Search

Aims: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation-driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real-world setting., Methods: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography-mass spectrometry (LC-MS) assay across serial timepoints. As part of this study, inter-individual variability by dose and ethnicity as well as intra-individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)-based quantitation as an accurate alternative to plasma quantitation., Results: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra-individual variability across timepoints., Conclusions: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy., Methods: This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m 2 intravenously once every 3 weeks. The primary end point was overall survival (OS)., Results: One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively)., Conclusion: Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Background: Seminal trials with first-line pembrolizumab for metastatic non-small cell lung cancer (NSCLC) mandated a maximum two-years treatment. We describe real-world outcomes of a multi-site Australian cohort of patients who completed two-years of pembrolizumab., Methods: Retrospective data were collected from the national AUstralian Registry and biObank of thoRacic cAncers (AURORA). Primary endpoints were progression rate post pembrolizumab discontinuation; and progression free survival (PFS). Local treatment of oligoprogressive disease during pembrolizumab was allowed., Results: A total of 71 patients from six centers, median age 66.0 years, 49% male and 90% ECOG ≤ 1 were identified. Patients were Caucasian (82%) or Asian (16%); past (66%) or current (24%) smokers with mean 37 pack-years. Histology comprised 73% adenocarcinoma and 16% squamous. 18 patients (25%) had brain metastases at diagnosis. Median PD-L1 tumor proportion score (TPS) was 68%; 12 patients (17%) TPS < 1% and 43 (61%) TPS ≥ 50%. No patients had EGFR/ALK/ROS1 alterations; 29/49 tested (60%) had KRAS mutations. Median follow up was 38.7 months. Objective response rate 78.6%. Median PFS 46.1 months (95% CI 39.5-NR), not reached (46.1-NR) in PD-L1 TPS ≥ 1% versus 28.1 months (16.3-NR) in TPS < 1% (P = .013). 17 patients (24%) received additional local therapy for oligoprogression. Post pembrolizumab discontinuation, 20 patients (28%) had disease progression. Higher rates of progression occurred with TPS < 1% (OR 3.46, P = .06), without complete response (OR 5.06, P = .04), and with treated oligoprogression (OR 3.11, P = .05). 36-month landmark survival was 98.2%., Conclusion: Patients completing two-years of pembrolizumab for NSCLC in an Australian cohort had high rates of KRAS mutation and PD-L1 expression; a proportion had brain metastases and treated oligoprogression. Progression post pembrolizumab was higher in PD-L1 TPS < 1% and in those without complete response., Competing Interests: Disclosure The authors declare the following conflicts of interest: Dr Andrew Fantoni: Speaker fee/Honoraria from Novartis. Dr Lydia Warburton: Honoraria from BMS, MSD, Roche, Astrazeneca. Dr Ben Solomon: Consulting fees for Advisory for Pfizer, Roche, AstraZeneca, Glaxo Smith Kline, Bristol Myers Squibb, Amgen, Merck, Takeda, Eli Lilly, Janssen, Takeda. Honoraria from Pfizer, Amgen, Glaxo Smith Kline, AstraZeneca, Roche. Royalties/Licenses from UpToDate. Leadership role for Cancer Council Victoria, Thoracic Oncology Group of Australasia (TOGA), and International Association for the study of Lung Cancer. Ms Marliese Alexander: Travel support from Astrazenca. Advisory board Pfizer/BMS. Dr Meghana Maddula: None. Dr Lauren Julia Brown: None. Dr Ines Da Silva: Consulting fees for MSD. Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre. Travel support from BMS, MSD, Roche. Dr Adnan Nagrial: Advisory board for MSD, BMS, Takeda, Pfizer, Astra Zeneca. Dr Farah Abu Al-Hial: None. Dr Malinda Itchins: Grants from Pfizer. Consulting Fees Roche, Merck. Honoraria from Pfizer, AstraZeneca, Takeda, Roche, Novartis, BMS, MSD, Bayer, Janssen. Advisory board for Pfizer, Takeda, Bayer, MSD, Amgen, Merck, Roche, Janssen. Leadership role for Clinical Oncology Society of Australia (COSA). Dr Nick Pavlakis: Grants from Bayer, Pfizer, Roche. Consulting fees from Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Pfizer, Roche, Amgen, Beigene. Honoraria from Boehringer Ingelheim, Merck, Pfizer, Roche, Takeda, Pierre-Faber, Illumina, Bayer. Leadership role for The Thoracic Oncology Group of Australia (TOGA). Dr Samantha Bowyer: Honoraria from BMS, MSD (Australia), Sanofi. Travel support from Astrazenca, MSD (Australia). Advisory for Roche, Sanofi, MSD (Australia), Ipsen, Lilly., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy., Methods: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m 2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA)., Results: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS., Conclusion: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials., (© 2024 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: Osimertinib is an oral small-molecule tyrosine kinase receptor inhibitor used to treat non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor mutation. Patients may experience drug toxicity and require dose deescalation. The study aimed to quantitate osimertinib and its 2 active metabolites, AZ5104 and AZ7550, in microsampled dried blood spots (DBS) collected from patients with NSCLC using a hemaPEN device and compare them with plasma drug levels., Methods: A 6-min ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated using plasma and DBS. The accuracy, selectivity, matrix effect, recovery, and stability were assessed using bioanalytical validation criteria. The hematocrit effect was investigated in DBS. Drug levels were measured in 15 patients with NSCLC, and the Bland-Altman method was used to compare measurements between plasma and DBS., Results: The validated assay determined accurate and precise quantities, respectively, for osimertinib in both plasma (93.2%-99.3%; 0.2%-2.3%) and DBS (96.7%-99.6%; 0.5%-10.3%) over a concentration of 1-729 ng/mL. The osimertinib metabolites, AZ5104 and AZ7550, were similarly validated in accordance with bioanalytical guidelines. For 30%-60% patient hematocrit, no hematocrit bias was observed with DBS for all analytes. The Bland-Altman method showed high concordance between plasma and DBS analyte levels. Stability experiments revealed that osimertinib and its metabolites were poorly stable in plasma at room temperature, whereas all analytes were stable in DBS for 10 days at room temperature., Conclusions: The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels., Competing Interests: N. Pavlakis Astra Zeneca-Advisory Board Honoraria. M. Itchins Astra Zeneca- Honoraria. S. J. Clarke Astra Zeneca–Expert testimony, Advisory Board honoraria. The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Background: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice., Methods: Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0., Results: A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event., Conclusions: Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing ( EGFR / ALK/ROS1 ). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies., (© 2024. The Author(s).)

