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Background: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here., Patient and Methods: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay)., Results: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]., Conclusions: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC)., Methods: PD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining., Results: When examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1-high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups., Conclusions: The SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab., Trial Registration Number: NCT02486718., Competing Interests: Competing interests: CZ reports consulting fees from Innovent Biologics, Qilu, Hengrui, and TopAlliance Biosciences Inc; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eli Lilly China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone LUYE Pharma, TopAlliance Biosciences Inc, Amoy Diagnostics, and AnHeart. MS reports employment by Genentech and stockholding in Roche. HX reports stockholding in Roche as a former Roche employee. EF reports grants or contracts from Merck Healthcare KGaA and Fundación Merck Salud; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and is an independent member of the board for Grífols. HW reports grants or contracts from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; participation on a data safety monitoring board or advisory board for AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership or fiduciary role in other board, society, committee, or advocacy group (paid or unpaid) for International Association for the Study of Lung Cancer (IASLC) and ECOG-ARIN. MR reports consulting fees from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; support for attending meetings and/or travel from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, and Roche; and participation on a data safety monitoring board or advisory board for Sanofi and Daiichi Sankyo. SO reports grants or contracts from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceuticals, Daiichi Sankyo, Ono Pharmaceutical, Pfizer, MSD, Sanofi, Taiho, and Takeda. Hiroshi Tanaka reports grants or contracts from Chugai Pharmaceuticals, AstraZeneca, MSD, Ono Pharmaceutical, and Bristol Myers Squibb; and honoraria for Chugai Pharmaceuticals, AstraZeneca, MSD, Ono Pharmaceutical, and Bristol Myers Squibb. SLM reports support from Genentech as a research site for this trial. EB reports employment by Genentech and stockholding in Roche. BG reports employment by Genentech and stockholding in Roche. VM reports employment by Roche and stockholding in Roche. MB reports employment by Genentech and stockholding in Roche. MM reports being a former employee of Roche/Genentech. WZ reports employment by Roche and stockholding in Roche. MDT reports stock or stock options as a former employee of Roche/Genentech. SN reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Amgen, Boehringer Ingelheim, Roche, Pfizer, Takeda, Novartis, Sanofi, Janssen, and GSK; and participation on a data safety monitoring board or advisory board for AstraZeneca, Amgen, Boehringer Ingelheim, Roche, Pfizer, Takeda, Novartis, Sanofi, Janssen, and GSK. NA, RL, AK and JH declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This review describes a new therapeutic landscape in the adjuvant treatment of resectable non-small cell lung cancer (NSCLC) and discusses the role of the surgeon in ensuring the best outcomes within this treatment paradigm., Methods: We conducted a narrative literature review using the search terms "non-small cell lung cancer" and "adjuvant" to identify randomized Phase III trials of systemic adjuvant therapy for NSCLC through March 17, 2022. We also searched ClinicalTrials.gov to identify ongoing trials of adjuvant immunotherapies and targeted therapies for NSCLC., Results: Three recent randomized Phase III trials reported significant improvements in disease-free survival with adjuvant immune checkpoint inhibitors or targeted therapy in patients with resectable NSCLC: IMpower010 (atezolizumab vs best supportive care; NCT02486718), KEYNOTE-091 (PEARLS) (pembrolizumab vs placebo; NCT02504372), and ADAURA (osimertinib vs placebo; NCT02511106). Numerous other Phase III trials evaluating adjuvant immune checkpoint inhibitors and targeted therapies are currently underway, many of which demonstrate an evolution of trial design and end points for adjuvant therapy trials. This rapidly changing treatment landscape requires a shift in the role of the surgeon to facilitate appropriate biomarker screening for planning of the perioperative period and molecular testing of the surgical specimen to guide adjuvant therapy., Conclusions: After decades of stagnation in the management of NSCLC, recent results with immune checkpoint inhibitors and targeted therapies are ushering in a new era of precision medicine in the adjuvant treatment of early-stage NSCLC. Surgeons have an important role in facilitating multidisciplinary care in this rapidly evolving landscape., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients., Methods: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting)., Findings: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%)., Interpretation: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests All authors report editorial support from F Hoffmann-La Roche. EF received advisory or consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Sharp & Dohme (MSD), Merck Serono, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, and Takeda; received honoraria from Amgen, AstraZeneca, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, Janssen, Medscape, Medical Trends, MSD, Merck Serono, Peervoice, Pfizer, Springer, and Touch Medical; and is an independent member of the board for and has received personal fees from GRIFOLS. NA received grants or contracts from AstraZeneca, the National Cancer Institute, New York Genome Center P1000 and LC200388 the US Department of Defense; and received honoraria from AstraZeneca and Regeneron. CZ received honoraria from Lilly China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent, C-Stone, LUYE Pharma, TopAlliance Bioscience, and Amoy Diagnostics; and participated in a data safety monitoring board or advisory board for Innovent Biologics, Hengrui, Qilu, and TopAlliance Bioscience. AM-M received personal fees and travel expenses from Bristol–Myers Squibb, F Hoffmann-La Roche, MSD, Pfizer, Boehringer Ingelheim, MSD