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Background: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone., Methods: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants., Findings: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group., Interpretation: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone., Funding: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895)., Competing Interests: Declaration of interests EL reports grants from Boehringer Ingelheim, Medela, Johnson & Johnson/Ethicon, Covidien/Medtronic, Guardant Health, Takeda, Lilly Oncology, and Bayer, paid to his institution, his company, or personally; consulting fees from BeiGene, Roche, and BMS; honoraria from Medela; two patents (P52435GB and P57988GB) issued to Imperial Innovations; and being founder of My Cancer Companion, Healthcare Companion. SP reports consulting fees from AnHeart Therapeutics, Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Ellipses, EQRx, Daiichi Sankyo, GSK, Guardant Health, IO Biotech, Janssen, Lilly, Merck Serono, Mirati, MSD, Novocure, Novartis, PharmaMar, Roche, Takeda, Pfizer, Pierre Fabre, and Turning Point Therapeutics; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda; fees for expert testimony from Roche and Merck Serono; support for meeting attendance from Janssen, Roche, and Gilead; and being a member of the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. NT reports honoraria from BMS. DF reports grants from Astex Therapeutics, Boehringer Ingelheim, Bayer Oncology, Bergen Bio, GSK, MSD, Owkin, Roche, and RS Oncology paid to his institution; consulting fees from MSD, Cambridge Clinical Laboratories, and RS Oncology; honoraria from BMS, BI, MSD, Ikena, and Owkin; and meeting support from RS Oncology and MSD, all paid to Thoracic Oncology Services where he is director. RCR reports research funding from Cancer Research UK, Asthma and Lung UK, June Hancock Mesothelioma Research Fund, Mick Knighton Mesothelioma Research Fund, and Mesobank; and participation on an advisory board for the UK Lung Cancer Coalition. PT reports honoraria from AstraZeneca. LC-S reports support for meeting attendance from Lilly. RC reports honoraria from AstraZeneca, MSD, Takeda, Janssen, Roche, and GSK; support for meeting attendance from Takeda and Janssen; participation on advisory boards for GSK, Takeda, Janssen, Pharmamar, and Amgen; and stock options with TCC and Supportive Care UK. YS reports honoraria from Amgen, AstraZeneca, AbbVie, BMS, MSD, Lilly, Roche, and Takeda; and support for meeting attendance from Takeda and Roche. ZT reports honoraria from AstraZeneca. RS reports honoraria and support for meeting attendance from Lilly and BMS. EF reports membership of the National Lung Cancer and Mesothelioma Clinical Experts Group and Northern Cancer Alliance Targeted Lung Health Check Clinical Lead. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: On the basis of the findings of the phase 3 PACIFIC trial (NCT02125461), durvalumab is standard of care for patients with stage III, unresectable NSCLC and no disease progression after concurrent chemoradiotherapy (cCRT). Many patients are considered unsuitable for cCRT owing to concerns with tolerability. The phase 2 PACIFIC-6 trial (NCT03693300) evaluates the safety and tolerability of durvalumab after sequential CRT (sCRT)., Methods: Patients with stage III, unresectable NSCLC and no progression after platinum-based sCRT were enrolled to receive durvalumab (1500 mg intravenously) every 4 weeks for up to 24 months. The primary end point was the incidence of grade 3 or 4 adverse events possibly related to treatment occurring within 6 months. Secondary end points included investigator-assessed progression-free survival (PFS; Response Evaluation Criteria in Solid Tumors version 1.1) and overall survival., Results: Overall, 117 patients were enrolled (59.8% with performance status >0, 65.8% aged ≥65 y, and 37.6% with stage IIIA disease). Median treatment duration was 32.0 weeks; 37.6% of patients remained on treatment at data cutoff (July 15, 2021). Grade 3 or 4 AEs occurred in 18.8% of patients. Five patients had grade 3 or 4 possibly related adverse events within 6 months (incidence: 4.3%; 95% confidence interval: 1.4-9.7), including two pneumonitis cases. Two patients (1.7%) had grade 5 AEs of any cause. Survival data maturity was limited. Median PFS was 10.9 months (95% confidence interval: 7.3-15.6), and 12-month PFS and overall survival rates were 49.6% and 84.1%, respectively., Conclusions: Durvalumab after sCRT had a comparable safety profile with that observed with durvalumab after cCRT in PACIFIC and had encouraging preliminary efficacy in a frailer population., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom., Methods: Electronic prescribing records of treatment-naive patients starting first-line (1 L) treatment for aNSCLC between June 2016 and March 2018 (follow-up until December 2018) in the United Kingdom were assessed retrospectively. Patient characteristics and treatment patterns were analyzed descriptively. Outcomes assessed included overall survival (OS), time to treatment discontinuation, time to next treatment, and real-world tumor response., Results: In all, 1003 patients were evaluated (median age, 68 years [range, 28-93 years]; 53.9% male). Use of 1 L IO monotherapy (0-25.9%) and targeted therapy (11.8-15.9%) increased during the study period, but chemotherapy remained the most common 1 L treatment at all time points (88.2-58.2%). Median OS was 9.5 months (95% CI, 8.8-10.7 months) for all patients, 8.1 months (95% CI, 7.4-8.9 months) with chemotherapy, 14.0 months (95% CI, 10.7-20.6 months) with IO monotherapy, and 20.2 months (95% CI, 16.0-30.5 months) with targeted therapy. In the 28.6% of patients who received second-line treatment, IO monotherapy was the most common drug class (used in 51.6%)., Conclusions: Although use of 1 L IO monotherapy for aNSCLC increased in the United Kingdom during the study period, most patients received 1 L chemotherapy. An OS benefit for first-line IO monotherapy vs chemotherapy was observed but was numerically smaller than that reported in clinical trials. Targeted therapy was associated with the longest OS, highlighting the need for improved treatment options for tumors lacking targetable mutations.

Introduction: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left., Methods and Analysis: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery-(extended) pleurectomy decortication-versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment., Ethics and Dissemination: Research ethics approval was granted by London - Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal., Trial Registration Numbers: ISRCTN-ISRCTN44351742 and ClinicalTrials.gov-NCT02040272., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM., Methods: After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy., Results: Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0)., Conclusion: There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.