpoints were also assessed by the presence or absence of baseline brain metastases. This study is registered with ClinicalTrials.gov, NCT03052608.Between May 11, 2017, and Feb 28, 2019, 425 patients were screened for eligibility, of whom 296 were enrolled and randomly assigned to the lorlatinib (n=149) or crizotinib (n=147) group. At data cutoff for this unplanned analysis (Sept 20, 2021), median duration of follow-up for progression-free survival was 36·7 months (IQR 31·3-41·9) for lorlatinib and 29·3 months (10·8-35·0) for crizotinib. Median progression-free survival by blinded independent central review was not reached (95% CI not reached-not reached) for lorlatinib and was 9·3 months (7·6-11·1) for crizotinib (hazard ratio [HR] 0·27 [95% CI 0·18-0·39]). 3-year progression-free survival was 64% (95% CI 55-71) in the lorlatinib group and 19% (12-27) in the crizotinib group. Progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and duration of response were improved with lorlatinib versus crizotinib. In patients with baseline brain metastases (n=37 lorlatinib; n=39 crizotinib), the HR for time to intracranial progression for lorlatinib versus crizotinib was 0·10 (95% CI 0·04-0·27); in patients without baseline brain metastases (n=112 lorlatinib; n=108 crizotinib), the HR was 0·02 (95% CI 0·002-0·14). In patients without brain metastases, one (1%) in the lorlatinib group and 25 (23%) in the crizotinib group had intracranial progression. Grade 3-4 adverse events occurred in 113 (76%) of 149 patients (most commonly due to altered lipid levels) with lorlatinib and in 81 (57%) of 142 patients with crizotinib. Adverse events led to treatment discontinuation in 11 (7%) patients in the lorlatinib group and 14 (10%) patients in the crizotinib group. There were no new safety signals.These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases.Pfizer.

Next-generation sequencing (NGS) is able to identify targetable mutations to guide therapy and endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) offers a potential route to routinely obtain specimens for analysis. However, the suitability of EBUS-TBNA samples for NGS remains uncertain.A search was conducted from inception till 28th August 2020. Pooled proportion of adequate EBUS-TBNA samples for NGS was obtained based on binomial distribution with Freeman-Tukey double-arcsine transformation. meta-analysis of means was conducted to determine mean weight of DNA extracted from EBUS-TBNA samples. meta-regression was performed to explore sources of heterogeneity. The random-effects model was used for all analyses to account for variation between studies.Twenty-one studies comprising 1,175 patients were included. The pooled proportion of adequate EBUS-TBNA samples for NGS (yield) was 86.5% (95%-CI: 80.9% to 91.4%). Pooled mean weight of DNA extracted from EBUS-TBNA samples was 868.7 ng (95%-CI: 446.3 ng to 1291.1 ng). However, considerable heterogeneity (IEBUS-TBNA was associated with a high yield for NGS and the success of EBUS-TBNA sampling for NGS was proportional to the number of passes.

Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC.Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included.There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B's median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD.Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib.

Currently, early detection of lung cancer relies on the characterisation of images generated from computed tomography (CT). However, lung tissue biopsy, a highly invasive surgical procedure, is required to confirm CT-derived diagnostic results with very high false-positive rates. Hence, a non-invasive or minimally invasive biomarkers is essential to complement the existing low-dose CT (LDCT) for early detection, improve responses to a certain treatment, predict cancer recurrence, and to evaluate prognosis. In the past decade, liquid biopsies (e.g., blood) have been demonstrated to be highly effective for lung cancer biomarker discovery. In this review, the roles of emerging liquid biopsy-derived biomarkers such as circulating nucleic acids, circulating tumour cells (CTCs), long non-coding RNA (lncRNA), and microRNA (miRNA), as well as exosomes, have been highlighted. The advantages and limitations of these blood-based minimally invasive biomarkers have been discussed. Furthermore, the current progress of the identified biomarkers for clinical management of lung cancer has been summarised. Finally, a potential strategy for the early detection of lung cancer, using a combination of LDCT scans and well-validated biomarkers, has been discussed.

