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Objective: The uPath PD-L1 (SP263) is an AI-based platform designed to aid pathologists in identifying and quantifying PD-L1 positive tumor cells in non-small cell lung cancer (NSCLC) samples stained with the SP263 assay., Methods: In this preliminary study, we explored the diagnostic performance of the uPath PD-L1 algorithm in defining PD-L1 tumor proportion score (TPS) and predict clinical outcomes in a series of patients with advanced stage NSCLC treated with single agent PD-1/PD-L1 checkpoint blockade previously assessed with the SP263 assay in clinical practice., Results: 44 patients treated from August 2015 to January 2019 were included, with baseline PD-L1 TPS of ≥ 50%, 1-49% and < 1% in 38.6%, 25.0% and 36.4%, respectively. The median uPath PD-L1 score was 6 with a significant correlation with the baseline PD-L1 TPS (r: 0.83, p < 0.01). However, only 27 cases (61.4%) were scored within the same clinically relevant range of expression (≥ vs < 50%). In the study population the baseline PD-L1 TPS was not significantly associated with clinical outcomes, while the uPath PD-L1 score showed a good diagnostic ability for the risk of death at the ROC curve analysis [AUC: 0.81 (95%CI: 0.66-0.91), optimal cut-off of ≥ 3.2], resulting in 19 patients (43.2%) being u-Path low and 25 patients (56.8%) being uPath high. The objective response rate in uPath high and low was 51.6% and 25.0% (p = 0.1), respectively, although the uPath was significantly associated with overall survival (OS, HR 2.45, 95%CI: 1.19-5.05) and progression free survival (PFS, HR 3.04, 95%CI: 1.51-6.14). At the inverse probability of treatment weighting analysis used to balance baseline covariates, the uPath categories confirmed to be independently associated with OS and PFS., Conclusions: This preliminary analysis suggests that AI-based, digital pathology tools such as uPath PD-L1 (SP263) can be used to optimize already available biomarkers for immune-oncology treatment in patients with NSCLC., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted., Patients and Methods: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method., Results: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy., Conclusion: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We described time to death and rates of palliative sedation during home palliative care leveraging a retrospective cohort of patients with advanced cancer., Methods: The cohort consists of 143 patients with solid or haematological malignancies admitted to home palliative care in the Tuscany region in central Italy. Only patients for whom a date of death was available were included. The outcome measures were time from admission to home palliative care to death and receipt of palliative sedation., Results: 143 patients were included in this report. Lower Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores were significantly associated with anticancer treatment at admission, as was younger age. Increasing ECOG PS scores were associated with lower survival time. Women and patients on anticancer treatment had longer survival time. Thirty-eight per cent of patients underwent palliative sedation at home; palliative sedation was more frequent among younger patients and among patients with brain or lung cancer. The most common reasons for palliative sedation were delirium and dyspnoea., Conclusions: ECOG PS, sex and anticancer treatment had a significant impact on survival time. Thirty-eight per cent of patients in our cohort underwent home palliative sedation for refractory symptoms, most often delirium and dyspnoea., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of neoadjuvant or perioperative anti-PD(L)1 was recently tested in multiple clinical trials. We performed a systematic review and meta-analysis of randomised trials comparing neoadjuvant or perioperative chemoimmunotherapy to neoadjuvant chemotherapy in resectable NSCLC. Nine reports from 6 studies were included. Receipt of surgery was more frequent in the experimental arm (odds ratio, OR 1.39) as was pCR (OR 7.60). EFS was improved in the experimental arm (hazard ratio, HR 0.55) regardless of stage, histology, PD-L1 expression (PD-L1 negative, HR 0.74) and smoking exposure (never smokers, HR 0.67), as was OS (HR 0.67). Grade > = 3 treatment-related adverse events were more frequent in the experimental arm (OR 1.22). The experimental treatment improved surgical outcomes, pCR rates, EFS and OS in stage II-IIIB, EGFR/ALK negative resectable NSCLC; confirmatory evidence is warranted for stage IIIB tumours and with higher maturity of the OS endpoint., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DM: none. FTG: none. SP: none. MADC: none. AT: none. RG: none. AJG: none. MR: none. MV: none. EM: none. RT: none. FLC: none. LL: none. PN: none. NP: none. MO: sub-investigator in KEYNOTE-671. MB: none. PMF: consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, F-Star, G1 Therapeutics, Genentech, Iteos, Janssen Global Services LLC, Merck, Novartis, SANOFI PASTEUR INC, Surface Oncology; grant/contract (to institution) from AstraZeneca, BioNTech, Bristol-Myers Squibb, Corvus, Kyowa Hakko Kirin, LUNGevity Foundation, Mark Foundation, NCI Cancer Center Support Grant, Novartis, Regeneron Pharmaceuticals, Stand Up To Cancer; gift (research funding) from Bloomberg Philantropies, Earl & Darielle Linehan, Martha Furman, Susan Troll. SVL: advisory board/consultant for Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; research grant (to institution) from Alkermes, Elevation Oncology, Genentech, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics; data safety monitoring board for Candel Therapeutics. AB: none. SN: consultant for Thermo Fisher Scientific; grant/contract (to institution) from Amgen, AstraZeneca, BeiGene Switzerland GmbH, Boehringer Ingelheim, Eli Lilly and Company, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, PFIZER CANADA INC, SANOFI PASTEUR INC, Takeda Oncology; speaker bureau from AstraZeneca, BeiGene Switzerland GmbH, Bristol-Myers Squibb, Novartis, Takeda Oncology. GC: none. EC: none. FF: none. FC: personal fees from Roche/Genentech, AstraZeneca, Takeda, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, and Bayer. DS: Advisory Board role and speaker honoraria with Astra Zeneca, MSD, BMS, Astellas, Janssenn, EISAI, Merck, Pfizer, Bayer, Novartis, Astra Zeneca, Lilly., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors., Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes., Results: A total of 1,395 patients were included. Primary tumors included non-small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07-1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03-1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16-2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04-1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM., Conclusions: In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population., (©2023 American Association for Cancer Research.)

