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Anti-programmed cell death protein (death-ligand) 1 [PD-(L)1] therapy alone [cancer immunotherapy (CIT)-mono] or combined with platinum-based chemotherapy (CIT-chemo) is used as the first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). Our study compared clinical outcomes with CIT-mono versus CIT-chemo in the specific clinical scenario of non-squamous (Nsq)-NSCLC with a high PD-L1 expression of ≥50% [tumor proportion score (TPS) or tumor cells (TC)]. This was a retrospective cohort study using a real-world de-identified database. Patients with metastatic Nsq-NSCLC with high PD-L1 expression initiating first-line CIT-mono or CIT-chemo between 24 October 2016 and 28 February 2019 were followed up until 28 February 2020. We compared overall survival (OS) and real-world progression-free survival (rwPFS) using the Kaplan–Meier methodology. Hazard ratios (HRs) were adjusted (aHR) for differences in baseline key prognostic characteristics using the inverse probability of treatment weighting methodology. Patients with PD-L1−high Nsq-NSCLC treated with CIT-mono (n = 351) were older and less often presented with de novo stage IV disease than patients treated with CIT-chemo (n = 169). With a median follow-up of 19.9 months for CIT-chemo versus 23.5 months for CIT-mono, median OS and rwPFS did not differ between the two groups [median OS: CIT-chemo, 21.0 months versus CIT-mono, 22.1 months, aHR = 1.03, 95% confidence interval (CI) 0.77-1.39, P = 0.83; median rwPFS: CIT-chemo, 10.8 months versus CIT-mono, 11.5 months, aHR = 1.04, 95% CI 0.78-1.37, P = 0.81]. CIT-chemo showed significant and meaningful improvement in OS and rwPFS versus CIT-mono only in the never-smoker subgroup, albeit among a small sample of patients (n = 50; OS HR = 0.25, 95% CI 0.07-0.83, interaction P = 0.02; rwPFS HR = 0.40, 95% CI 0.17-0.95, interaction P = 0.04). Except in the subgroup of never-smoker patients, sparing the chemotherapy in first-line CIT treatment does not appear to impact survival outcomes in Nsq-NSCLC patients with high PD-L1 expression. • PD-L1−high Nsq-NSCLC patients treated with CIT-mono versus CIT-chemo had older age and higher frequency of recurrent disease. • No difference was found in median OS between PD-L1-high Nsq-NSCLC patients treated with CIT-mono as compared to CIT-chemo. • No difference was found in median rwPFS between PD-L1-high Nsq-NSCLC patients treated with CIT-mono as compared to CIT-chemo. • In exploratory analysis, superior OS and rwPFS were found for the small never-smoker subgroup treated with CIT-chemo. [ABSTRACT FROM AUTHOR]

Summary: From 5 March 2001 to 19 October 2001, outbreaks of broncho-alveolar lavage (BAL) contamination with Enterobacteraceae were detected in our 700-bed institution. We report the investigation of these outbreaks. A case was defined as the occurrence of pairs of specific Enterobacteraceae in BAL specimens among any patients who underwent bronchoscopy in the respiratory unit during the period of the outbreak. Contamination was identified in 117 BAL samples during three outbreaks among 418 patients, and was associated with bronchoscopes 11 and 12 (P<0.001). The other five devices in use were not linked with the outbreaks. During the first outbreak, particular pairs of micro-organisms were associated with a specific bronchoscope (Klebsiella pneumoniae/Proteus vulgaris with bronchoscope 11, and Morganella morganii/Proteus mirabilis with bronchoscope 12). Cultures of sputa from two patients also yielded M. morganii some days after bronchoscopic examination. Isolates from contaminated BAL samples and bronchoscope 11 had similar patterns by pulsed-field gel electrophoresis. No further cases occurred after removal of the implicated bronchoscopes. No deficiencies in disinfection procedures were detected and the source of contamination was found to be a loose port of the biopsy channel of the bronchoscope. Our findings underscore the urgent need to test bronchoscopic samples regularly and to improve the design and structure of bronchoscopes. [Copyright &y& Elsevier]