Summary Background We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. Methods In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov , NCT01982955 , and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. Findings From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9–6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2–6·8; hazard ratio [HR] 0·67, 90% CI 0·35–1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1–37·3) versus 18·7 months in the chemotherapy group (15·9–20·7; HR 0·69, 0·34–1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1–16·6] vs 4·4 months [4·1–6·8]; HR 0·35, 0·17–0·74; median OS 37·3 months [90% CI 24·2–37·3] vs 17·9 months [12·0–20·7]; HR 0·33, 0·14–0·76) or MET amplification (n=19; median PFS 16·6 months [8·3–not estimable] vs 4·2 months [1·4–7·0]; HR 0·13, 0·04–0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25–not estimable]; HR 0·08, 0·01–0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. Interpretation Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. Funding Merck KGaA.

Background The importance of immune-checkpoint inhibitors (ICI) can no longer be understated since its move to front-line treatment in non-small cell lung cancer (NSCLC) in recent years. However, the safety and efficacy of ICI in special populations such as those with infections like tuberculosis (TB) and hepatitis B (HBV) remain unknown as they are routinely excluded from clinical trials. Methods Records of patients with advanced NSCLC who were treated with ICI from January 2014 to June 2019 at a single Asian centre were reviewed. Those with a history of HBV and/or TB were selected. In this group, safety and treatment outcomes including overall survival (OS), progression-free survival (PFS) and response rate were reported and compared against control. Results 191 patients received ICI, 47 (24.6%) had a history of TB/HBV. The median PFS in those with a history of TB/HBV was 5.7 months (95% CI 3.9-7.6), compared to 3.1 months (95% CI 2.4-3.8) in control (HR 0.61, 95% CI 0.39-0.93, p = 0.021). Median OS was 15.6 months (95% CI 10.2-21.0) compared to 11.1 months (95% CI 7.6-14.7 months) in the control group (HR 0.58, 95% CI 0.34-0.99, p = 0.046). Adverse events of any grade (G) were similar in both groups; slightly more patients with TB/HBV experienced G3 or higher adverse events. Four patients developed TB after initiation of ICI, none with previously documented TB experienced reactivation. Of the 42 patients with a history of HBV, eight had inactive chronic HBV and six had detectable viral load. None of the 34 patients who were previously exposed to HBV had reactivation. Conclusion The use of ICI appears to be safe and efficacious in patients with TB/HBV infection. Prospective studies are required to identify those at risk in order to optimise care to these groups of patients.

Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies.

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.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines.

Summary Background Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. Methods In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1–6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1–5 only), and safety data for all treated patients (EXP1–6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Findings Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5–97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4–99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2–5), objective responses were achieved in 93 (47·0%; 39·9–54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5–73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1–80·8) of 59 patients who had only received previous crizotinib (EXP2–3A), nine (32·1%; 15·9–52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6–48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4–5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4–97·2) of 23 patients with measurable baseline CNS lesions in EXP2–3A, five (55·6%; 21·2–86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3–67·5) of 49 patients in EXP4–5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3–4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3–4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. Interpretation Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. Funding Pfizer.

The global coronavirus disease 2019 pandemic continues to escalate at a rapid pace inundating medical facilities and creating substantial challenges globally. The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer seems to be higher, espe- cially as they are more likely to present with an immuno- compromised condition, either from cancer itself or from the treatments they receive. A major consideration in the delivery of cancer care during the pandemic is to balance the risk of patient exposure and infection with the need to provide effective cancer treatment. Many aspects of the SARS-CoV-2 infection currently remain poorly characterized and even less is known about the course of infection in the context of a patient with cancer. As SARS-CoV-2 is highly contagious, the risk of infection directly affects the cancer patient being treated, other cancer patients in close prox- imity, and health care providers. Infection at any level for patients or providers can cause considerable disruption to even the most effective treatment plans. Lung cancer pa- tients, especially those with reduced lung function and cardiopulmonary comorbidities are more likely to have increased risk and mortality from coronavirus disease 2019 as one of its common manifestations is as an acute respi- ratory illness. The purpose of this manuscript is to present a practical multidisciplinary and international overview to assist in treatment for lung cancer patients during this pandemic, with the caveat that evidence is lacking in many areas. It is expected that firmer recommendations can be developed as more evidence becomes available. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research.

