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Introduction: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap., Methods: A total of 696 consecutive patients with programmed death-ligand 1-high (≥50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of The Cancer Genome Atlas lung adenocarcinoma cohort., Results: Proportion of KRASmut and TP53mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [TP53mut versus wild-type (wt)], p = 0.004; non-G12C: 55.4% versus 39.5%, p = 0.03), progression-free survival (G12C: hazard ratio [HR] = 0.59, p = 0.009, non-G12C: HR = 0.7, p = 0.047), and overall survival (G12C: HR = 0.72, p = 0.16, non-G12C: HR = 0.56, p = 0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest progression-free survival and overall survival (33.7 and 65.3 mo), which correlated with high tumor-infiltrating lymphocyte densities in the TME and up-regulation of interferon gamma target genes. Proinflammatory pathways according to TP53 status (mut versus wt) were less enhanced and not different in non-G12C and KRASwt, respectively., Conclusions: G12C/TP53 comutations identify a subset of patients with a very favorable long-term survival with immune checkpoint inhibitor monotherapy, mediated by highly active interferon gamma signaling in a proinflammatory TME., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials., Methods: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels., Results: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival., Conclusion: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JAS reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Roche, personal fees from BMS, personal fees from Amgen, personal fees from LEO pharma, personal fees from Novartis, personal fees from Takeda, outside of the submitted work. FCA has received a research grant from Novartis, support for attending meetings and/or travel from Amgen, and consultant fees from IQVIA.PD has nothing to disclose. JR has nothing to disclose. AT has nothing to disclose. ANH has nothing to disclose. NF reports personal fees from AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol Myers&Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, outside of the submitted work. HY has nothing to disclose. PC has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. OB has nothing to disclose. CMB has nothing to disclose. ABVD has nothing to disclose. JA has nothing to disclose. SPA as nothing to disclose. MW has nothing to disclose. SK has nothing to disclose. MU has nothing to disclose. GT has nothing to disclose. CFW has nothing to disclose. AR reports grants from AbbVie, grants from AstraZeneca, grants from BMS, grants from Boehringer Ingelheim, grants from Daichi Sankyo, grants from Eli Lilly, grants from GSK, grants from MSD, grants from Novartis, grants from Pfizer, grants from Roche, outside the submitted work. PH has nothing to disclose. JB has nothing to disclose. HGK has nothing to disclose. CG has nothing to disclose. MSch has nothing to disclose. CSch has nothing to disclose. FG reports personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens, Amgen, Ariad, Abbvie, Tesaro / GSK, Sanofi, Daiichi-Sankyo, Beigene, outside of the submitted work. MSch has nothing to disclose. MS reports personal fees from Lilly, Astra-Zeneca, Bristol-Myers & Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Roche, AbbVie, Boehringer-Ingelheim, Celgene, Novartis, grants from Astra Zeneca outside the submitted work. NR reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo, personal fees from GSK, personal fees from Hoffmann-La Roche, personal fees from Janssen, personal fees from MSD, personal fees from Merck, personal fees from Lilly, personal fees from Pfizer, personal fees from Takeda, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses., Methods: Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety., Results: Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively., Conclusion: Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.

Evaluating cancer treatments in real-world data (RWD) requires informative endpoints. This study replicated the atezolizumab and docetaxel arms of the OAK trial using RWD and compared progression-free survival (PFS) outcomes derived from abstracted physician's notes in RWD (rwPFS) against PFS outcomes derived from the clinical trial PFS (ctPFS). Atezolizumab and docetaxel arms of the phase III OAK randomized controlled trial (RCT; NCT02008227) were replicated in a US nationwide real-world database using selected OAK inclusion/exclusion criteria and propensity score-based adjustment for baseline prognostic variables. Concordance of outcomes was assessed using Kaplan-Meier medians and hazard ratios (HRs). The RWD cohorts comprised 133 patients on atezolizumab and 479 patients on docetaxel. After adjustment, prognostic variables were balanced between RCT arms and corresponding RWD cohorts. The rwPFS and ctPFS outcomes showed better concordance for docetaxel (2.99 vs. 3.52 months; HR: 0.99, 95% confidence interval (CI): 0.85-1.15) than for atezolizumab (3.71 vs. 2.76 months; HR: 0.8, 95% CI: 0.61-1.02). Excluding events labeled "pseudo-progression" from both RWD and RCT improved concordance for atezolizumab (4.24 vs. 4.14 months; HR: 0.95, 95% CI: 0.70-1.25). These findings were robust across sensitivity analyses. Replicating RCTs using RWD and comparing outcomes can help characterize RWD endpoints. Similarity of results between rwPFS and ctPFS at the cohort level may depend on drug category, highlighting the need for further studies to verify and understand when the corresponding outcomes can be compared, including within the same patient., (© 2023 F. Hoffmann-La Roche Ltd and The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Background: Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy., Methods: This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0-1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786., Findings: Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4-11·9] vs 9·2 months [5·9-11·2]; stratified hazard ratio 0·78 [0·63-0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3-29·4) with atezolizumab compared with 12% (6·7-18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3-4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%])., Interpretation: First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy., Funding: F Hoffmann-La Roche and Genentech Inc, a member of the Roche group., Competing Interests: Declaration of interests SML declares support from Roche for attending meetings and travelling to present the first-line atezolizumab versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS) trial at