Background: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement., Method: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type., Results: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation., Conclusion: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective., Policy Summary: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities., Competing Interests: Declaration of Competing Interest MA has received financial support to attend conferences and meetings by AstraZeneca and serves on the advisory board for Pfizer and Bristol Myers Squibb. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Canofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He has received research funding grants from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. He has received travel support from Pfizer. SA has served uncompensated on the boards of Health Issues Centre, Australia, Victorian Agency for Health Information, and Safer Care Victoria. MPB has received honoraria from BNS Australia, USD Oncology, and Novartis. He holds an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Cartherics for which his institution receives reimbursements. His institution has also received reimbursement for research support from Bristol Myers Squibb, Merck Sharp & Dohme, Pharmaust, Zucero Therapeutics, and CStone Pharmaceuticals. MB has received compensation and research support as an advisor and consultant to Pierre Fabre, MSD, GSK, Servier, and AstraZeneca. MI is on the advisory boards of Pfizer, Roche, Takeda, BeiGene, Amgen, Merck, and MSD and has received honoraria from Pfizer, Roche, Takeda, Novartis, as well as research funding from Pfizer. TJ reports consulting fees from AstraZeneca and MSD, and advisory boards and committees for AstraZeneca, Amgen, Bristol Myers Squibb, Merck & Co., MSD, Gilead, Puma, Pfizer Inc., Roche AG, Specialised Therapeutics, and Takeda Pharmaceutical, outside the submitted work. SK reports honoraria to institution from Astra Zeneca, Roche, Pfizer, Bristol Myers Squibb, MSD and Takeda; consulting fees from AstraZeneca, Pfizer, MSD, Novartis, Roche, Takeda, Amgen; and research funding to institution from Astra Zeneca. MK reports institutional grants from Nordic Farma, Merck-Serono, Pierre Fabre, Servier, Bayer, Bristol Myers Squibb, Merck, and Roche; and consulting fees and honoraria paid to institution from Pierre Fabre and Servier. BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Amgen, Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. BTL is supported by the Memorial Sloan Kettering Cancer Centre Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. JML receives research support from Ipsen Pharmaceuticals, Novartis and Amgen, and reports consulting fees and/or honoraria from Amgen, Ipsen, Taiho, Novartis, SAGA Diagnostics and Natera. BM is on the advisory boards of Amgen, MSD, Bristol Myers Squibb, Beigene and AstraZeneca. GAM has received research support from Bristol Myers Squibb and as Principal Investigator his institution has received reimbursement of trial costs from Roche-Genentech. TMM reports consulting fees and participation on advisory boards for Bristol Myers Squibb, MSD, Merck, AstraZeneca, Novartis, GSK, Eisai, and honoraria from AstraZeneca. TMM has received support to attend meetings from Bristol Myers Squibb and AstraZeneca. LN has received institutional consulting fees from Bristol Myers Squibb, Pfizer, and Merck Sharp & Dohme, and reports support to attend a research meeting from AstraZeneca. NP has served on advisory boards or received personal honoraria from Boehringer Ingelheim, MSD, Merck, Bristol-Myers Squib, Astra Zeneca, Takeda, Pfizer, Roche, Novartis, Ipsen and Bayer and has received research funding to his institution from Bayer, Pfizer and Roche. TMP has received research support from Roche and Pfizer, and holds a consulting or advisory role for Merck, Bristol Myers Squibb, Novartis, Sanofi/Regeneron, and Pfizer. SP is compensated consultant to Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, declares expert testimony to Roche and Merck Serono, and travel support from Janssen and Roche.BJS is on the Advisory Boards/Honoraria for Pfizer, Novartis, Roche, AstraZeneca, Merck, Bristol Myers Squibb, Eli Lilly, Amgen, BeiGene, Janssen, Takeda. JAS has received support for conference attendance from MSD (virtual registration ASCO). JT has received consulting fees or honoraria from Haystack Oncology, Servier, Pierre Fabre, MSD, Merck Serono, Amgen, Novartis, Seres and AstraZeneca. JT is on the advisory boards of Beigene, Daiichi Sankyo, Gilead, Illumina, Novartis, BMS, and MSD. WX has received research support from Merck, honoraria from MSD, Merck and AstraZeneca, and support for attending meetings from MSD (virtual registration ASCO) and Eli Lilly (virtual registration SABCS). WX is on the advisory boards of MSD, Merck and Novartis, and holds unpaid positions as Chair of the Melanoma and Skin Cancer trials group and Australasian Merkel Cell Carcinoma interest group.DY has received institutional payments for his role on advisory boards for AstraZeneca, Servier, Specialised Therapeutics, MSD and BayerJZ serves in an advisory/consultancy role for Merck Sharp & Dohme, Specialised Therapeutics, CEND, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novotech, Alloplex Biotherapeutics, NOUS Consulting, and Oncology Republic; owns stock in Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, and Teladoc; has received honoraria from Gilead Sciences, MSD Oncology, and Viatris; and his institution has received research funding from Bristol-Myers Squibb, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology and Servier; and has received travel, accommodations, expenses from ICON Group, MSD Oncology, and PRAXIS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC). The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation. Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged., (Copyright © 2022. Published by Elsevier Inc.)