Following the approval of the first antibody–drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal–epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes. • As the number of available ADCs increases, biomarkers are required to optimise treatment algorithms and patient selection. • Combination therapy of ADCs should be scientifically driven and studied in biomarker-driven trials of enriched populations. • Efforts to optimise ADC treatment duration, sequencing and the potential for ADC rechallenge are essential. • In clinical trials, biopsy sample collection and translational research are critical to improve our understanding of ADCs. • Effective collaborations are required to accelerate progress, which will ultimately help improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). Patients and methods Advanced NSCLC patients with c-MET ≥6 copies, c-MET -mutated, or ROS-1 -translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. Results From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET -mutation, and 78 ROS-1 -translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET -mutation cohort, and 37 in the ROS-1 -translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET -≥6 copies cohort, 36% in the c-MET -mutated, and 69.4% in the ROS-1 -translocation cohort. Safety data were consistent with that previously reported. Conclusions Crizotinib activity in patients with ROS1 -translocated tumours was confirmed. In the c-MET -mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. Clinical trial number NCT02034981. [ABSTRACT FROM AUTHOR]

Background Genomic alterations of receptor tyrosine kinases (RTK) or ligands are biomarkers for some targeted therapies in a fraction of cancers, with heterogeneous responses across tumor types. A general model to predict the efficacy of a targeted treatment in a given tumor type bearing a RTK genomic alteration is lacking. Through database and literature review, we investigated whether the role of a RTK in the normal lineage could predict the response to RTK inhibitors in cancers arising from the same lineage. Methods An analysis of the literature and query of public databases on RTK function in normal cell lineages and neoplastic cells was conducted, for 16 selected RTK (EGFR, HER2, KIT, FLT3, TRKA-B-C, ROS1, ALK, RET, MET, and FGFR1-2-3-4). The physiological role of RTK in the development/maintenance of cell lineages was assessed by looking at the phenotypes resulting from the alteration of the RTK in animal models and/or known human germline mutations. The activity of TKI monotherapy in genomic-driven clinical trials was analyzed through a systematic review of published phase I-II-III studies. Efficacy was defined as a median progression-free survival > 6 months and of a response rate > 30%. A matrix was built to test the association between the physiological role and clinical activity of each RTK according to lineage contexts. Results This analysis reveals a relationship between the role in lineage development and the magnitude of clinical activity of a TKI in a cancer arising from the same lineage. For missense mutations only, the clinical activity was higher when the RTK is involved in the development or maintenance of the normal cell lineage. Conversely, in cancers harboring fusion genes and proteins involving an RTK, TKI were active regardless of cell lineage. Single agent TKI activity was consistently limited in cancers bearing RTK gene amplifications. Conclusions This analysis identifies two preferred genomic biomarkers to select candidate patient for single agent TKI, 1) fusions genes involving an RTK; 2) activating missense mutations in RTK involved in normal cell lineage physiology. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure P.A. Cassier: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Research grant / Funding (institution): Blueprint; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution): Tayo; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Innate. I.L. Ray-Coquard: Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Research grant / Funding (institution): Amgen; Honoraria (self), Research grant / Funding (institution): Genmab; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer. D. Pérol: Honoraria (self): AstraZeneca; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Bristol-Myers Squibb. J-Y. Blay: Research grant / Funding (self): PharmaMar; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Novartis; Research grant / Funding (self): Eisai; Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck Sharp and Dohme; Research grant / Funding (self): Bristol-Myers Squibb. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32e0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46e0.98). The 5-year OS rate was 62.5% (95% CI 54.3e70.8) with alectinib and 45.5% (95% CI 33.6e57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34e1.00)] and those without [HR 0.76 (95% CI 0.45 e1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALKpositive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

Background The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK +) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n  =   64; crizotinib, n  =   58), 43 had measurable lesions (alectinib, n  =   21; crizotinib, n  =   22), and 46 had received prior radiotherapy (alectinib, n  =   25; crizotinib, n  =   21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P  <   0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK + NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration ClinicalTrials.gov NCT02075840 [ABSTRACT FROM AUTHOR]