the European Society of Medical Oncology 2022 meeting, and membership for the UK commission on Human Medicines and the Oncology and Haematology Expert Advisory Group. CS declares provision of study material from Roche; clinical trial support, consulting fees, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, from AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche, and Takeda; and support for attending meetings or travel from AstraZeneca, Boehringer Ingelheim, Roche, and Takeda. KP declares institutional funding from Alkem Laboratories and Roche. DK declares membership on an advisory board for Bristol Myers Squibb, MSD, Amgen, Roche, Pfizer, AstraZeneca, Boehringer Ingelheim, Novartis, Takeda, Sanofi-Aventis, and Janssen. AR declares consulting fees from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer, and Roche and support for attending meetings or travel from Bristol Myers Squibb, GlaxoSmithKline, and Roche. TT declares payment for advisory board activity relating to atezolizumab in early-stage NSCLC. DV declares consulting fees from Lilly, Roche, AstraZeneca, Pfizer, Novartis, MSD, Bristol Myers Squibb, Takeda, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Roche, MSD, Bristol Myers Squibb, Pfizer, Gilead, Takeda, and Bayer; and support for attending meetings or travel from AstraZeneca and Pfizer. RC declares receiving a grant to run the study; consulting fees from AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, Bristol Myers Squibb, Takeda, Bayer, Sanofi, Novartis, and Janssen; honoraria from AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, Bristol Myers Squibb, Takeda, Bayer, Sanofi, Novartis, and Janssen; support for attending meetings or travel from MSD, Takeda, Roche, and Janssen; participation on advisory boards for AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, Bristol Myers Squibb, Takeda, Bayer, Sanofi, Novartis, and Janssen; and owning stock or stock options for Leaders in Oncology at The Christie Private Care. DC declares payment for speakers bureaus or scientific advisory from MSD, Bristol Myers Squibb, Roche, AstraZeneca, Boehringer Ingelheim, Novartis, Amgen, and Sanofi Genzyme. GL declares institutional grants or contracts from the US National Cancer Institute, the Canadian Institutes of Health Research, Canadian Cancer Society Research Institute (Canada), AstraZeneca, Takeda, Boehringer Ingelheim, and Amgen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Pfizer, EMD Serono, Takeda, Jazz, and Novartis; and participation on a data safety monitoring board or advisory board for AstraZeneca, Pfizer, EMD Serono, Merck, AbbVie, Jazz, Takeda, Roche, Bristol Myers Squibb, Novartis, and Lilly. MR declares consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and support for attending meetings or travel from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, GlaxoSmithKline, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; and participation on a data safety monitoring board or advisory board for Sanofi and Daiichi-Sankyo. RP declares consulting fees from AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Guardant Health and Pfizer; support for attending meetings or travel from MSD; and participation on a data safety monitoring board or advisory board for AstraZeneca. MPM declares honoraria for lectures from Roche and MSD. YH and SM are employed by Roche. EH declares study support from Roche, discounted prices on stocks as a Roche employee, and employment by Roche. MC declares stocks as part of employment at Genentech and employment at Genentech. HKV is employed by Roche and declares holding stock for Roche. SP declares consultation or an advisory role for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi-Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, PharmaMar, Phosplatin Therapeutics, Physicians' Education Resource, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche and Genentech, Research to Practice, Sanofi, Seattle Genetics, Takeda, and Vaccibody; speaking in a company's organised public event for AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, GlaxoSmithKline, Illumina, Imedex, Ipsen, Medscape, Merck Sharp & Dohme, Mirati, Novartis, PER, Peerview, Pfizer, Prime, Roche and Genentech, RTP, Sanofi, and Takeda; and receipt of grants and research support (institutional financial support for clinical trials) as a principal investigator in trials sponsored by Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, and Roche and Genentech. SML is partially supported by the University College London Hospitals and University College London Biochemical Research Centre. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Smoking cessation in patients with diagnosed lung cancer has positive effects on cancer therapy and overall prognosis. Despite this, knowledge on smoking cessation in lung cancer patients is sparse., Methods: This is an observational single centre, 12-week, prospective, single-arm trial at a tertiary lung cancer centre. Responsive patients were enrolled following confirmed lung cancer diagnosis. Smoking cessation intervention included counselling as well as pharmacotherapy. The primary endpoint was the point prevalence abstinence rate at week 12 based on biochemical verification. Secondary endpoints were the abstinence rate at week 26, quality of life and side effects., Results: 80 patients were enrolled. Mean age was 62.6 ± 7.9 years. Most patients (63%) were treated with chemotherapy or radiochemotherapy. 39 patients used nicotine replacement therapy, 35 varenicline whereas six patients did not use pharmacotherapy. During the study period 13 patients died. Data were available in 72 patients after 12 weeks and 57 patients at week 24. Point prevalence abstinence rates were 37.5% (95% CI 26.4-49.7%) at week 12 and 32.8% (95% CI 21.8-45.4%) at week 26, respectively. Quality of life and side effects were not significantly affected by pharmacotherapy., Conclusion: In conclusion, our results suggest that smoking cessation is feasible in patients with newly diagnosed lung cancer. The observed abstinence rate is comparable to other patient cohorts. Furthermore, pharmacotherapy in addition to cancer therapy was safe and did not show novel side effects in these seriously ill patients. Thus, smoking cessation should be an integral part of lung cancer treatment. Trial registration The study was conducted in accordance with good clinical practice standards (GCP) and approved by the local ethics committee (16/3/14), the European PAS registry (EUPAS8748) and the German BfArM (NIS-Studien-Nr. 5508). All patients provided written informed consent before study enrollment., (© 2022. The Author(s).)