Background: There are limited real world data on the IMpower150 regimen in oncogene driven tumors and central nervous system metastases; this study aims to address this gap., Materials and Methods: Retrospective analysis of patients with advanced non-small cell lung cancer treated with the IMpower150 regimen across 12 Australian sites between July 2018 and April 2021. Clinicopathologic and treatment parameters were correlated with efficacy and toxicity., Results: A total of 106 patients identified with median follow up of 8 months (range 0-72). Median age was 61 years (range 33-83), 34% Asian and 58% never-smokers. An oncogene was reported in 94 (89%) patients, EGFR in 72 (68%). At treatment commencement, 50 (47%) patients had brain metastases, 21 (20%) leptomeningeal disease (LMD) and 47 (44%) liver metastases. 27% were treatment-naïve and pemetrexed was substituted for paclitaxel in 44 (42%). The overall response rate was 51% for all patients; 52% in patients with EGFR mutations. Patients with untreated brain metastases prior to commencing IMpower150 had a similar intracranial response as those with treated brain metastases (55% vs. 53%). The median time to treatment failure and overall survival from commencement of IMpower150 was 5.7 and 11.4 months respectively for the entire cohort and 5.2 and 10.5 months in those with an EGFR sensitizing mutation. Overall survival in patients with liver, brain metastases and LMD was 11.0, 11.4, and 7.1 months respectively. No new safety signals seen., Conclusion: In this largely oncogene positive, pre-treated population the IMpower150 regimen demonstrated clinically-meaningful responses, including in patients with CNS disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aim: Systemic therapies for lung cancer are rapidly evolving. This study aimed to describe lung cancer treatment patterns in New South Wales, Australia, prior to the introduction of immunotherapy and latest-generation targeted therapies., Methods: Systemic therapy utilization and treatment-related factors were examined for participants in the New South Wales 45 and Up Study with incident lung cancer ascertained by record linkage to the New South Wales Cancer Registry (2006-2013). Systemic therapy receipt to June 2016 was determined using medical and pharmaceutical claims data from Services Australia, and in-patient hospital records. Factors related to treatment were identified using competing risks regressions., Results: A total of 1,116 lung cancer cases were identified with a mean age at diagnosis of 72 years and median survival of 10.6 months. Systemic therapy was received by 45% of cases. Among 400 cases with metastatic non-small cell lung cancer, 51% and 28% received first- and second-line systemic therapy, respectively. Among 112 diagnosed with small-cell lung cancer, 79% and 29% received first- and second-line systemic therapy. The incidence of systemic therapy was lower for participants with indicators of poor performance status, lower educational attainment, and those who lived in areas of socioeconomic disadvantage; and was higher for participants with small-cell lung cancer histology or higher body mass index., Conclusion: This population-based Australian study identified patterns of systemic therapy use for lung cancer, particularly small-cell lung cancer. Despite a universal healthcare system, the analysis revealed socioeconomic disparities in health service utilization and relatively low utilization of systemic therapy overall., (© 2021 John Wiley & Sons Australia, Ltd.)