Major advances with the development of epidermal growth factor receptor tyrosine kinase inhibitors and immune check-point inhibitors have ushered in a new era in lung cancer therapy. Whilst pre-clinical studies suggest EGFR-driven NSCLC inhibit antitumor immunity through the activation of the PD-1/PD-L1 pathway, epidemiology studies suggest EGFR mutant NSCLC are more likely to have decreased PD-L1 expression. The superiority of single agent PD-1/PD-L1 inhibitors over docetaxel in pre-treated EGFR mutant NSCLC appears to be moderated. Several mechanisms for a poor response to immune checkpoint have been proposed including a lower tumor mutation burden, and an uninflamed and immunosuppressive tumor microenvironment. Predictive biomarkers to PD-1/PD-L1 inhibitors sensitivity in patients with EGFR mutations are required. The role of EGFR TKI in combination with an immune checkpoint inhibitor is currently being investigated intensively in multiple clinical trials and outcomes from these trials are immature and the optimal sequence, schedule and dosing remains to be determined. A careful evaluation will be required in view of the increased toxicities reported in some of the early studies of combination therapy.

Summary Use of immune checkpoint inhibitors targeting the programmed cell death protein-1/programmed cell death-ligand 1 and cytotoxic T lymphocyte-associated protein-4 axes has yielded impressive results in some clinical trials. However, only a subset of patients initially respond to these inhibitors, and increasing clinical evidence indicates that a substantial proportion of initial responders ultimately relapse with lethal, drug-resistant disease months or years later. Studies that have used massively parallel sequencing have shed light on the rich functional landscape of mutations that endow tumour cells with the ability to evade T-cell-mediated immunosurveillance. Cancer genomes bear signatures of clonal evolution and selection, particularly implicating acquired defects in interferon receptor signalling and antigen presentation. In this Review, we discuss the biological processes that operate in the formation of so-called immunoresistant niches, and describe the latest progress in the development of combination strategies to reinstate immunosurveillance in immune-refractory tumours.

Background Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients and methods Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80–120 mg/day, depending on body surface area; days 1–28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. Results A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833–1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913–1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. Conclusion S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. Clinical trial number Japan Pharmaceutical Information Center, JapicCTI-101155.

The development of cancer therapies using monoclonal antibodies has been successful during the last 30 years. Recently much progress was achieved with technologies involving bispecific and multi-specific antibodies. Bispecific antibodies (BsAbs) are antibodies that bind two distinct epitopes, and a large number of potential clinical applications of BsAbs have been described. Here we review mechanism of action, clinical development and future challenges of BsAbs which could be a serve as a valuable arsenal in cancer patients.