Background: This phase III OAK trial (NCT02008227) subgroup analysis (data cutoff, January 9, 2019) evaluated the predictive value of 2 PD-L1 IHC tests (VENTANA SP142 and Dako 22C3) for benefit from atezolizumab versus docetaxel by programmed death ligand 1 (PD-L1) status in patients with previously treated metastatic non-small cell lung cancer., Methods: PD-L1 expression was assessed prospectively with SP142 on tumor cells (TC) and tumor-infiltrating immune cells (IC) and retrospectively with 22C3 using a tumor proportion score (TPS) based on TC membrane staining. Efficacy was assessed in the 22C3 biomarker-evaluable population (22C3-BEP) (n = 577; 47.1% of SP142-intention-to-treat population) and non-22C3-BEP (n = 648) in PD-L1 subgroups (high, low, and negative) and according to selection by 1 or both assays., Results: In the 22C3-BEP, overall survival benefits with atezolizumab versus docetaxel were observed across PD-L1 subgroups; benefits were greatest in SP142-defined PD-L1-high (TC3 or IC3: hazard ratio [HR], 0.39 [95% confidence interval (CI), 0.25-0.63]) and 22C3-defined PD-L1-high (TPS ≥ 50%: HR, 0.56 [95% CI, 0.38-0.82]) and low (TPS, 1% to < 50%: HR, 0.55 [95% CI, 0.37-0.82]) groups. Progression-free survival improved with increasing PD-L1 expression for both assays. SP142 and 22C3 assays identified overlapping and unique patient populations in PD-L1-high, positive, and negative subgroups. Overall survival and progression-free survival benefits favored atezolizumab over docetaxel in double PD-L1-positive and negative groups; patients with both SP142- and 22C3-positive tumors derived the greatest benefit., Conclusions: Despite different scoring algorithms and differing sensitivity levels, the SP142 and 22C3 assays similarly predicted atezolizumab benefit at validated PD-L1 thresholds in patients with non-small cell lung cancer., Competing Interests: Disclosure Dr. Gadgeel reports personal fees from Genentech/Roche, AstraZeneca, Merck, Bristol Myers Squibb, Novartis, Daichii-Sanyko, Boehringer-Ingelheim, Xcovery, Jazz Pharmaceuticals, Pfizer, and Janssen, outside the submitted work. Dr. Hirsch reports scientific advisory board for Genentech/Roche, Merck, Bristol Myers Squibb, Novartis, AstraZeneca/Daiichi, Regeneron/Sanofi, and Amgen, outside the submitted work. Dr. Kerr reports personal fees from AbbVie, Amgen, AstraZeneca, Archer Diagnostics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Debiopharm, Diaceutics, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, and Roche Diagnostics/Ventana, outside the submitted work. Dr. Barlesi reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda, outside the submitted work. Dr. Park has nothing to disclose. Dr. Rittmeyer reports grants from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Roche, and Novartis, outside the submitted work. Dr. Zou reports employment from Genentech, outside the submitted work. Dr. Bhatia reports employment from Genentech, outside the submitted work. Dr. Koeppen reports employment from Genentech, outside the submitted work. Dr. Paul reports employment from Genentech, outside the submitted work. David Shames reports employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. Yi reports employment and spousal employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. Matheny reports employment from Genentech, during the conduct of the study, and employment from Genentech, outside the submitted work. Dr. Ballinger reports employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. McCleland reports employment from Genentech, outside the submitted work. Dr. Gandara reports personal fees and institutional grants from Genentech, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Immune checkpoint inhibition after radiochemotherapy (RTCT) has become a new standard of care for locally advanced non-small cell lung cancer with programmed death-ligand 1 (PD-L1) expression. However, little is known about the prognostic role of immune response markers in this setting. We analysed PD-L1 expression and tumour infiltrating lymphocytes (TiLs) in tumour biopsies from the multicenter German Intergroup Lung Trial (GILT), which previously randomised patients with stage III NSCLC to RTCT with or without consolidation chemotherapy., Materials and Methods: We retrospectively analyzed tumour biopsies from patients treated in the GILT trial. PD-L1 expression was analysed using the Ventana SP263 assay and TiL score (low, intermediate, high) and pattern (excluded, inflamed, desert) were assessed. The primary endpoint of the biomarker analysis was PFS in patients with PD-L1 ≥ 1% vs. PD-L1 < 1% NSCLC. Secondary endpoints explored the prognostic relevance of additional PD-L1 expression levels and TiL score and pattern., Results: Biopsies were available from 92 patients treated with RTCT. Patients with available tumor tissue did not differ significantly from the whole study population. PD-L1 scores from 78 samples were available for analysis. There was no difference in PFS in the PD-L1 < 1% vs. PD-L1 ≥ 1% subgroups. TiL score was available in 66 patients. Patients with high TiL score showed favourable overall survival compared to the low TiL subgroup. This trend was most pronounced in those patients treated with consolidative chemotherapy., Conclusion: In this analysis, PD-L1 expression did not correlate with PFS following RTCT. However, patients with TiLs > 10% were found to have longer overall survival, especially for those patients treated with consolidation chemotherapy after the end of RTCT. Further analyses to explore the prognostic and predictive relevance of TiLs in the context of consolidative checkpoint inhibition with durvalumab are required., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: As incidence rates for lung cancer are still very high and lung cancer remains the most deadly cancer since the turn of the millennium, efforts have been made to find new approaches in cancer research. This systematic review highlights how therapeutic options were extended and how the development of new drugs has picked up speed during the last 20 years., Methods: A systematic search was performed in PubMed, Cochrane Library and the European Union Trial Register and 443 records were identified. Our inclusion criteria constituted completed phase I, II and III studies investigating drugs approved by the European Medicines Agency (EMA). Overall, 127 articles were analysed., Results: During the 5 year interval from 2015 to 2020, significantly more drugs were approved after phase III, and occasionally after phase II, trials than between 2000 and 2005 (p=0.002). Furthermore, there was a significant time difference (p=0.00001) indicating an increasingly briefer time interval between the publication of phase I and phase III results in the last few years., Discussion: Due to novel therapeutic approaches, numerous new drugs in lung oncology were approved. This has improved symptoms and prognoses in patients with advanced lung cancer. However, faster approval could make it difficult to scrutinise new options regarding safety and efficacy with sufficient diligence., Competing Interests: Conflict of interest: A. Rittmeyer reports grants from EliLilly, BMS, Boehringer Ingelheim, AstraZeneca, MSD, Pfizer, AbbVie, Novartis and Roche, outside the submitted work. Conflict of interest: A. Schiwitza has nothing to disclose. Conflict of interest: L. Sahovic has nothing to disclose. Conflict of interest: B. Eul has nothing to disclose. Conflict of interest: S. Andreas reports grants and personal fees from Boehringer Ingelheim, personal fees from Novartis, AstraZeneca, GSK, Chiesi and Merini, and grants from Pfizer, outside the submitted work., (Copyright ©ERS 2021.)