Introduction: Lung cancer is the leading cause of cancer mortality, comprising the largest national cancer disease burden in Australia and New Zealand. Regional reports identify substantial evidence-practice gaps, unwarranted variation from best practice, and variation in processes and outcomes of care between treating centres. The Australia and New Zealand Lung Cancer Registry (ANZLCR) will be developed as a Clinical Quality Registry to monitor the safety, quality and effectiveness of lung cancer care in Australia and New Zealand., Methods and Analysis: Patient participants will include all adults >18 years of age with a new diagnosis of non-small-cell lung cancer (NSCLC), SCLC, thymoma or mesothelioma. The ANZLCR will register confirmed diagnoses using opt-out consent. Data will address key patient, disease, management processes and outcomes reported as clinical quality indicators. Electronic data collection facilitated by local data collectors and local, state and federal data linkage will enhance completeness and accuracy. Data will be stored and maintained in a secure web-based data platform overseen by registry management. Central governance with binational representation from consumers, patients and carers, governance, administration, health department, health policy bodies, university research and healthcare workers will provide project oversight., Ethics and Dissemination: The ANZLCR has received national ethics approval under the National Mutual Acceptance scheme. Data will be routinely reported to participating sites describing performance against measures of agreed best practice and nationally to stakeholders including federal, state and territory departments of health. Local, regional and (bi)national benchmarks, augmented with online dashboard indicator reporting will enable local targeting of quality improvement efforts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase ( ALK ) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.

Introduction: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial., Methods and Analysis: This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma., Ethics and Dissemination: The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences., Drug Supply: AstraZeneca., Protocol Version: CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021., Trial Registration Number: ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909., Competing Interests: Competing interests: ZS, CB, AC, SY, KaF, KarF, AB, MMC have nothing to disclose. PSK reports grants and fees from AstraZeneca and Pfizer, she is a consultant/ advisory board member of MSD, outside the submitted work; PMF reports grants and fees from AstraZeneca, BMS, Corvus, Novartis, Kyowa; he is a consultant/ advisory board member of Amgen, AstraZeneca, BMS, Novartis, Janssen, Iteos, Mirati, Sanofi; he is a Data Safety Monitoring Board member of Polaris, Flame, outside the submitted work; BH is a consultant/ advisory board member of MSD, BMS, Roche, Pfizer, AstraZeneca, Eisai, Takeda; his institution received grants from Amgen, outside the submitted work; SR reports grants and fees from Amgen, AstraZeneca, Genmab, Eisai, Lilly, Roche, Merck, Takeda and GSK; he is a Data Safety Monitoring Board member of Jansen; a member of Board for Gergia Society of Oncology and IASLC; his institution received grants from AstraZenca, Amgen, BMS, Merck, Genmab, Takeda, Advaxis and Pfizer, outside the submitted work; WJL reports grants and fees from Douglas Pharmaceuticals, and patents relating to immune checkpoint therapy, unrelated to this study, outside the submitted work; KO'B has received advisory board and/or speaker bureau and/or meeting travel/registration support from BMS, MSD, LillyOncology, Boehringer-Ingelheim, Pfizer, Novartis, Roche-Genentech,Teva, Mundipharma, Astrazeneca, Janssen, Natera and TriStar. He is a board member and stock holder for Carpe Vitae Pharmaceuticals and a stock holder for RepLuca Pharmaceuticals and DGC Diagnostics and holds patents for novel therapeutics and diagnostic tests, outside the submitted work; NP reports grants and fees from Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche, Takeda and Ipsen; he is an advisory board member of Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Pfizer and Roche; his institution received grants from Bayer, Pfizer and Roche, outside the submitted work; JB reports grants and fees from AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines, Amgen, Eli Lilly, GlaxoSmithKline, Sanofi, Regeneron; she is a Data Safety Monitoring Board member of GlaxoSmithKline, Sanofi, Janssen; she is an advisory board member of IASLC; outside the submitted work; VA institution received grants from BMS and AstraZeneca; outside the submitted work; MS institution received grants from the following competitive funding bodies: Australian National Health and Medical Research Council, Canadian Cancer Trials Group, Cancer Australia, Medical Research Future Fund of Australia; and the following pharmaceutical companies: Astellas, Amgen, Astra Zeneca, Bayer, Beigene, Bionomics, Bristol-Myers Squibb, Celgene, Medivation, Merck, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Tilray, outside the submitted work; AKN reports grants and fees from Bayer Pharmaceuticals; Roche Pharmaceuticals; Boehringer Ingelheim; Merck Sharpe Dohme; Douglas Pharmaceuticals, Atara Biotherapeutics, Astra Zeneca (payment to institution); Pharmabcine; Trizell Ltd; Seagen; honoraria from Bristol Myers Squibb and her institution received grants from AstraZeneca and Douglas Pharmaceuticals, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Nick PavlakisConsulting or Advisory Role: Roche, Boehringer Ingelheim, AstraZeneca, Merck KGaA, Merck Serono, Amgen, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, Bristol Myers SquibbResearch Funding: Bayer, Pfizer, RocheNo other potential conflicts of interest were reported.