Objectives: The selective RET-inhibitor pralsetinib has shown therapeutic activity in early clinical trials in patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) gene fusions. To date, the real-world efficacy of pralsetinib in this population is unknown., Materials and Methods: A retrospective efficacy and safety analysis was performed on data from patients with RET-fusion positive NSCLC enrolled in the pralsetinib Italian expanded access program between July 2019 and October 2021., Results: Overall, 62 patients with RET-fusion positive NSCLC received pralsetinib at 20 Italian centers. Next-generation sequencing was used to detect RET alterations in 44 patients (73 %). The most frequent gene fusion partner was KIF5B (75 % of 45 evaluable). Median age was 62 years (range, 36-90), most patients were female (57 %) and never smokers (53 %). Brain metastases were known in 18 patients (29.5 %) at the time of pralsetinib treatment. 13 patients were treatment naïve (unfit for chemotherapy), 48 were pretreated (median number of previous lines: 1, range, 1-4). The objective response rate (ORR) was 66 % [95 % confidence interval (CI), 53-81] in the evaluable population (n = 59). The disease control rate (DCR) was 79 %. After a median follow-up of 10.1 months, the median progression free survival was 8.9 months (95 %CI, 4.7-NA). In patients with measurable brain metastases (n = 6) intracranial ORR was 83 %, intracranial DCR was 100 %. Overall, 83.6 % of patients experienced any-grade treatment-related adverse events (TRAEs), 39 % grade 3 or greater (G ≥ 3). The most common G ≥ 3 TRAEs were neutropenia (9.8 %), dry mouth/oral mucositis (8.2 %), and thrombocytopenia (6.6 %). Seven patients (12 %) discontinued pralsetinib due to TRAEs, twenty-six had at least one dose level modification due to TRAEs. Two treatment-related deaths were observed (1 sepsis, 1 typhlitis)., Conclusions: In the real-world setting, pralsetinib confirmed durable systemic activity and intracranial response in RET-fusion positive NSCLC. Toxicity profile was consistent with previous reports., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood., Methods: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point., Results: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288)., Conclusions: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time., Methods: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables., Results: A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% versus -3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36)., Conclusions: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts., Competing Interests: Disclosure DS received personal fees from AstraZeneca, Merck Sharp & Dohme (MSD), Boehringer Ingelheim and received travel grants from Roche, AstraZeneca, Bristol Myers Squibb (BMS), MSD. AMo received honoraria from Roche, AstraZeneca, Boehringer, Pfizer, MSD, BMS, Novartis, Lilly, Takeda. RC received fees for speaker's bureau and advisory boards participation in BMS, MSD, Roche, Pfizer, AstraZeneca, Takeda, Amgen, Boehringer, Novartis. FM received founding from AstraZeneca, Incyte and served as consultant for MSD. RB is a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli Lilly, Roche. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (mNSCLC) and ECOG performance status (PS) of 2 treated with first-line immunotherapy have heterogeneous clinical assessment and outcomes., Methods: To explore the role of immune-inflammatory surrogates by the validated lung immuno-oncology prognostic score (LIPS) score, including the neutrophil-to-lymphocyte ratio (NLR) and the pretreatment use of steroids, alongside other prognostic variables. A retrospective analysis of 128 patients with PS2 and PD-L1 ≥50% mNSCLC treated between April 2018 and September 2019 with first-line pembrolizumab in a real-world setting was performed., Results: With a median follow-up of 15.3 months, the 1-year overall survival (OS) and median progression-free survival (PFS) were 32.3% (95% CI: 30.9-33.9) and 3.3 months (95% CI: 1.8-4.7), respectively. The NLR, lactate dehydrogenase (LDH) and pretreatment steroids results were the only significant prognostic factors on the univariate analysis and independent prognostic factors by the multivariate analysis on both OS and PFS. The LIPS score, including the NLR and pretreatment steroids, identified 