Oncology, and AstraZeneca, outside the submitted work. HK received research funding from Chugai Pharmaceutical, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK; and received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly KK, Kyowa Hakko Kirin, Bristol–Myers Squibb, MSD, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK, Pfizer, and Taiho Pharma. SS received honoraria from Chugai Pharma. DV, YD, and MM are employed by Genentech. FW is employed by Roche (China). JY, EB, and BG are employed by Genentech and have stock ownership of F Hoffmann-La Roche. HW received research funding (to institution) from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol–Myers Squibb, Celgene, Clovis Oncology, Genentech/Roche, Merck, Novartis, Pharmacyclics, SeaGen, Xcovery, and Eli Lilly; received honoraria from Novartis and AstraZeneca; received compensation for advisory boards from AstraZeneca, Xcovery, Janssen, Daiichi Sankyo, Blueprint, Mirati, and Helsinn; served in an uncompensated role for advisory boards for Merck, Takeda, Genentech/Roche, and Cellworks; and reports an uncompensated leadership role with the International Association for the Study of Lung Cancer. All other authors have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The disc diffusion test is used for antimicrobial susceptibility testing worldwide. In this study, the performance of both Bio-Rad® antibiotic discs (as compared with Oxoid® discs) and the ADAGIO™ automated system for the reading of disc diffusion test results was evaluated with American Type Culture Collection (ATCC) quality control (QC) and wild strains of bacteria. Inhibition zones of both disc brands were read manually and through use of the ADAGIO™ system. Categorized interpretation of the results for each strain and antibiotic combination was summarized according to the Clinical Laboratory Standards Institute MS-100 (2017 update) manual and ADAGIO™ readings. Eight ATCC QC strains and 120 different wild strains were evaluated, to give a total of 1226 antibiotic/bacteria combinations and 2486 manual readings. One major error and four minor errors (0.08% and 0.34%, respectively) were detected via manual readings of the Bio-Rad® discs as compared with the Oxoid® discs. For the same number of antibiotic/bacteria combinations, five minor errors and one major error (0.42% and 0.08%, respectively) were detected with the Bio-Rad® discs read by the ADAGIO™ system. In addition, the number of times the automatic reading needed manual edition with Bio-Rad® discs was statistically lower than it did with Oxoid® discs (3.7% vs. 5.7%, p < 0.05). These findings support the hypothesis that Bio-Rad discs are not inferior to Oxoid® discs, and the performance of the ADAGIO™ system is comparable to that of manual readings with both disc brands.

Background: Overall response rate is frequently used as an end point in phase 2 trials of platinum-treated extensive stage (ES) small-cell lung cancer (SCLC). We hypothesized that disease control rate (DCR) would be a superior surrogate for subsequent survival outcomes., Methods: Updated patient-level data from Southwest Oncology Group (SWOG) trials in second- and/or third-line ES-SCLC patients were pooled. Landmark analysis was performed among patients alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors with DCR was assessed using logistic regression. A Cox proportional hazard model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors., Results: Of the 319 ES-SCLC patients, 263 were alive at the 8-week landmark and constituted the pooled study population. Only 8 patients had a response. Disease control at 8 weeks was seen in 98 patients. Bivariate analysis of OS from the 8-week landmark revealed that DCR (hazard ratio [HR], 0.47; P < .0001) and elevated lactate dehydrogenase (HR, 1.70; P = .0004) were significantly associated with OS. In multivariable analysis, DCR remained an independent predictor of subsequent survival from the 8-week landmark (HR, 0.50; P < .0001)., Conclusion: In this large second- and third-line ES-SCLC database, DCR at 8 weeks was found to be a significant predictor of subsequent survival in patients receiving investigational therapy. These results have critical implications in the selection of surrogate end points in future prospective ES-SCLC trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinib-sensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients., Experimental Design: Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20% at 12 weeks (stratum 2: EGFR wild-type)., Results: Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively, 9% and 40% in stratum 1; 3% and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2., Conclusions: Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC., (©2015 American Association for Cancer Research.)

Objectives: Acquired resistance mutations to anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib and alectinib have been documented in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangement (ALK+). Of note I1171T/N/S mutations in the ALK kinase domain have recently been described by several groups to confer resistance to alectinib, a second-generation ALK inhibitor. Additionally one of these reports demonstrated one ALK+ NSCLC patient harboring an I1171T acquired mutation has responded to ceritinib, another second-generation ALK inhibitor., Materials and Methods: We reported the presence of an ALK I1171N resistance mutation from comprehensive genomic profiling from a liver biopsy of a progressing metastatic lesion in an ALK+ patient on alectinib after an initial partial response. The patient then responded to ceritinib 750 mg orally once daily but required dose reduction to 600 mg once daily. She initially had grade 3 elevation of liver enzymes from crizotinib necessitating the original switch to alectinib but experienced no transaminase elevations with alectinib or ceritinib., Conclusions: This is the fifth patient case to date demonstrating that ALK I1171 mutation confers resistance to alectinib and the second reported case of ALK I1171 mutation being sensitivity to ceritinib. Substitutions of isoleucine at amino acid 1171 in the ALK kinase domain may distinguish which second generation ALK inhibitor will be effective after crizotinib failure. This case also provides evidence that transaminase elevations is likely a unique adverse event associated with crizotinib and unlikely a "class" effect involving all ALK inhibitors., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)