Objectives: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited., Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response., Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%-99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%-74%) were concordant with plasma ctDNA. ctDNA matched patients to ALK-directed therapy with subsequent clinical response, including four patients matched on the basis of ctDNA results alone due to inadequate or delayed tissue testing. Serial ctDNA analysis detected MET amplification (n = 2) and ALK G1202R mutation (n = 2) as mechanisms of acquired resistance to ALK-directed therapy., Conclusion: Our findings support a complementary role for ctDNA in detection of ALK fusions and other alterations at diagnosis and therapeutic resistance settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

KRAS -mutant non-small-cell lung cancer is the most common molecular driver of lung adenocarcinoma in western populations. No  KRAS  specific therapy has been approved by the US FDA until 2021. Despite significant heterogeneity in comutations, patients typically receive single-agent immunotherapy or chemoimmunotherapy as standard first-line therapy. It is unclear whether KRAS mutations predict outcomes with immunotherapy; however, there is emerging data suggesting improved outcomes in patients with a  TP53 comutation and worse outcomes in patients with a  STK11 /LKB1 or  KEAP1 comutation.

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach., Competing Interests: Competing interests: BGMH: research funding (institution): Amgen. Advisory board or consultation: Roche, AstraZeneca; Bristol-Myers Squibb, Merck Sharpe and Dohme, Pfizer, Eisai, Takeda, Boehringer-Ingelheim. BJS: Advisory board/honoraria: Roche/Genentech, AstraZeneca, Pfizer, Novartis, Bristol-Myers-Squibb, Merck, Amgen, Loxo oncology. EA: research funding (institution): Amgen. Non-financial support: Amgen, Bristol-Myers Squibb. KO: Advisory board/honoraria: Pfizer, Roche, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Merck, Lilly Oncology, Novartis, Janssen, Yuhan, Teva, Amgen and Natera; shareholder and board member: Carpe Pharmaceuticals; Carpe Vitae Pharmaceuticals; DGC Diagnostics. NP: research funding (institution): Bayer, Pfizer. Advisory board or consultation: Bristol-Myers Squibb, MSD, Merck-KgA, Boehringer-Ingelheim, AstraZeneca, Roche, Bayer, Novartis, Merck-Sorono, Pfizer, Takeda, Ipsen. RH: Advisory board: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Merck Sharpe and Dohme, Novartis, Oncosec, Pfizer, Roche, Seagen; Speaker honorarium: Merck Sharpe and Dohme, Novartis, Roche., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Predictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients., Materials and Methods: Patients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression., Results: A total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6-4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9-5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival., Conclusion: In this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma., Methods: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m 2 , pemetrexed 500 mg/m 2 , and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415., Findings: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment., Interpretation: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative., (© AlphaMed Press 2020.)

Objectives: Alectinib demonstrated superior efficacy and a safety profile that compared favorably with crizotinib in treatment-naïve ALK+ non-small-cell lung cancer (NSCLC) in the phase III ALEX study. We present patient-reported outcomes (PROs) from ALEX to assess disease burden, treatment-related symptom tolerability, and health-related quality of life (HRQoL) with alectinib versus crizotinib., Materials and Methods: Patients were randomized to receive alectinib 600 mg or crizotinib 250 mg twice daily until disease progression, death, or withdrawal. Pre-specified PRO endpoints were: mean change from baseline in symptoms, HRQoL, and functioning; and time to deterioration (TTD) in cough, dyspnea, chest pain, arm/shoulder pain, fatigue, and a composite of three symptoms (cough, dyspnea, chest pain). PRO data were collected using EORTC QLQ-C30 and LC13 questionnaires. Raw scores were standardized to a 0-100-point range, with a ≥10-point score change defined as clinically meaningful. TTD was defined as the time from randomization until confirmed clinically meaningful deterioration (i.e., a ≥10-point score change from baseline)., Results: Baseline completion rates and characteristics were balanced in the PRO-evaluable population (alectinib n = 100, 66%; crizotinib n = 97, 64%). On average, alectinib-treated patients reported clinically meaningful improvements in lung cancer symptoms for longer than crizotinib-treated patients. Between-treatment differences in lung cancer symptoms tended to favor alectinib from 11.1 months (45 weeks) onwards, around the time of median PFS with crizotinib (11.1 months). TTD in lung cancer symptoms was similar between treatment arms, despite longer duration of symptom improvement with alectinib; composite symptom endpoint (hazard ratio 1.10 [95% confidence interval: 0.72-1.68]). Duration of clinically meaningful improvement in HRQoL was longer with alectinib versus crizotinib (Week 88 vs. Week 68, respectively). Better patient-reported tolerability was observed with alectinib versus crizotinib on common treatment-related symptoms., Conclusion: PRO data support the superior efficacy and tolerability of alectinib relative to crizotinib demonstrated in the ALEX study., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma., Methods: This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100., Findings: Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5·3 months (IQR 2·8-7·3) in the nintedanib group and 5·1 months (2·7-7·8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6·8 months [95% CI 6·1-7·0]) and the placebo group (7·0 months [6·7-7·2]; HR 1·01 [95% CI 0·79-1·30], p=0·91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%])., Interpretation: The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported., Funding: Boehringer Ingelheim., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: 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-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017)., Methods: Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant., Results: Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib., Conclusion: Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use., Methods: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided., Results: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI = 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI = 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI = 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI = 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response., Conclusions: Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM)., Methods: This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool., Results: Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0; 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite., Conclusion: Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.