29 (23%) favourable-risk patients, with 0 factors, 1-year OS of 67.6% and median PFS of 8.2 months; 57 (45%) intermediate-risk patients, with 1 factor, 1-year OS 32.1% and median PFS 2.7 months; 42 (33%) poor-risk patients, with both factors, 1-year OS of 10.7% and median PFS of 1.2 months., Conclusions: The assessment of pre-existing imbalance of the host immune response by combined blood and clinical immune-inflammatory markers may represent a way to unravel the heterogeneous outcome and assessment of patients with mNSCLC and poor PS in the immune-oncology setting., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: The connection between driver mutations and the efficacy of immune checkpoint inhibitors is the focus of intense investigations. In lung adenocarcinoma (LUAD), KEAP1/STK11 alterations have been tied to immunoresistance. Nevertheless, the heterogeneity characterizing immunotherapy efficacy suggests the contribution of still unappreciated events., Methods: Somatic interaction analysis of top-ranking mutant genes in LUAD was carried out in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) (N = 6208). Mutational processes, intratumor heterogeneity, evolutionary trajectories, immunologic features, and cancer-associated signatures were investigated, exploiting multiple data sets (AACR GENIE, The Cancer Genome Atlas [TCGA], TRAcking Cancer Evolution through therapy [Rx]). The impact of the proposed subtyping on survival outcomes was assessed in two independent cohorts of immune checkpoint inhibitor-treated patients: the tissue-based sequencing cohort (Rome/Memorial Sloan Kettering Cancer Center/Dana-Farber Cancer Institute, tissue-based next-generation sequencing [NGS] cohort, N = 343) and the blood-based sequencing cohort (OAK/POPLAR trials, blood-based NGS cohort, N = 304)., Results: Observing the neutral interaction between KEAP1 and TP53, KEAP1/TP53-based subtypes were dissected at the molecular and clinical levels. KEAP1 single-mutant (KEAP1 SM) and KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD share a transcriptomic profile characterized by the overexpression of AKR genes, which are under the control of a productive superenhancer with NEF2L2-binding signals. Nevertheless, KEAP1 SM and KEAP1/TP53 DM tumors differ by mutational repertoire, degree of intratumor heterogeneity, evolutionary trajectories, pathway-level signatures, and immune microenvironment composition. In both cohorts (blood-based NGS and tissue-based NGS), KEAP1 SM tumors had the shortest survival; the KEAP1/TP53 DM subgroup had an intermediate prognosis matching that of pure TP53 LUAD, whereas the longest survival was noticed in the double wild-type group., Conclusions: Our data provide a framework for genomically-informed immunotherapy, highlighting the importance of multimodal data integration to achieve a clinically exploitable taxonomy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Importance: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population., Objective: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer., Design, Setting, and Participants: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021., Main Outcomes and Measures: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs., Results: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008)., Conclusions and Relevance: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

Small cell lung cancer (SCLC) is an aggressive disease, difficult to treat. There have been no significant therapeutic advances over platinum and etoposide chemotherapy in the last 20 years until the introduction of immunotherapy. In 2020 atezolizumab, an immune checkpoint inhibitor against PD-L1 was approved in Italy in combination with carboplatin and etoposide for the first-line treatment of patients with extensive stage disease (ES-SCLC), becoming the new standard treatment. On May 20, 2021, a virtual meeting, directed by profs. Federico Cappuzzo and Emilio Bria, was held in which 14 clinicians from different oncology centers in Lazio, Umbria and Sardinia discussed the issues of ES-SCLC patients treatment, after the advent of immunotherapy. The aim of the meeting was to share their clinical experience and to provide a series of practical indications that can support clinicians in the management of ES-SCLC patients in first-line with chemo-immunotherapy.