Introduction La sequence optimale des inhibiteurs de la tyrosine kinase (TKI) ciblant l’EGFR pour optimiser la survie globale des patients atteints d’un CBNPC avec mutation EGFR (EGFRm + ) demeure une question ouverte en situation de vie reelle. GioTag ( NCT03370770 ) est une etude observationnelle internationale portant sur des patients atteints de CBNPC EGFRm+ qui ont ete traites par afatinib suivi d’osimertinib, comprenant des patients de mauvais pronostic (ECOG PS ≥ 2 : 15 % ; metastases cerebrales stables : 10 %) [1] . Dans l’analyse primaire, le temps sous traitement (TST) etait de 27,6 mois chez tous les patients, 30,3 mois chez les patients Del19+ et 46,7 mois chez les patients asiatiques. Dans cette analyse, nous rapportons la survie globale (SG) des patients de la cohorte. Methodes Les donnees ont ete recueillies retrospectivement entre decembre 2017 et juin 2018 a partir des donnees de sante electroniques (DSE ; n = 126) ou des dossiers medicaux (n = 77) des patients atteints d’un CBNPC EGFRm+ (Del19, L858R). Tous les patients etaient T790M+ apres une premiere ligne par afatinib et ont ensuite recu de l’osimertinib. Le critere principal etait le TST ; l’analyse de la SG etait exploratoire. Resultats Apres un suivi median de 34,8 mois, la SG mediane etait de 41,3 mois (IC90 % : 36,8–46,3) pour l’ensemble des patients (n = 203) et de 45,7 mois (IC90 % : 45,3–51,5) pour les patients Del19+ (n = 149). Le TST actualise etait de 28,1 mois (IC90 % : 26,8–30,3) pour l’ensemble des patients et de 30,6 mois (IC90 % : 27,6–32,0) pour les patients Del19+. Parmi les 168 patients qui ont commence l’afatinib a 40 mg, l’OS mediane etait de 45,3 mois (IC90 % : 37,6–47,6) et le TST median de 28,1 mois (IC 90 % : 26,8–30,6). Le temps median sous osimertinib etait de 15,6 mois (IC90 % : 13,8–17,1) pour l’ensemble des patients et de 16,4 mois (IC90 % : 14,9–17,9) pour les patients Del19+. Conclusion Chez les patients atteints d’un CBNPC EGFRm+ T790M+, nous avons observe une SG mediane encourageante de pres de 3,5 ans pour la sequence afatinib suivi par osimertinib, avec un benefice superieur chez les patients Del19+. Ces donnees confortent la faisabilite de cette approche sequentielle. Notamment, un temps sous osimertinib prolonge, de 15,6 mois, a ete observe en deuxieme ligne, alors que tous les patients avaient deja recu de l’afatinib. L’analyse finale, prevue debut 2020, apportera de nouveaux elements sur la survie a long terme des patients traites par cette sequence afatinib-osimertinib.

Introduction Treatment of non-small cell lung cancer (NSCLC) is an important and often unmet medical need regardless of the disease stage at the time of first diagnosis. Antigen-specific immunotherapy may be a feasible therapeutic option if tumor associated antigens (TAAs) that can be targeted by the patient's immune system are identified. The study objective (NCT01837511) was to investigate the expression rates of MAGE-A3 and PRAME in tumors from East Asian NSCLC patients, and the associations between TAA expression and clinico-pathologic patient characteristics. Methods Archived formalin-fixed paraffin-embedded tumor tissue specimens were tested for MAGE-A3 and PRAME expression by quantitative reverse transcription polymerase chain reaction. Exploratory analyses of the impact of patient and tumor characteristics on antigen expression were performed by multivariate logistic regression analyses. Results A total of 377 specimens were tested and a valid expression result was obtained for 86.5% and 92.6% for MAGE-A3 and PRAME , respectively. Of the specimens with valid test results, 26.4% expressed MAGE-A3 , 49.9% PRAME , 20.0% both and 57.5% expressed at least one TAA. The same pattern of associations between antigen expression and patient and tumor characteristics was found for both TAAs: higher rates of antigen-positive tumors were found in squamous cell carcinomas compared to adenocarcinomas, and for smokers compared to non-smokers. Conclusions Expression of MAGE-A3 and PRAME suggests an association with tumor histology and the patient's smoking status. The rates of TAA-positive tumors found in these East and South East Asian NSCLC patients indicate that both antigens may serve as targets for antigen-specific immunotherapies.