A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9 months of first-line treatment initiation.

Introduction: HER2 mutations occur in 1-3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor., Methods: We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival., Results: We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4-33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5-10); median time on treatment was 3 months (range 1-30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18-53 months)., Conclusions: Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1)., Methods: Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%)., Results: A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected., Conclusion: These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Aim: To report on the pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+NSCLC) in a real-world retrospective cohort from an Australian tertiary referral center., Methods: Individuals with a pathological diagnosis of ALK+NSCLC via immunohistochemistry and fluorescence in situ hybridization and a radiological diagnosis of stage IV disease were eligible. Patients were identified via the Pathology Department specimen database and electronic patient chart review. Data were collected and analyzed for baseline demographics, radiological pattern of disease and response to treatment, treatment sequencing, toxicity and survival., Results: Thirty-five patients were identified over a 7-year period from 2010 to 2016 and followed for a median of 23 months. Median overall survival (OS) in the entire cohort was immature at data cut, 46.0 months (95% confidence interval [CI], 22.53-69.47 months), with the longest surviving patient was alive 62.1 months since diagnosis. Objective radiological response rate overall across six potential treatments and six treatment lines (range 1-6) was 58.2%. Almost 50% received at-least two lines of ALK inhibitor therapy with median OS in this group estimated to be 53.4 months (95% CI, 35.1 months-not reached). Toxicity was manageable with a low rate of ≥ grade 3 toxicity (n = 7). Forty-eight percent relapsed within the CNS and 43% overall died due to CNS progression. In those with CNS diagnosis at baseline and/or progression within the CNS (n = 32), median OS was also 46.0 months (95% CI, 24.22-66.78 months)., Conclusion: This retrospective cohort analysis of a single tertiary institution experience in treating ALK+NSCLC demonstrates impressive OS and the importance and impact of careful management of CNS disease in this patient population., (© 2018 John Wiley & Sons Australia, Ltd.)

Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry. Results We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months (95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study. Conclusion Ado-trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted.

Background: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma., Methods: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 10 9 , 7 × 10 9 , and 9 × 10 9 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 10 9 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651., Findings: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 10 9 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 10 9 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 10 9 TargomiRs once weekly. We established that 5 × 10 9 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation., Interpretation: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors., Funding: Asbestos Diseases Research Foundation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: To assess the prevalence of ROS1 rearrangements in a retrospective and prospective diagnostic Australian cohort and evaluate the effectiveness of immunohistochemical screening., Methods and Results: A retrospective cohort of 278 early stage lung adenocarcinomas and an additional 104 prospective non-small-cell lung cancer (NSCLC) cases referred for routine molecular testing were evaluated. ROS1 immunohistochemistry (IHC) was performed (D4D6 clone, Cell Signaling Technology) on all cases as well as fluorescence in-situ hybridization (FISH) using the ZytoVision and Abbott Molecular ROS1 FISH probes, with ≥15% of cells with split signals considered positive for rearrangement. Eighty-eight cases (32%) from the retrospective cohort showed staining by ROS1 IHC, and one case (0.4%) showed ROS1 rearrangement by FISH. Nineteen of the prospective diagnostic cases showed ROS1 IHC staining, 12 (12%) cases of which were confirmed as ROS1 rearranged by FISH. There were no ROS1 rearranged cases that showed no expression of ROS1 with IHC. The ROS1 rearranged cases in the prospective cohort were all EGFR wild-type and anaplastic lymphoma kinase (ALK) rearrangement-negative. The sensitivity of ROS1 IHC in the retrospective cohort was 100% and specificity was 76%., Conclusions: ROS1 rearrangements are rare events in lung adenocarcinomas. Selection of cases for ROS1 FISH testing, by excluding EGFR/ALK-positive cases and use of IHC to screen for potentially positive cases, can be used to enrich for the likelihood of identifying a ROS1 rearranged lung cancer and prevent the need to undertake expensive and time-consuming FISH testing in all cases., Competing Interests: W. Cooper has participated in Lung Cancer Advisory Boards and has received honoraria from Pfizer Oncology. S. O’Toole has received honoraria from Roche, Pfizer, and Lilly Oncology. A. Gill has received honoraria from Pfizer Oncology and Astra Zeneca. N. Pavlakis has participated in Lung Cancer Advisory Boards for Pfizer, and received honoraria. The other authors state that they have no conflicts of interest., (© 2016 John Wiley & Sons Ltd.)