Background: Recent researches suggested that statins, beside their role in inhibiting endogenous cholesterol synthesis and in cardiovascular prevention, could influence several processes in cancer biology. In fact, a recent meta-analysis demonstrated that statins could positively influence OS in lung cancer patients., Aim: There is a lack of large cohort studies that could support a potential antineoplastic role of statins in clinical practice. We collected data from 162 patients treated with immunotherapy for Nonsmall Cell Lung Cancer (NSCLC) in first- and second-line setting to investigate the impact of these drugs on survival parameters., Methods and Results: In our observational study, we enrolled 162 patients who received immunotherapy for lung cancer between October 2015 and April 2020. We used descriptive statistics to analyze patients' baseline features. Tumor response was evaluated using RECIST version 1.1 guidelines. Uni and multivariate analysis were conducted to investigate the relationship between statin use and response to immunotherapy, using the χ 2 -test. We used Kaplan-Meier curves to estimate OS and PFS in statin and nonstatin users. We included 122 patients in the final analysis. Median PFS was 17.57 months in the statin group and 9.57 months in the nonstatin group, with a P = <.001. Moreover, median OS was superior in the statin-users group, with a statistically significant difference (19.94 vs 10.94 months, P = <.001)., Conclusion: Although in our study, statin use positively correlates with PFS and OS in lung cancer patient treated with immunotherapy, these results require a further validation with randomized clinical trials., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy., Methods: The present analysis aims to describe clinicians' attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy., Results: Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p < 0.0001) and with a higher burden of disease (69.3% vs 59.4%, p = 0.0266). In total, 35 patients (6.2%) started ICIs within 30 days of death; among them there was a higher proportion of patients with ECOG-PS ≥ 2 (45.7% vs 14.5%, p < 0.0001) and with a higher burden of disease (82.9% vs 60.9%, p = 0.0266). Primary tumors were significantly different across subgroups (p = 0.0172), with a higher prevalence of NSCLC patients (80% vs 60.9%) among those who started ICIs within 30 days of death. Lastly, 123 patients (21.7%) started ICIs within 3 months of death. Similarly, within this subgroup there was a higher proportion of patients with ECOG-PS ≥ 2 (29.3% vs 12.8%, p < 0.0001), with a higher burden of disease (74.0% vs 59.0%, p = 0.0025) and with NSCLC (74.0% vs 58.8%, p = 0.0236)., Conclusion: Our results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.

Background: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4., Methods: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy)., Results: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts., Conclusion: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients., Competing Interests: Conflict of interest statement S.B. received honoraria as a speaker at scientific events and for the advisory role from Bristol Myers Squibb (BMS), Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca and Novartis. M.B. received honoraria as a speaker at scientific events from Bristol Myers Squibb (BMS), Novartis, AstraZeneca and Pfizer and as a consultant for the advisory role from Novartis, BMS and Pfizer; she also received fees for copyright transfer from Sciclone Pharmaceuticals and research funding from Seqirus UK, Pfizer, Novartis, BMS, AstraZeneca, Roche S.p.A. and Sanofi Genzyme. R.G. received speaker fees and grant consultancies from AstraZeneca and Roche. J.G.J.V.A. reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, MSD and Roche. A.F. received grant consultancies from Roche, Pfizer, Astellas and BMS. F.M. received grant consultancies from MSD and Takeda. R.C. received speaker fees from BMS, MSD, Takeda, Pfizer, Roche and AstraZeneca. C.G. received speaker fees/grant consultancies from AstraZeneca, BMS, Boehringer Ingelheim, Roche and MSD. M.R. received honoraria for scientific events from Roche, AstraZeneca, BMS, MSD and Boehringer Ingelheim. E.B. received speaker and travel fees from MSD, AstraZeneca, Pfizer, Helsinn, Eli Lilly, BMS, Novartis and Roche and grant consultancies from Roche and Pfizer. M.C.G. received grants from MSD, AstraZeneca, Novartis, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck, Bayer, GSK, Spectrum and Blueprint; personal fees from Eli Lilly, Boehringer Ingelheim, Otsuka Pharma, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Inivata, Takeda, Bayer, MSD, Sanofi, Seattle Genetics and Daiichi Sankyo and other financial supports from Eli Lilly, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck Serono, MSD, GSK, Spectrum and Blueprint. A.A. received grant consultancies from Takeda, MSD, BMJ, AstraZeneca, Roche and Pfizer. M.D.M. received research funding from Tesaro-GlaxoSmithKline and acted in a consulting/advisory role for Novartis, Pfizer, Eisai, Takeda, Janssen, Astellas, Roche and AstraZeneca. D.J.P. received lecture fees from ViiV Healthcare and Bayer Healthcare; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche and AstraZeneca and research funding (to the institution) from MSD and BMS. M.T. received honoraria from MSD, BMS, Boehringer (BI), Takeda and AstraZeneca and research funding from AstraZeneca. A.C. received speaker fees and grant consultancies from AstraZeneca, MSD, BMS, Roche, Novartis, Istituto Gentili and Astellas. All the other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Treatment sequencing with first-line immunotherapy, followed by second-line chemotherapy, is still a viable option for NSCLC patients with PD-L1 expression ≥50%., Methods: We evaluated post-progression treatment pathways in a large real-world cohort of metastatic NSCLC patients with PD-L1 expression ≥ 50% treated with first-line pembrolizumab monotherapy., Results: Overall, 974 patients were included. With a median follow-up of 22.7 months (95%CI: 21.6-38.2), the median overall survival (OS) of the entire population was 15.8 months (95%CI: 13.5-17.5; 548 events). At the data cutoff, among the 678 patients who experienced disease progression, 379 (55.9%) had not received any further treatment, and 359 patients (52.9%) had died. Patients who did not receive post-progression therapies were older (p = 0.0011), with a worse ECOG-PS (p < 0.0001) and were on corticosteroids prior to pembrolizumab (p = 0.0024). At disease progression, 198 patients (29.2%) received a switched approach and 101 (14.9%) received pembrolizumab ByPD either alone (64 [9.4%]) or in combination with local ablative treatments (37 [5.5%]) (LATs). After a random-case control matching according to ECOG-PS, CNS metastases, bone metastases, and (previous) best response to pembrolizumab, patients receiving pembrolizumab ByPD plus LATs were confirmed to have a significantly longer post-progression OS compared to patients receiving pembrolizumab ByPD alone 13.9 months versus 7.8 months (p = 0.0179) 241 patients (35.5%) among the 678 who had experienced PD, received a second-line systemic treatment (regardless of previous treatment beyond PD). As compared to first-line treatment commencement, patients' features at the moment of second-line initiation showed a significantly higher proportion of patients aged under 70 years (p = 0.0244), with a poorer ECOG-PS (p < 0.0001) and having CNS (p = 0.0001), bone (p = 0.0266) and liver metastases (p = 0.0148)., Conclusions: In the real-world scenario NSCLC patients with PD-L1 expression ≥50% treated with first-line single-agent pembrolizumab achieve worse outcomes as compared to the Keynote-024 trial. Poor post-progression outcomes are major determinants of the global results that should be considered when counselling patients for first-line treatment choices., Competing Interests: Conflict of interest statement Dr Alessio Cortellini received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis, Istituto Gentili and Astellas. Dr Raffaele Giusti received speaker fees and grant consultancies by Astrazeneca and Roche. Dr Joachim GJV Aerts reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD and Roche. Dr Alex Friedlaender received grant consultancies by Roche, Pfizer, Astellas and BMS. Dr Alessandro Morabito received speaker fees by Astra, Roche, BMS, MSD, Boehringer, Pfizer, Takeda. Dr Francesca Mazzoni received grant consultancies by MSD and Takeda. Dr Rita Chiari received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. Dr Carlo Genova received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD. Dr Marco Russano received honoraria for scientific events by Roche, Astrazeneca, BMS, MSD and Boehringer Ingelheim. Dr Marcello Tiseo received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre. Dr Alfredo Addeo received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. Dr Rita Chiari received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. Dr Carlo Genova received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD. Dr David J Pinato received lecture fees from ViiV Healthcare, Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, Astra Zeneca; received research funding (to institution) from MSD, BMS. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy., Methods: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis., Results: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis., Conclusions: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC., Competing Interests: Disclosure AC received speaker fees and grant consultancies from AstraZeneca, MSD, BMS, Roche, Novartis and Astellas. EB received speaker and travel fees from MSD, Astra-Zeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; received grant consultancies from Roche and Pfizer. MT received speaker fees and grant consultancies from AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. AM received speaker fees from Astra, Roche, BMS, MSD, Boehringer, Pfizer and Takeda. FM received grant consultancies from MSD and Takeda. RG received speaker fees and grant consultancies from AstraZeneca and Roche. AF received grant consultancies from Roche, Pfizer, Astellas and BMS. AA received grant consultancies from Takeda, MSD, BMJ, AstraZeneca, Roche and Pfizer. RC received speaker fees from BMS, MSD, Takeda, Pfizer, Roche and AstraZeneca. CG received speaker fees/grant consultancies from Astra Zeneca, BMS and Boehringer-Ingelheim. GLB personal fees from Janssen Cilag, Boehringer Ingelheim, AstraZeneca and Roche, outside the submitted work. All other authors have declared no conflicts of interest. Data sharing The datasets used during this study are available from the corresponding author upon reasonable request., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate., Methods: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses., Results: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate., Conclusion: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features., Competing Interests: Competing interests: AC received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis, Istituto Gentili and Astellas. RG received speaker fees and grant consultancies by Astrazeneca and Roche. JA reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD and Roche. AF received grant consultancies by Roche, Pfizer, Astellas and BMS. FM received grant consultancies by MSD and Takeda. RC received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. CG received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD. MR received honoraria for scientific events by Roche, Astrazeneca, BMS, MSD and Boehringer Ingelheim. EB received speaker and travel fees from MSD, Astra-Zeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; grant consultancies by Roche and Pfizer. MCG received grants from MSD, Astrazeneca, Novartis, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck, Bayer, GSK, Spectrum, Blueprint, personal fees from Eli Lilly, Boheringer, Otsuka Pharma, Astrazeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Inivata, Takeda, Bayer, MSD, Sanofi, Seattle Genetics, Daichii Sankyo, other financial supports from Eli Lilly, Astrazeneca, Novartis, BMS, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck Serono, MSD, GSK, Spectrum and Blueprint. AA received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. MDM received research funding from Tesaro-GlaxoSmithKline; acted in a consulting/advisory role for Novartis, Pfizer, Eisai, Takeda, Janssen, Astellas, Roche, AstraZeneca. FP received grant consultancies by MSD and Astrazeneca. PB received grant consultancies by Astrazeneca and Boehringer-Ingelheim. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, Astra Zeneca; received research funding (to institution) from MSD, BMS. All other authors declare no competing interests. DJP is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and has received direct project funding by the NIHR Imperial Biomedical Research Centre (BRC), ITMAT Push for Impact Grant Scheme 2019. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (© 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.)