Background Most pts with EGFR mutation-positive (EGFRm) NSCLC develop first-line (1L) EGFR-TKI resistance. Previous analyses of US insurance databases have studied healthcare utilisation and expenditure in pts with EGFRm NSCLC starting first-/second-generation (1G/2G) EGFR-TKIs. We examined treatment patterns and survival rates among pts with locally advanced/metastatic NSCLC, who received 1L 1G/2G EGFR-TKIs, in a retrospective analysis of data from the MarketScan Commercial and Medicare Supplemental databases (all US census regions). We also assessed the effect of central nervous system metastases (CNS mets) on survival rates. Methods Pts ≥18 yrs with EGFRm NSCLC who received 1L 1G/2G EGFR-TKI were analysed from date of first lung cancer diagnosis (index date) through a variable-length follow-up period. Pts included had ≥1 pharmacy claim for 1G/2G EGFR-TKI on/within 60 days post index, and ≥2 non-diagnostic claims with a diagnosis code for lung cancer within 90 days of each other between 1/1/2015 and 31/3/2018. Excluded: pts receiving chemotherapy suitable for SCLC. Data were stratified by CNS mets status. Data that could be linked to the social security administration (SSA) death file were used for mortality analyses. Results Of 578 pts (median age 63 yrs, 64% female), 275 (48%) had CNS mets and 303 (52%) had no CNS mets. Of the pts with CNS mets, 149 (54%) discontinued 1L EGFR-TKI, of whom 124 (83%) initiated 2L therapy; 121 (40%) pts with no CNS mets discontinued 1L, 85 (70%) of whom initiated 2L therapy. The most frequently prescribed 1L EGFR-TKI was erlotinib (n = 414, 72%). Overall, at 1L, 6% of pts received an add-on therapy, bevacizumab (n = 17, 3%) being the most common. The most frequent 2L therapy was osimertinib (n = 96, 46%). In pts with available SSA mortality data, unadjusted mortality rates were 138 and 92 deaths per 1000-person-years, for pts with (n = 179) and without (n = 202) CNS mets, respectively. Conclusions Most pts who discontinued 1L treatment commenced 2L; with osimertinib as most frequent. Pts with no CNS mets had numerically lower mortality rates than pts with CNS mets. Editorial acknowledgement Charlotte Terry, MSc, from iMed Comms, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure R. Soo: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Taiho; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Yuhan. T. Seto: Honoraria (self): Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, ; Research grant / Funding (institution): AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis, Pfizer Japan, Takeda, Bayer Yakuhin, Daiichi Sankyo, Kissei Pharmaceutical, LOXO Oncology, Merck Serono. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda, Inviata; Advisory / Consultancy: AstraZeneca, Squibb, Celgene, Takeda, Inviata; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. P. Karimi: Full / Part-time employment: AstraZeneca. A. Taylor: Full / Part-time employment: AstraZeneca. W. Sawyer: Full / Part-time employment, Full time Contractor: AstraZeneca. E. Thiel: Research grant / Funding (institution): AstraZeneca. E. Marchlewicz: Research grant / Funding (institution): AstraZeneca. M. Brouillette: Research grant / Funding (institution): AstraZeneca.

Upfront resistance to c-Met inhibitors currently in clinical development is ubiquitous and poorly understood. We discovered that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to heterodimerize with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 heterodimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-Met inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. Clinical proof-of-concept is afforded by radiological and biochemical responses observed in two METN375S-heterozygous patients with refractory HNSCC whom we successfully treated with HER2 inhibitors. These results establish METN375S as a biologically-distinct and clinically-actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