Objectives: The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy., Materials and Methods: We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology., Results: The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI., Conclusion: The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

miRNAs are responsible for post-transcriptional control of gene expression, and are frequently downregulated in cancer. It has become well established that restoring miRNA levels can inhibit tumor growth, and many studies have demonstrated this in preclinical models. This in turn has led to the first clinical trials of miRNA replacement therapy. This special report focuses on the development of TargomiRs - miRNA mimics delivered by targeted bacterial minicells - and the very first clinical experience of a miRNA replacement therapy in thoracic cancer patients in the Phase I MesomiR-1 trial.

Lung cancer is a leading cause of cancer-related deaths worldwide, and is considered one of the most aggressive human cancers, with a 5 year overall survival of 10-15%. Early diagnosis of lung cancer is ideal; however, it is still uncertain as to what technique will prove successful in the systematic screening of high-risk populations, with the strongest evidence currently supporting low dose computed tomography (LDCT). Analysis of exhaled breath condensate (EBC) has recently been proposed as an alternative low risk and non-invasive screening method to investigate early-stage neoplastic processes in the airways. However, there still remains a relative paucity of lung cancer research involving EBC, particularly in the measurement of lung proteins that are centrally linked to pathogenesis. Considering the ease and safety associated with EBC collection, and advances in the area of mass spectrometry based profiling, this technology has potential for use in screening for the early diagnosis of lung cancer. This review will examine proteomics as a method of detecting markers of neoplasia in patient EBC with a particular emphasis on LC, as well as discussing methodological challenges involving in proteomic analysis of EBC specimens.

Background: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM)., Methods: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts., Results: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC., Conclusions: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.

Background: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer., Methods: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy., Results: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively., Conclusions: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Human epidermal growth factor 2 (HER2, ERBB2) mutations in lung cancers are oncogenic drivers that respond to HER2 targeted therapies. Little is known about the sensitivity of subtypes of HER2 mutant lung cancers to targeted agents. We present a patient with HER2 mutant lung cancer with a 12 base pair insertion YVMA (p.A775&#95;G776insYVMA), who had a long natural history and durable partial response to afatinib. We demonstrate that afatinib has activity in patients with HER2 mutant lung cancers with exon 20 YVMA insertions, the most common variant., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Accurate assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small-cell lung cancers (NSCLCs) is critical to identify patients who are likely to respond to crizotinib. The aim of this study was to evaluate the ALK/EML4 TriCheck FISH probe in a series of NSCLCs enriched for tumours with equivocal ALK status., Methods and Results: ALK FISH was prospectively performed on 45 NSCLCs with the ALK/EML4 TriCheck probe (ZytoVision) and the Vysis ALK break-apart probe (Abbott Molecular). ALK immunohistochemistry was performed with 5A4 and D5F3 antibodies. Fourteen cases had equivocal ALK status, based on borderline or focal FISH positivity, an atypical FISH pattern, or discrepancy between ALK FISH and immunohistochemistry. Four of the 14 equivocal cases showed discordance between the two FISH probes. All other cases were concordant. The TriCheck probe showed that, of 31 unequivocal cases, 15 were ALK-rearranged, and 60% of these had EML4 as the translocation partner. Within the group of 14 equivocal cases, 12 showed rearrangement with the Tricheck probe; only one of these showed EML4 rearrangement. Of the six equivocal cases that received crizotinib, four showed clinical benefit., Conclusions: The ALK/EML4 TriCheck FISH probe may be useful for the detection of ALK rearrangements, especially in borderline or atypical cases, where an additional unique ALK FISH probe may provide further confirmation of rearrangement., (© 2015 John Wiley & Sons Ltd.)