Background: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts., Methods: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy., Results: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15-1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02-1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52-1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45-1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case-control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17-2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84-2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49-0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45-0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts., Conclusions: Among metastatic NSCLC patients with PD-L1 expression ≥50% receiving first-line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first-line chemotherapy., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The discovery of gene driver mutations and the increase of next-generation sequencing techniques have radically changed the natural history of NSCLCs. Neuroendocrine lung cancers are a heterogeneous entity whose biology is little known. Sporadic actionable mutations are also reported in this subtype of neoplasms, especially in tumors derived from a transformation of adenocarcinomas. ROS-1 gene rearrangements are found in about 1-2% of lung neoplasms and are characterized by a high sensitivity to specific tyrosine kinase inhibitors (TKis). Here we report the case of a large cell neuroendocrine carcinoma precisely framed and treated thanks to a next-generation genomic approach.

Background: Concomitant medications are known to impact on clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs). We aimed weighing the role of different concomitant baseline medications to create a drug-based prognostic score., Methods: We evaluated concomitant baseline medications at immunotherapy initiation for their impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in a single-institution cohort of patients with advanced cancer treated with ICIs (training cohort, N = 217), and a drug-based prognostic score with the drugs resulting significantly impacting the OS was computed. Secondly, we externally validated the score in a large multicenter external cohort (n = 1012)., Results: In the training cohort (n = 217), the median age was 69 years (range: 32-89), and the primary tumours were non-small-cell lung cancer (70%), melanoma (14.7%), renal cell carcinoma (9.2%) and others (6%). Among baseline medications, corticosteroids (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.60-3.30), systemic antibiotics (HR = 2.07; 95% CI: 1.31-3.25) and proton-pump inhibitors (PPIs) (HR = 1.57; 95% CI: 1.13-2.18) were significantly associated with OS. The prognostic score was calculated using these three drug classes, defining good, intermediate and poor prognosis patients. Within the training cohort, OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0297) were significantly distinguished by the score stratification. The prognostic value of the score was also demonstrated in terms of OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0006) within the external cohort., Conclusion: Cumulative exposure to corticosteroids, antibiotics and PPIs (three likely microbiota-modulating drugs) leads to progressively worse outcomes after ICI therapy. We propose a simple score that can help stratifying patients in routine practice and clinical trials of ICIs., Competing Interests: Conflict of interest statement M.B. reports receiving research funding by Roche, Seqirus, Pfizer and Novartis and personal fees as a speaker/consultant from AstraZeneca, Novartis, Pfizer and BMS. M.T. reports receiving speaker fees and grant consultancies from AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. A.C. reports receiving speaker fees and grant consultancies from Roche, MSD, BMS, AstraZeneca, Novartis and Astellas. R.G. reports receiving speaker fees and grant consultancies from AstraZeneca and Roche. M.G.V. reports receiving speaker fees, grant consultancies and travel support from BMS, Ipsen, Novartis, Pfizer, Astellas, Jansen and Pierre-Fabre. A.R. reports receiving grant consultancies from AstraZeneca and MSD. F.S. reports receiving speaker fees and grant consultancies from Roche, Novartis, BMS, MSD, Pierre-Fabre, Sanofi, Merck and Sunpharma. D.J.P. reports receiving lecture fees from ViiV Healthcare and Bayer Healthcare; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche and AstraZeneca and research funding (to institution) from MSD and BMS. P.A.A. reports receiving speaker fees and grant consultancies from BMS, Roche-Genentech, MSD, Dohme, Array, Novartis, Merck-Serono, Pierre-Fabre, Incyte, New Link Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar and Boehringer-Ingelheim and research funds from BMS, Roche-Genentech and Array. All other authors declared no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Lung cancer is a disease extremely heterogeneous in the molecular aspect and knowing the mutational profile of patients is essential in order to initiate the most appropriate treatment. In 2018, alectinib was approved in Italy for the first-line treatment of patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), becoming a new therapeutic option for this patient group which constitutes approximately 3-7% of patients with NSCLC. On October 26th a virtual meeting was held in which 10 clinicians from various oncology centers in Lazio took part on the management of therapy of patients with Alk translocation, directed by Dr. Maria Rita Migliorino. The aim of the meeting was to share their clinical experience and to provide a series of practical that can help clinicians during treatment with target therapies in ALK-positive NSCLC.