Background: Treatment-induced accelerated tumor growth is a progression pattern reported with immune checkpoint inhibitors that has never been evaluated in randomized phase III studies because it requires two pretreatment scans. This study aimed to develop clinically relevant and applicable criteria for fast progression (FP), incorporating tumor growth kinetics and early death from disease progression to analyze data from the randomized phase III OAK study., Methods: The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer. FP rates and associated baseline factors were analyzed. FP was defined as either a ≥50% increase in the sum of largest diameters (SLDs) within 6 weeks of treatment initiation or death due to cancer progression within 12 weeks (absent post-baseline scan)., Results: Forty-two of 421 patients (10%) receiving atezolizumab and 37 of 402 (9%) receiving docetaxel had FP. Twenty patients with FP (48%) receiving atezolizumab versus 12 (30%) receiving docetaxel had a ≥50% SLD increase within 6 weeks. FP was significantly associated with an ECOG (Eastern Cooperative Oncology Group) performance status of 1 (vs 0), ≥3 metastatic sites at baseline, and failure of preceding first-line treatment within 6 months, but not with epidermal growth factor receptor mutation, programmed cell death 1 ligand 1 or tumor mutational burden. Overall survival in patients with FP and a ≥50% SLD increase at week 6 was similar with atezolizumab and docetaxel (unstratified HR 0.89 (95% CI 0.41 to 1.92))., Conclusions: FP rates were similar with atezolizumab and docetaxel in the OAK study, suggesting that FP may not be unique to checkpoint inhibitors, although the underlying mechanisms may differ from those of chemotherapy. Applying the FP criteria to other phase III checkpoint inhibitor trials may further elucidate the risk factors for FP., Trial Registration Number: NCT02008227., Competing Interests: Competing interests: Editorial support, funded by the sponsor, was provided by an independent medical writer under the guidance of the authors. DG reports research grants from Amgen, Merck, and Roche/Genentech; personal fees for consulting or advisory roles for Inivata, Lilly, Merck, Roche/Genentech, and Samsung Bioepis; and institutional grants with no personal income for CellMax, Guardant Health, IO Biotech, and Oncocyte. MR reports grants and non-financial support from F. Hoffmann-La Roche during the conduct of the study and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Lilly, Merck, Merck Sharpe and Dohme, Novartis, Pfizer, and Roche outside the submitted work. SP reports personal fees for speaking or attending advisory boards, and has participated in investigation in trials for Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, and Pfizer; and personal fees for speaking or attending advisory boards for AbbVie, Bayer, Biocartis, Bioinvent, Daiichi Sankyo, Debiopharm, Eli Lilly, Foundation Medicine, Janssen, Merrimack, Pharma Mar, Regeneron, Sanofi, Seattle Genetics, and Takeda. DM-S reports grants, personal fees, and non-financial support from Roche/Genentech related to the current work, and from AbbVie, AstraZeneca, Boehringer, Bristol-Myers Squibb, and Pfizer; personal fees and non-financial support from Merck Sharp and Dohme; and personal fees from Novartis and Takeda. JM reports grants, personal fees, and non-financial support from Roche/Genentech related to the current work, and from Bristol-Myers-Squibb; grants or personal fees for participation in advisory boards or speaking for Amgen, AstraZeneca, Lilly/ImClone, Merck Sharp and Dohme, Novartis, and Pierre Fabre; and personal fees and non-financial support for participation in advisory boards or speaking for Pfizer. SMG reports personal fees from Genentech/Roche related to the current work, and from AstraZeneca, Takeda, Boehringer-Ingelheim, Bristol-Myers Squibb, Novocure, Xcovery, and AbbVie. SM is an employee of and has ownership interest in F. Hoffmann-La Roche. AC is an employee of F. Hoffmann-La Roche. DM is an employee of Genentech, Inc. MB is an employee of Genentech, Inc. AR reports personal fees from Roche/Genentech related to this work, and from Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, AstraZeneca, Merck Sharpe and Dohme, Pfizer, AbbVie, and Novartis., (© 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: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the "real-world" setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany., Patients and Methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1., Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4-10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9-9.2) with druggable ALK alterations., Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The phase 2 POPLAR and phase 3 OAK studies of the anti-programmed death-ligand 1 (PD-L1) immunotherapy atezolizumab in patients with previously treated advanced NSCLC revealed significant improvements in survival versus docetaxel (p = 0.04 and 0.0003, respectively). Longer follow-up permits evaluation of continued benefit of atezolizumab. This study reports the final overall survival (OS) and safety findings from both trials., Methods: POPLAR randomized 287 patients (atezolizumab, 144; docetaxel, 143) and OAK randomized 1225 patients (atezolizumab, 613; docetaxel, 612). The patients received atezolizumab (1200 mg fixed dose) or docetaxel (75 mg/m 2 ) every 3 weeks. Efficacy and safety outcomes were evaluated., Results: A longer OS was observed in patients receiving atezolizumab versus docetaxel in POPLAR (median OS = 12.6 mo versus 9.7 mo; hazard ratio = 0.76, 95% confidence interval [CI]: 0.58-1.00) and OAK (median OS = 13.3 versus 9.8 mo; hazard ratio = 0.78, 95% CI: 0.68-0.89). The 4-year OS rates in POPLAR were 14.8% (8.7-20.8) and 8.1% (3.2-13.0) and those in OAK were 15.5% (12.4-18.7) and 8.7% (6.2-11.3) for atezolizumab and docetaxel, respectively. Atezolizumab had improved OS benefit compared with docetaxel across all PD-L1 expression and histology groups. Most 4-year survivors in the docetaxel arms received subsequent immunotherapy (POPLAR, 50%; OAK, 65%). Of the 4-year survivors, most had Eastern Cooperative Oncology Group performance status of 0 and nonsquamous histological classification and approximately half were responders (POPLAR: atezolizumab, seven of 15; docetaxel, three of four; OAK: atezolizumab, 24 of 43; docetaxel, 11 of 26). Treatment-related grade 3/4 adverse events occurred in 27% and 16% of atezolizumab 4-year survivors in POPLAR and OAK, respectively., Conclusions: Long-term follow-up suggests a consistent survival benefit with atezolizumab versus docetaxel in patients with previously treated NSCLC regardless of PD-L1 expression, histology, or subsequent immunotherapy. Atezolizumab had no new safety signals, and the safety profile was similar to that in previous studies., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The abscopal effect describes the ability of locally administered radiotherapy to induce systemic antitumor effects. Over the past 40 years, reports on the abscopal effect following conventional radiation have been relatively rare, especially in less immunogenic tumors such as lung cancer. However, with the continued development and use of immunotherapy, reports on the abscopal effect have become increasingly frequent during the last decade. Here, we present three illustrative case reports from our own institution and previous published cases of the abscopal effect in patients with non-small cell lung cancer, treated with immune checkpoint inhibitors and radiotherapy. We also present a concise review of the clinical and experimental literature on the abscopal effect in non-small cell lung cancer.

Background: Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer., Methods: IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m 2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFR wt and ALK wt ) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781., Findings: Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group., Interpretation: IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer., Funding: F. Hoffmann-La Roche., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Radiological criteria alone do not reflect the entire population benefitting from checkpoint inhibitor therapy (CIT). This study aimed to detect patterns to assess CIT efficacy in non-small-cell lung cancer (NSCLC) patients. Materials & methods: We evaluated clinical, radiological and laboratory parameters in a retrospective cohort of NSCLC patients treated with nivolumab. Results:  A total of 51 patients were included in the analysis. Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit. Conclusion: A weighted score integrating common serum markers could help detect patients benefitting from checkpoint inhibitors during ongoing CIT.