Purpose: We examined the impact of different epidermal growth factor receptor (EGFR) mutations and clinical characteristics on progression-free survival (PFS) in patients with advanced EGFR-mutated non-small-cell lung cancer treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy., Patients and Methods: This meta-analysis included randomized trials comparing EGFR TKIs with chemotherapy. We calculated hazard ratios (HRs) and 95% CIs for PFS for the trial population and prespecified subgroups and calculated pooled estimates of treatment efficacy using the fixed-effects inverse-variance-weighted method. All statistical tests were two sided., Results: In seven eligible trials (1,649 patients), EGFR TKIs, compared with chemotherapy, significantly prolonged PFS overall (HR, 0.37; 95% CI, 0.32 to 0.42) and in all subgroups. For tumors with exon 19 deletions, the benefit was 50% greater (HR, 0.24; 95% CI, 0.20 to 0.29) than for tumors with exon 21 L858R substitution (HR, 0.48; 95% CI, 0.39 to 0.58; Pinteraction < .001). Never-smokers had a 36% greater benefit (HR, 0.32; 95% CI, 0.27 to 0.37) than current or former smokers (HR, 0.50; 95% CI, 0.40 to 0.63; Pinteraction < .001). Women had a 27% greater benefit (HR, 0.33; 95% CI, 0.28 to 0.38) than men (HR, 0.45; 95% CI, 0.36 to 0.55; treatment-sex interaction P = .02). Performance status, age, ethnicity, and tumor histology did not significantly predict additional benefit from EGFR TKIs., Conclusion: Although EGFR TKIs significantly prolonged PFS overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials., (© 2015 by American Society of Clinical Oncology.)

Mutations in EGFR guide treatment in non-small cell lung cancer (NSCLC). The most common mutations, exon 19 (delE746-A750) and exon 21 (L858R), can be identified by mutation specific immunohistochemistry (IHC). We present our prospective experience of universal reflex IHC and molecular testing in non-squamous NSCLC in the routine clinical setting.A total of 411 specimens from 332 patients were encountered over two years. Of these, 326 (98%) patients underwent EGFR IHC, 15 (5%) were positive for exon 19 deletions and 27 (8%) for exon 21 (L858R); 244 (73%) patients underwent molecular testing. Seventy-six mutations in 64 patients (19% of all patients encountered; 26% with sufficient material for testing) were identified. These comprised nine exon 18 (G719X) mutations, three also with exon 20 mutations; 24 exon 19 deletions, six also with exon 20 mutations; 23 exon 21 (L858R), three also with exon 20 mutations; and 8 exon 20 alone.All 15 exon 19 IHC positive patients were proven mutated (100% specificity, 63% sensitivity). Twenty-two of 27 exon 21 IHC positive cases were proven mutated while three patients had insufficient material for molecular testing (92% specificity, 96% sensitivity). The overall specificity and sensitivity of IHC for any EGFR mutation was 95% and 58%. Five patients initially thought to be wild type for EGFR but IHC positive underwent repeat molecular testing because of the discrepancy which confirmed the IHC result in three cases (60%).We conclude IHC is very specific but not sensitive. Whilst IHC cannot replace molecular testing, it is a useful adjunct which requires minimal tissue and identifies false negative molecular results which occurred in 5% of our patients with eventually confirmed EGFR mutations.

Aim: Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are well established in treating metastatic pulmonary adenocarcinoma, especially patients with activating EGFR mutations. EGFR mutations are rare in pulmonary squamous cell carcinomas (SCCs). There are conflicting data supporting the efficacy of EGFR-TKIs in advanced lung SCC. We analyzed the impact of EGFR-TKIs on progression-free survival (PFS) and overall survival (OS) in unselected patients with lung SCC., Methods: We searched for randomized controlled trials (RCTs) comparing EGFR-TKIs alone with placebo in patients with metastatic non-small cell lung cancer. RCTs in all settings (front line/maintenance/subsequent) were included. The primary outcome was OS in the SCC population. We used published hazard ratios (HRs), and when unavailable, unpublished data were sought. Pooled estimates of treatment effect on OS and PFS were calculated using the fixed-effects inverse variance weighted method., Results: Eight eligible RCTs were included: 2 first-line, 6 second-line or beyond, evaluating 1781 patients. Data were available for OS in four studies (second-line; N=1420) and for PFS in four studies (3 second-line, 1 first-line; N=788). EGFR-TKIs significantly prolonged OS with a HR of 0.88 (95% confidence interval [CI] 0.78-1.00, P=0.04), and significantly prolonged PFS with a HR of 0.77 (95% CI 0.65-0.92, P=0.004)., Conclusion: EGFR mutations are rare in lung SCC. However, EGFR-TKIs have a modest therapeutic effect compared to placebo in unselected patients with advanced pulmonary SCC, and can be considered in these patients. EGFR-mutation-independent mechanisms may explain efficacy of EGFR inhibitors in this setting., (© 2014 Wiley Publishing Asia Pty Ltd.)

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors., (© 2014 Wiley Publishing Asia Pty Ltd.)

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)