Objectives: In the most of cases, for non-small cell lung cancer (NSCLC) patients who progressed to previous immune checkpoint inhibitors (CKI) administered as first- or as second-line therapy, chemotherapy (CT) remains the only viable options in the absence of "druggable" mutations. We aimed to explore the efficacy of salvage chemotherapy after immunotherapy (SCAI) in advanced NSCLC patients., Materials and Methods: We designed a retrospective, multicenter study, involving 20 Italian centers, with the primary objective of describing the clinical outcome of advanced NSCLC patients treated with SCAI at the participating institutions from November 2013 to July 2019. The primary endpoint of the study was represented by overall survival (OS), defined as the time from CT initiation to death. Secondary outcome endpoints of the SCAI (progression free survival, PFS, objective response rate, ORR and toxicity) and explorative biomarkers (lactate dehydrogenase, LDH, and neutrophil-to-lymphocyte ratio, NLR during immunotherapy) were also analyzed., Results: In our study population of 342 NSCLC patients, SCAI obtained a median OS of 6.8 months (95 % confidence interval, CI 5.5-8.1), median PFS of 4.1 months (95 % CI 3.4-4.8) and ORR of 22.8 %. A "Post-CKI score" was constructed by combining significant predictors of OS at the multivariate analyses (sex, ECOG PS, disease control with prior immunotherapy), Harrell'C was 0.65, (95 % CI:0.59-0.71)., Conclusions: Despite the late-line settings, our findings support the hypothesis that previous immunotherapy might increase the sensitivity of the tumor to the subsequent chemotherapy. The "Post-CKI score" was clinically effective in successfully discriminating three distinct prognostic subgroups of patients after the failure of CKI, representing a possibly useful tool for the tailored decision-making process of advanced treatment-line settings in NSCLC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy., Patients and Methods: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study., Results: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes., Conclusions: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease., Competing Interests: Disclosure LP received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees from Roche, Pfizer, Novartis, Gentili. PVici received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RG received advisory boards/honoraria/speakers' fee from Astra Zeneca and Roche. RDM is a scientific advisory board member at Exosomics SpA (Siena IT), HiberCell Inc. (New York, NY), Kiromic Inc. (Houston, TX) and Exiris Inc. (Rome, IT). All other authors declare no conflicts of interest. Data sharing Data concerning the Rome cohort are provided in supplementary Data File S1, available at https://doi.org/10.1016/j.annonc.2020.08.2105. The MSKCC and DFCI studies are available at www.cbioportal.org. The OAK and POPLAR trials are available as supplementary information in Gandara DR et al.(23) Immunogenomic features related to the TCGA LUAD study were downloaded from the CRI iAtlas Portal (available at www.cri-iatlas.org)., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%., Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%., Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis., Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Background: The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression., Methods: We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group., Results: 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts., Conclusions: Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes., Competing Interests: Competing interests: AC received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis and Astellas. JA reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD and Roche. EB received speakers’ and travels’ fee from MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche. EB received consultant’s fee from Roche, Pfizer. EB received institutional research grants from Astra-Zeneca, Roche. MT received speaker fees and grant consultancies by Astrazeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. AM received speaker fees by Astra, Roche, BMS, MSD, Boehringer, Pfizer, Takeda. FM received grant consultancies by MSD and Takeda. RG received speaker fees and grant consultancies by Astrazeneca and Roche. FP received grant consultancies by MSD and Astrazeneca. AF received grant consultancies by Roche, Pfizer, Astellas and BMS. AA received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. RC received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. CG received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD. MR received honoraria for scientific events by Roche, Astrazeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice., Methods: We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS)., Results: In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH mut /HR mut signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH mut /HR mut genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH mut /HR mut signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002)., Conclusions: Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions., Competing Interests: Competing interests: MM, MF, MO, DM, SS, IT, FS, MP, FR, AG, AB, GS, ADN, EK, MB, SC, MF, FDN, LC, FG, AV, GC, PM and MM-S declare no conflicts of interest. LP received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees from Roche, Pfizer, Novartis, Gentili. PV received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RDM declares to be a scientific advisory board member at ExosomicsSpA (Siena IT), Hibercell Inc. (New York, New York USA), Kiromic Inc. (Houston, Texas, USA) and at Exiris Inc. (Rome, Italy). RG received advisory boards/honoraria/speakers’ fee from AstraZeneca and Roche., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression., Methods: We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC)., Results: 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3 months vs 7.8 months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2 months and 9.9 months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs)., Conclusion: Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.