Lung cancer is the leading cause of cancer death worldwide. Older patients represent approximately half of the patient population and optimal management of these patients is challenging. In early-stagenon-small cell lung cancer (NSCLC), lobectomy should be considered in fit older patients. For unfit patients, stereotactic body radiotherapy (SBRT) represents a good alternative. While data on the benefit and risk of concurrent chemo-radiotherapy (cCRT) in older patients with locally advanced NSCLC is conflicting, age alone should not preclude cCRT. Multidisciplinary collaboration is essential for appropriate patient selection. In limited disease small cell lung cancer (SCLC), older patients appear to benefit similarly from standard treatment compared to their younger counterparts, however, with a higher risk of toxicity. Appropriately selected older patients with lung cancer seem to derive as much benefit from active oncological treatment as their younger counterparts. Geriatric screening tests and comprehensive geriatric assessments (CGA) can be helpful when choosing between treatment strategies. Older patients are at risk for under-treatment; this should be avoided by proper selection and multidisciplinary management. This review outlines the management of lung cancer in older patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To assess the safety and efficacy of atezolizumab and docetaxel in patients with and without a history of asymptomatic, treated brain metastases in the phase III OAK trial., Materials and Methods: Patients received 1200 mg atezolizumab or 75 mg/m 2 docetaxel every 3 weeks until unacceptable toxicity, disease progression, or loss of clinical atezolizumab benefit. Patients with asymptomatic, treated supratentorial metastases were eligible. Patients had brain scans before enrollment; follow-up brain scans and treatment were required when clinically indicated., Results: Approximately 14% of patients in each arm had a history of asymptomatic, treated brain metastases (61/425 in the atezolizumab arm and 62/425 in the docetaxel arm). Fewer treatment-related adverse events (AEs), serious AEs, and treatment-related neurologic AEs were reported with atezolizumab than with docetaxel, regardless of history of asymptomatic, treated brain metastases. In patients with a history of asymptomatic, treated brain metastases, median overall survival (OS) was longer with atezolizumab than with docetaxel (16.0 vs 11.9 months; hazard ratio = 0.74; 95% CI: 0.49-1.13). Median OS was also longer with atezolizumab in patients without a history of asymptomatic, treated brain metastases (13.2 vs 9.3 months; hazard ratio = 0.74; 95% CI: 0.63-0.88). Landmark analyses showed that patients with a history of asymptomatic, treated brain metastases had a lower probability of developing new symptomatic brain lesions with atezolizumab vs docetaxel at 6-24 months. Patients without a history had a lower probability with atezolizumab at 18-24+ months., Conclusion: Atezolizumab had an acceptable neurologic safety profile, showed a trend toward an OS benefit, and led to a prolonged time to radiographic identification of new symptomatic brain lesions compared with docetaxel in patients who had a history of asymptomatic, treated brain metastases. Clinicaltrials.gov registration number: NCT02008227., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of atezolizumab (anti-programmed death-ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of atezolizumab treatment beyond progression (TBP)., Methods: Eight hundred fifty patients included in the OAK primary efficacy analysis were evaluated. Atezolizumab was continued until loss of clinical benefit. Docetaxel was administered until Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) disease progression (PD)/unacceptable toxicity; no crossover to atezolizumab was allowed. ORR, PFS, post-PD OS, target lesion change, and safety were evaluated., Results: In atezolizumab-arm patients, ORR was 16% versus 14% and median PFS was 4.2 versus 2.8 months per immune-modified RECIST versus RECIST v1.1. The median post-PD OS was 12.7 months (95% confidence interval [CI]: 9.3-14.9) in 168 atezolizumab-arm patients continuing TBP, 8.8 months (95% CI: 6.0-12.1) in 94 patients switching to nonprotocol therapy, and 2.2 months (95% CI: 1.9-3.4) in 70 patients receiving no further therapy. Of the atezolizumab TBP patients, 7% achieved a post-progression response in target lesions and 49% had stable target lesions. Atezolizumab TBP was not associated with increased safety risks., Conclusions: Within the limitations of this retrospective analysis, the post-PD efficacy and safety data from OAK are consistent with a positive benefit-risk profile of atezolizumab TBP in patients performing well clinically at the time of PD., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The randomized phase III OAK (a study of atezolizumab compared with docetaxel in participants with locally advanced or metastatic non-small-cell