Background Identifying the optimal sequence of EGFR TKIs is important to maximise survival in EGFR mutation-positive (EGFRm+) NSCLC. The observational GioTag study (NCT03370770) investigated outcomes in patients (pts) with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a ‘real-world’ clinical setting, including pts with poor prognosis (ECOG PS ≥ 2: 15%; stable brain metastases: 10%).1 In the primary analysis, time to treatment failure (TTF) was 27.6 months in the overall population, 30.3 months in Del19-positive pts, and 46.7 months in Asians. Here we report overall survival (OS) and updated TTF. Methods Data were retrospectively collected from Dec 2017–June 2018 for 203 pts with EGFRm + (Del19, L858R) NSCLC who were T790M positive after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n = 126) or medical charts (n = 77). For logistical reasons, this interim analysis includes updated data (at April 2019) from pts with available EHRs (all USA; n = 94); final analysis with updated data from manual chart reviews is anticipated in early 2020. Results After median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n = 203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive pts (n = 149); 2-year OS was 80%. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in all pts, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive pts. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive pts. Median time from osimertinib discontinuation to death was 8 months. In 168 pts starting on afatinib 40 mg, median OS was 45.3 months (90% CI: 37.6–47.6); median TTF was 28.1 months (90% CI: 26.8–30.6). Conclusions Encouraging OS and TTF was seen in pts with EGFR T790M-positive NSCLC with sequential afatinib and osimertinib, especially Del19-positive pts. Of note, prior afatinib treatment did not preclude prolonged TTF with second-line osimertinib. 1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74. Clinical trial identification NCT03370770. Editorial acknowledgement Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure M.J. Hochmair: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp and Dohme. D. Hao: Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca. R.A. Soo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Ignyta; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Yuhan. J.C-H. Yang: Honoraria (self): Merck Sharp and Dohme; Advisory / Consultancy: Merck Serono; Honoraria (self): Novartis; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono pharmaceuticals; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Hansoh Pharmaceuticals; Advisory / Consultancy: Takeda Pharmaceuticals; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: G1 Therapeutics; Honoraria (self): Pfizer. B. Halmos: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp and Dohme; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy: Genentech; Advisory / Consultancy: Spectrum; Advisory / Consultancy: Ignyta; Research grant / Funding (self): Takeda; Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Mirati; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Novartis; Research grant / Funding (self): GSK; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Guardant Health. L. Wang: Full / Part-time employment: Boehringer Ingelheim. A. Marten: Full / Part-time employment: Boehringer Ingelheim. T. Cufer: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background In patients with EGFR-mutant NSCLC, MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). In the randomized phase Ib/II INSIGHT study (NCT01982955) that halted full enrolment due to low recruitment, tepotinib (TEP), a potent, selective MET TKI, plus gefitinib (GEF) improved progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy (CTx) in patients with EGFR-mutant NSCLC and resistance to 1st-line EGFR TKIs due to METamp (≥6-month follow-up). We now present long-term survival outcomes (≥18-month follow-up) for this predefined analysis. Methods Patients were randomized to TEP 500 mg + GEF 250 mg orally once daily (until progressive disease, intolerable toxicity or other withdrawal) or platinum + pemetrexed IV (≤6 x 21-day cycles). METamp was defined as GCN ≥5 and/or MET/CEP7 ratio ≥2. Primary endpoint was investigator-assessed (INV) PFS. Secondary endpoints included overall survival (OS), ORR, PFS by independent review (IRC), safety. Results From 04/24/15 to 06/12/17, 55 patients enrolled in the INSIGHT study and 19 were METamp (TEP+GEF 12; CTx 7); this predefined subgroup is analysed here. Median GCN was 8.8 (range 4.8–29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. At data cutoff (12/12/18), median treatment duration (weeks [range]) for TEP+GEF was 49 (4.6–110.9; 3 patients still ongoing for ≥24 months), pemetrexed was 18.0 (5.9–60.4), cisplatin 12.0 (6.6–25.1) or carboplatin 12.8 (5.9–19.7), all CTx patients discontinued. TEP+GEF compared with CTx improved PFS (INV mPFS 21.2 vs 4.2 months, HR [90% CI] 0.13 [0.04, 0.43]; IRC mPFS 19.3 vs 5.5 months; 0.18 [0.06, 0.61]) and OS (mOS 37.3 vs 13.1 months, 0.08 [0.01, 0.51]), as well as ORR (INV 66.7 v 42.9%; OR 2.67 [0.37, 19.56]; IRC 75.0 vs 42.9%; OR 4.00 [0.51, 31.38]). Grade ≥3 treatment-related AEs in METamp patients (≥15% in either arm, TEP+GEF vs CTx) were amylase or lipase increased (both 33.3% vs 0%), anemia, neutrophil or WBC count decreased (all 0 vs 28.6%). Conclusions TEP+GEF improved survival of patients with EGFR TKI-resistant NSCLC due to METamp. TEP + osmertinib is currently being investigated in patients with METamp, EGFR-mutant NSCLC with acquired EGFR TKI resistance (NCT03940703). Clinical trial identification NCT01982955. Editorial acknowledgement Medical writing assistance was provided by Lisa Jolly, Bioscript, Macclesfield, UK, and funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study Merck KGaA, Darmstadt, Germany. Funding Merck KGaA, Darmstadt, Germany. Disclosure K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. R.A. Soo: Honoraria (self): BMS, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. R. Bruns: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. A. Johne: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical, Daiichi Sankyo and AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceu. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim ; Advisory / Consultancy: Merck; Honoraria (self): Eli Lilly, Pierre Fabre, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