Background: Despite the efficacy of immune checkpoint inhibitors (ICIs) only the 20-30% of treated patients present long term benefits. The metabolic changes occurring in the gut microbiota metabolome are herein proposed as a factor potentially influencing the response to immunotherapy., Methods: The metabolomic profiling of gut microbiota was characterized in 11 patients affected by non-small cell lung cancer (NSCLC) treated with nivolumab in second-line treatment with anti-PD-1 nivolumab. The metabolomics analyses were performed by GC-MS/SPME and 1 H-NMR in order to detect volatile and non-volatile metabolites. Metabolomic data were processed by statistical profiling and chemometric analyses., Results: Four out of 11 patients (36%) presented early progression, while the remaining 7 out of 11 (64%) presented disease progression after 12 months. 2-Pentanone (ketone) and tridecane (alkane) were significantly associated with early progression, and on the contrary short chain fatty acids (SCFAs) (i.e., propionate, butyrate), lysine and nicotinic acid were significantly associated with long-term beneficial effects., Conclusions: Our preliminary data suggest a significant role of gut microbiota metabolic pathways in affecting response to immunotherapy. The metabolic approach could be a promising strategy to contribute to the personalized management of cancer patients by the identification of microbiota-linked "indicators" of early progressor and long responder patients.

With the advent of immunotherapy, the life expectancy of patients with advanced non-small cell lung cancer (NSCLC) is dramatically improved. As described in the most recent clinical trials, the addition of immunotherapy to the available therapeutic strategies, restoring an efficient immune response against neoplasms and establishing an immunological memory, is able to improve both patient's survival and quality of life. This paved the way for new therapeutic algorithms, new combination strategies, as well as the possible use of adoptive immunotherapy. Although the use of immunotherapy is now widely employed in the different phases of lung cancer, we have not yet fully understood what are both the actual mechanisms of action and resistance to checkpoint inhibitors, predictive factors of response, immuno-related response criteria, and interferences between immunotherapy and tumor microenvironment, as well as angiogenesis and its interactions with conventional therapies, such as chemotherapy. The objective of this critical review is to frame the relevant results obtained with immunotherapy in NSCLC, providing insights to help overcome decision-making for a better therapeutic choice. In addition, returning to the study of pulmonary physiology and preclinical data, we will address the new issues on the heterogeneity of response to anti-PD1/anti-PD-L1, including their combinations, in NSCLC. Moreover, to date, we are facing with patterns of response different from those previously seen with cytotoxic or target therapies. Indeed, different radiological evaluation criteria have been proposed to evaluate response to immunotherapy and further efforts are needed to identify a unique system of evaluation and other than PDL1 biomarkers, to integrate radiology in the assessment of response.

Background: Immune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Patients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis., Results: A total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed "single-site" irAEs and 40 (17.4%) "multiple-site" irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), "single-site" irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), "single-site" irAEs (P < .0001), "multiple-site" irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), "single-site" irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS., Conclusion: Our study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection., Methods: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process., Results: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age ≥ 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement., Conclusion: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.

Lung cancer is the most common tumor and the leading cause of cancer-related death worldwide. Approximately 6.7% of non-small-cell lung cancers (NSCLCs) show anaplastic lymphoma kinase (ALK) rearrangement and could benefit from ALK-targeted treatment. Various anti-ALK drugs have been developed during the past years, but it is actually controversial which sequence and which ALK inhibitor is recommended for a single patient. Leptomeningeal carcinomatosis (LC) is associated with a poor prognosis, with an overall survival of 2-4 months for treated patients. The data about LC management derive mainly from retrospective studies, being an exclusion criterion for most trials. Intrathecal chemotherapy and whole-brain radiotherapy (WBRT), associated with a systemic treatment, are the most commonly used approach. Here we present a case of NSCLC harboring an ALK translocation treated with four lines of ALK inhibitors and receiving WBRT for LC, showing an overall survival of ∼5 years from the diagnosis of metastatic disease. This case report focuses mainly on several controversial clinical aspects, that is, the sequence of treatment in ALK-positive NSCLC, the ALK inhibitors' efficacy on brain disease and beyond progression, the management of LC, and the role of WBRT despite the risk of cognitive impairment.

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is efficacious as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Dosage reduction is recommended in patients with intolerable adverse events; however, data regarding the efficacy of low-dose afatinib are limited. We report the case of a 71-year-old female patient who was diagnosed with advanced EGFR-mutated NSCLC and started treatment with oral afatinib 40 mg daily. The patient achieved partial tumor response on computed tomography imaging, but developed unacceptable skin-related toxicities requiring dosage reduction to 20 mg daily. The patient subsequently achieved complete tumor response and showed improvements in performance status. These observations suggest that low-dose afatinib is effective in patients with EGFR-mutated NSCLC who require dosage reduction for intolerable adverse events.

Objectives: Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed., Materials and Methods: We collected the data of 69 advanced ALK-positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded., Results: Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments (P=0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression (P=0.89)., Conclusion: Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)