lung cancer [NSCLC] who have failed platinum-containing therapy) trial investigated the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab for advanced or metastatic, previously treated, NSCLC. Atezolizumab significantly improved overall survival (OS) compared with docetaxel (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.62-0.87; P = .0003; median OS, 13.8 vs. 9.6 months, respectively). Patient-reported outcomes (PROs) were collected to evaluate disease-related symptoms and health-related quality of life (HRQoL) to support the finding of a survival benefit., Patients and Methods: The first 850 patients were randomized to receive atezolizumab (1200 mg every 3 weeks) or docetaxel (75 mg/m 2 every 3 weeks). PROs were collected on day 1 of cycle 1, day 1 of every subsequent cycle, and at the end-of-treatment visit for patients who completed ≥ 1 baseline and 1 postbaseline PRO assessment. The European Organisation for the Research and Treatment of Cancer QoL questionnaire and lung cancer module were used to assess PROs., Results: Atezolizumab delayed the time to deterioration (TTD) in physical function (HR, 0.75; 95% CI, 0.58-0.98) and role function (HR, 0.79; 95% CI, 0.62-1.00) and numerically improved patients' HRQoL from baseline compared with docetaxel. Atezolizumab also prolonged the TTD in chest pain (HR, 0.71; 95% CI, 0.49-1.05; P = .0823), although both arms showed an objective reduction relative to baseline. Overall, the patients had no clinically significant worsening in treatment-related symptoms, although the scores favored atezolizumab., Conclusion: These PRO data support the clinical benefit of atezolizumab in patients with previously treated advanced or metastatic NSCLC. Atezolizumab prolonged the TTD of patients' limitations in role and physical functions compared with docetaxel., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Introduction: The efficacy and safety of atezolizumab versus the efficacy and safety of docetaxel as second- or third-line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention-to-treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed., Methods: Patients received atezolizumab, 1200 mg, or docetaxel, 75 mg/m 2 , intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary end point was overall survival (OS) in the ITT population and programmed death-ligand 1-expressing subgroup. A sensitivity analysis was conducted to evaluate the impact of subsequent immunotherapy use in the docetaxel arm on the observed survival benefit with atezolizumab., Results: Atezolizumab demonstrated an OS benefit versus docetaxel in the updated ITT850 (hazard ratio [HR] = 0.75, 95% confidence interval: 0.64-0.89, p = 0.0006) and the ITT1225 (HR = 0.80, 95% confidence interval: 0.70-0.92, p = 0.0012) after minimum follow-up times of 26 and 21 months, respectively. Improved survival with atezolizumab was observed across programmed death-ligand 1 and histological subgroups. In the immunotherapy sensitivity analysis, the relative OS benefit with atezolizumab was slightly greater in the ITT850 (HR = 0.69) and ITT1225 (HR = 0.74) than the conventional OS estimate. Fewer patients receiving atezolizumab experienced grade 3 or 4 treatment-related adverse events (14.9%) than did patients receiving docetaxel (42.4%); no grade 5 adverse events related to atezolizumab were observed., Conclusions: The results of the updated ITT850 and initial ITT1225 analyses were consistent with those of the primary efficacy analysis demonstrating survival benefit with atezolizumab versus with docetaxel. Atezolizumab continued to demonstrate a favorable safety profile after longer treatment exposure and follow-up., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the predictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non-small cell lung cancer. Patients and Methods: OS benefit with atezolizumab versus docetaxel was observed in both POPLAR (phase II) and OAK (phase III), although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks. Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and number of metastatic sites as independent prognostic factors and estimated KG, predicted OS HR in subpopulations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval), 0.73 (0.63-0.85), versus 0.73 observed. The POPLAR OS model predicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS. Conclusions: KG has potential as a model-based early endpoint to inform decisions in cancer immunotherapy studies. Clin Cancer Res; 24(14); 3292-8. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Small cell lung cancer (SCLC) presents multiple interdisciplinary challenges with several paradigm shifts in its treatment in recent years. SCLC treatment requires multidisciplinary management and timely treatment. The aim of this review is to focus on the team management aspects in the treatment of limited disease SCLC and how this can contribute towards improving outcomes., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2017.)