Background Afatinib is effective in EGFRm+ NSCLC; however, resistance develops over time, most commonly due to emergence of the T790M mutation. Osimertinib has shown efficacy in the treatment of T790M-positive NSCLC after progression on a first-line TKI. Further information on sequencing outcomes is needed to optimize treatment outcomes. Methods This observational study is the first to evaluate real-world outcomes of sequential afatinib followed by osimertinib. Data were retrospectively collected from patients with EGFRm + (Del19, L858R) advanced NSCLC and acquired T790M after first-line afatinib. Patients must have completed afatinib and started osimertinib ≥10 months prior to enrollment. Those with active brain metastases were excluded. The primary outcome was time to treatment failure (TTF) from initiation of afatinib until discontinuation of osimertinib. Results 204 patients were included; 24.5/67.6% were Asian/non-Asian, 73.5/26.0% were Del19/L858R+, and 83.7% started on afatinib 40 mg. The study included patients with poor prognosis features who are often excluded from clinical trials; 31 (15.2%) patients had ECOG PS ≥ 2 and 21 (10.3%) had stable brain metastases. As of May 2018, overall median TTF was 27.6 months (90% CI: 25.9, 31.3). Median time on afatinib and osimertinib was 11.9 months (90% CI: 10.9, 12.2) and 14.3 months (90% CI: 12.8, 15.9), respectively. The 2-year OS rate was 78.9%. TTF was generally consistent across subgroups, but was longer in Asian patients (n = 50; median 46.7 months; 90% CI: 26.8, NR) and those with Del19+ disease (n = 150; median 30.3 months; 90% CI: 27.6, 44.5). Results were similar in patients who started on the approved 40mg dose of afatinib; median TTF was 27.6 months (90% CI: 26.3, 31.3) overall and 46.7 months (90% CI: 36.4, 46.7) in Asian Del19+ patients. OS and updated TTF data will be presented. Conclusions First-line afatinib followed by osimertinib is feasible in a broad, real-world patient population with EGFRm+ NSCLC and acquired T790M mutation. The benefit of sequential afatinib followed by osimertinib was observed across all patient subgroups, particularly in those with Del19+ disease and Asian patients. Clinical trial identification NCT03370770. Editorial acknowledgement Fiona Scott of GeoMed, an Ashfield company, part of UDG Healthcare plc; funded by Boehringer Ingelheim. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure M.J. Hochmair: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): Novartis. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme. D. Hao: Advisory / Consultancy, Research grant / Funding (self), Research funding/consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self), Research funding/consultancy: AstraZeneca. R. Soo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AZ; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BI; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Ignyta; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Yuhan. J.C. Yang: Honoraria (self): BI; Honoraria (self): Eli Lilly; Honoraria (self): Bayer; Honoraria (self): Roche/Genentech; Honoraria (self): Chugai; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): Ono Pharma; Advisory / Consultancy: Astellas; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Yuhan Pharma; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Hansoh Pharma; Advisory / Consultancy: Takeda Pharma; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: G1 Therapeutics. B. Halmos: Advisory / Consultancy, Research grant / Funding (self): AZ; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): BI; Advisory / Consultancy: Genentech; Advisory / Consultancy: Spectrum; Advisory / Consultancy: Ignyta; Advisory / Consultancy, Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Mirati; Research grant / Funding (self): AbbVie; Research grant / Funding (self): GSK; Advisory / Consultancy: Foundation Medicine. L. Wang: Full / Part-time employment: Boehringer Ingelheim. A. Golembesky: Full / Part-time employment: Boehringer Ingelheim. A. Marten: Full / Part-time employment: Boehringer Ingelheim. T. Cufer: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.