Introduction: Immunotherapy has recently come to the forefront of oncology treatment as a potential means of combating cancer by restoring the body's adaptive cancer-immunity cycle. Atezolizumab is a monoclonal antibody agent that specifically targets programmed death ligand 1 (PD-L1), a key molecule in the cancer-immunity pathway, to block binding to its receptors PD-1 and B7.1. Areas covered: This review covers the role of atezolizumab in the treatment of non-small-cell lung cancer (NSCLC). Several studies have reported promising efficacy in this indication. The phase II FIR and BIRCH studies evaluated atezolizumab monotherapy across different lines of therapy in NSCLC selected by PD-L1 expression status. The randomized POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated NSCLC reported improved efficacy in the atezolizumab arm. Several ongoing studies yet to report data are also described and treatment-related adverse events are discussed. Expert opinion: Clinical trials have shown that atezolizumab has a favorable risk-benefit ratio compared with standard chemotherapy in second-line treatment of non-oncogene-driven advanced NSCLC. Promising response rates and survival over 2 years has been reported in the first-line setting; however, more research is needed in this setting and in evaluating combinatorial strategies to treat NSCLC.

Background  Elderly patients (70 years or older) with non-small cell lung cancer (NSCLC) do benefit from systemic chemotherapy as shown in many studies. We prospectively collected multicentric data on therapeutic decisions from patients 70 years or older to reflect the reality in the German health care system. Material and Methods  Patients 70 years or older with NSCLC Stage IIIB or IV were eligible. No more than 20 consecutive patients from each center were included. Comorbidities, weighted by the Charlson-comorbidity-index, and survival data were collected. Results  253 patients were documented. Median age was 75.5 years (range 70 to 92) and 75 % were male. 2 % had no comorbidities, 5 % one, 15 % two, 24 % three and 55 % more than three. 237 patients (94 %) received systemic chemotherapy: 172 (73 %) as a combination and 58 (24 %) as monotherapy. Data from seven patients regarding therapy are missing. Combination regimens were in 66 % carboplatin- and in 30 % cisplatin-based. The most frequently given monotherapy was vinorelbin in 50 % of cases. In the group of the patients older than 80 years (n = 38), 53 % received mono therapy, 29 % a carboplatin-based regimen and 16 % no chemotherapy. Cisplatin was not administered in this age group. Median overall survival (OS) was 16.9 months. Patients with a Charlson-score ≤ 6 had 17.9 months, those > 6 12.0 months. With combination chemotherapy median OS was 23.5 months. Patients > 80 years had a median OS of 5.7 months. Conclusion  A high percentage of patients older than 70 years received systemic therapy. Survival depended more on comorbidities than on age., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer., Methods: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m 2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227., Findings: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group., Interpretation: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile., Funding: F. Hoffmann-La Roche Ltd, Genentech, Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The treatment options for squamous cell non-small-cell lung cancer (NSCLC) are limited. We assessed the efficacy and safety of onartuzumab plus platinum-doublet chemotherapy in previously untreated advanced squamous cell NSCLC., Patients and Methods: The patients were randomized to receive onartuzumab plus paclitaxel plus carboplatin/cisplatin (n = 55) or placebo plus paclitaxel plus carboplatin/cisplatin (n = 54). Randomization was stratified by MET diagnostic status: MET immunohistochemistry (IHC)-positive (MET IHC 3+/2+) or MET IHC-negative (MET IHC 1+/0). The co-primary endpoints were investigator-assessed progression-free survival in the intent-to-treat and the MET IHC + populations., Results: The risk of disease progression or death was similar between the 2 treatment arms in both the intent-to-treat (stratified hazard ratio, 0.95; 95% confidence interval, 0.63-1.43) and MET IHC + populations (unstratified hazard ratio, 1.27; 95% confidence interval, 0.69-2.32). Comparable results were obtained for overall survival and the objective response rate. In all safety-evaluable patients, the grade 3 to 5 adverse events occurring at a > 5% greater incidence in the onartuzumab-containing versus the placebo-containing arm were neutropenia (14.8% vs. 5.8%) and pulmonary embolism (5.6% vs. 0%). Eight patients died as a result of adverse events: 1 case each of pneumonitis, pneumonia, cardiac failure, and unexplained death in the onartuzumab arm and 1 case each of hemorrhage, cardiac arrest, hemoptysis, and febrile neutropenia in the placebo arm., Conclusion: Studies using alternative assays of MET activation might help to clarify the role of onartuzumab. However, with the lack of clinical activity seen in the present study, the development of onartuzumab for squamous cell NSCLC will not be pursued further., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Adjuvant platinum-based chemotherapy is standard treatment for surgically resected stage II to IIIA NSCLC, but the relapse rate is high. The preferentially expressed antigen of melanoma (PRAME) tumor antigen is expressed in two-thirds of NSCLC and offers an attractive target for antigen-specific immunization. A phase I dose escalation study assessed the safety and immunogenicity of a PRAME immunotherapeutic consisting of recombinant PRAME plus proprietary immunostimulant AS15 in patients with surgically resected NSCLC (NCT01159964)., Methods: Patients with PRAME-positive resected stage IB to IIIA NSCLC were enrolled in three consecutive cohorts to receive up to 13 injections of PRAME immunotherapeutic (recombinant PRAME protein dose of 20 μg, 100 μg, or 500 μg, with a fixed dose of AS15). Adverse events, predefined dose-limiting toxicity, and the anti-PRAME humoral response (measured by enzyme-linked immunosorbent assay) were coprimary end points. Anti-PRAME cellular responses were assessed., Results: A total of 60 patients were treated (18 received 20 μg of PRAME, 18 received 100 μg of PRAME, and 24 received 500 μg of PRAME). No dose-limiting toxicity was reported. Adverse events considered by the investigator to be causally related to treatment were grade 1 or 2, and most were injection site reactions or fever. All patients had detectable anti-PRAME antibodies after four immunizations. The percentages of patients with PRAME-specific CD4-positive T cells were higher at the dose of 500 μg compared with lower doses. No predefined CD8-positive T-cell responses were detected., Conclusion: The PRAME immunotherapeutic had an acceptable safety profile. All patients had anti-PRAME humoral responses that were not dose related, and 80% of those treated at the highest dose showed a cellular immune response. The dose of 500 μg was selected. However, further development was stopped after negative results with a similar immunotherapeutic in patients with NSCLC., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population., Methods: In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993., Findings: Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event., Interpretation: Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy., Funding: F Hoffmann-La Roche/Genentech Inc., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: In the phase III AVAPERL trial, patients with advanced nonsquamous non-small-cell lung cancer receiving bevacizumab-plus-pemetrexed maintenance after first-line induction had a significant progression-free survival benefit relative to those treated with single-agent bevacizumab maintenance but with an increase in grade ≥3 adverse events. Here, we compare health-related quality of life (HRQOL) between AVAPERL maintenance arms., Methods: Patient-reported outcomes were collected at designated intervals from preinduction to final visits. HRQOL was assessed using the self-administered European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the Quality of Life Lung Cancer-Specific Module 13. Differences in scores of 10 points or more between arms were above the minimum important difference threshold and considered clinically meaningful., Results: During induction, patient-reported coughing symptoms improved slightly, whereas fatigue and appetite loss scores worsened relative to preinduction baseline. During maintenance, changes in mean global health status and the majority of Quality of Life Questionnaire Core 30 and Quality of Life Lung Cancer-Specific Module 13 subscale scores did not differ between trial arms by the minimum important difference defining clinically meaningful (better or worse) patient-reported outcomes. Exceptions were patient-reported role functional status, fatigue symptoms and appetite loss symptoms (favoring bevacizumab), and pain in arm or shoulder symptoms (favoring bevacizumab-plus-pemetrexed maintenance), which differed by clinically meaningful amounts at more than one maintenance assessment., Conclusions: In AVAPERL, HRQOL remained relatively stable throughout maintenance and was generally similar in both arms. Despite an increase in adverse event rates, the addition of pemetrexed to bevacizumab maintenance resulted in similar stabilization of disease symptoms with improved efficacy outcomes.

Background: Lung cancer is the leading cause of death from cancer in Germany. 90% of cases are due to the inhalation of tobacco smoke. About 40% of patients with newly diagnosed lung cancer are still smokers. A structured smoking cessation program is medically reasonable in this situation but is only rarely offered., Methods: This review is based on a selective search in the PubMed database combined with a manual search for current publications., Results: Many cross-sectional and longitudinal studies have shown that patients with lung cancer benefit from smoking cessation. After resection with curative intent, second tumors are 2.3 times more common, and recurrent tumors 1.9 times more common, in patients who continue to smoke than in those who stop. The overall mortality in smokers is 2.9 times higher. Smoking cessation also lowers the rate of radiation pneumonitis and infection during radiotherapy and prolongs the median survival after chemoradiotherapy for small-cell lung cancer (18.0 vs. 13.6 months). For patients with non-small-cell lung cancer, smoking cessation is associated with a better general state of health (77.5% vs. 57.6%). For the many patients with lung cancer who are treated palliatively, smoking cessation offers the advantages of improved pulmonary function, weight gain, and better overall quality of life., Conclusion: Smoking cessation in patients with lung cancer is an important means of increasing the efficacy of treatment and improving their quality of life.

Purpose: Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment., Patients and Methods: Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m(2), and pemetrexed 500 mg/m(2) once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment., Results: In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed., Conclusion: In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.