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Importance: After the PACIFIC trial, concurrent chemo-radiotherapy followed by consolidation therapy with durvalumab for 1 year (limited to PD-L1 tumour proportion score ≥ 1% in the EMA region) is the firmly established standard of care treatment for unresectable NSCLC patients. Several relevant questions are emerging with the growing use of this approach, posing novel challenges in clinical practice. Treatment of oncogene-addicted NSCLCs, management of mediastinal disease recurrence after surgery and the optimal management of patients progressing during or after durvalumab are now some of the most clinically relevant issues., Observations: Patients with unresectable NSCLC harbouring EGFR and HER2 mutations or ALK/ROS1/RET /NTRK1,2,3 rearrangements are unresponsive to immunotherapy. Importance of knowing the tumour genotyping (NGS, preferable DNA and RNA) from the earliest stages of NSCLC, also for the possible use of immunotherapy both in the adjuvant and perioperative setting. In case of mediastinal disease recurrence after surgery, re-biopsy is essential to re-determine the histological and biological characteristics of the disease and the distinction of recurrence in curable and non-curable disease is of pivotal important for the optimal management of subsequent treatments., Conclusions and Relevance: Treatment of stage III NSCLC has always been controversial and challenging: Multidisciplinary approach is mandatory and defining resectability is a critical issue. Chemo-radiotherapy followed by maintenance Durvalumab is now the standard of treatment. Herein, we provide a comprehensive overview of the key challenges and open questions that we are currently facing in clinical practice, in unresectable stage III and in early-stage NSCLC, identifying the knowledge gaps and the possible solutions., Competing Interests: Declaration of Competing Interest Dr Catania reports advisory board role for AstraZeneca and compensated activity for projects for AstraZeneca. Dr Russo reports advisory board role for AstraZeneca, BMS, Novartis, Pfizer, and MSD, speaker bureau for AstraZeneca and BMS, and compensated activity for editorial projects for AstraZeneca, MSD, Novartis, and Roche., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) in pre-treated asMM., Methods: A systematic review of the literature of clinical trials testing single-agent anti PD-1/PD-L1 ICIs in pre-treated asMM was performed. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) data were extracted. The predictive role of PD-L1 was assessed., Results: We selected 13 studies including 888 patients. ORR and DCR were 18.1% (95% confidence interval [CI] 13.9-22.8%) and 55.4% (95% CI: 48.1-62.5%), respectively. Median PFS and OS ranged from 2.1 to 5.9 and from 6.7 to 20.9 months, respectively. ORR according to PD-L1 was 27.0% (95% CI: 18.7-36.2%)., Conclusions: Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We are witnessing a silent revolution in the treatment of early stage non-small cell lung cancer (NSCLC), with a series of practice-changing clinical trials enriching the therapeutic perspectives of lung cancer patients with potentially curable disease. The ADAURA study marked the advent of precision medicine and biomarker testing to the early stages setting. The IMPower-010 trial interrupted the negative trend of adjuvant lung cancer immunotherapy, paving the way to the application of immune-checkpoint inhibition in the resected disease. The ITACA trial definitively established no role for tailored adjuvant chemotherapy in NSCLC, while the Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease. Growing evidence is supporting MRD as effective adjuvant prognostic biomarker to stratify disease's recurrence risk after radical interventions and select best candidates to the adjuvant strategies. This work summarizes the recent major breakthroughs in lung cancer adjuvant treatment, and provides a snapshot of the current real-world scenario, discussing the upcoming challenges and opportunities featuring the clinical management of early stage NSCLC patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To define efficacy and toxicity of Immunotherapy (IT) with stereotactic radiotherapy (SRT) including radiosurgery (RS) or hypofractionated SRT (HFSRT) for brain metastases (BM) from non-small cell lung cancer (NSCLC) in a multicentric retrospective study from AIRO (Italian Association of Radiotherapy and Clinical Oncology)., Methods: NSCLC patients with BM receiving SRT + IT and treated in 19 Italian centers were analyzed and compared with a control group of patients treated with exclusive SRT., Results: One hundred patients treated with SRT + IT and 50 patients treated with SRT-alone were included. Patients receiving SRT + IT had a longer intracranial Local Progression-Free Survival (iLPFS) (propensity score-adjusted P = .007). Among patients who, at the diagnosis of BM, received IT and had also extracranial progression (n = 24), IT administration after SRT was shown to be related to a better overall survival (OS) (P = .037). A multivariate analysis, non-adenocarcinoma histology, KPS = 70 and use of HFSRT were associated with a significantly worse survival (P = .019, P = .017 and P = .007 respectively). Time interval between SRT and IT ≤7 days (n = 90) was shown to be related to a longer OS if compared to SRT-IT interval >7 days (n = 10) (propensity score-adjusted P = .008). The combined treatment was well tolerated. No significant difference in terms of radionecrosis between SRT + IT patients and SRT-alone patients was observed. The time interval between SRT and IT had no impact on the toxicity rate., Conclusions: Combined SRT + IT was a safe approach, associated with a better iLPFS if compared to exclusive SRT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The PACIFIC trial marked a new era in the treatment of stage III unresectable NSCLC, establishing durvalumab consolidation as new standard of care worldwide, with about 14 % increase of long-term survival and half of the patients alive at 4 years. A series of intensified immune-checkpoint inhibition regimens are currently under investigation in clinical trials in order to optimize the therapeutic benefit obtained in this population, while the identification of personalized approaches as well as the development of effective treatments in the post-durvalumab progression setting represent an actual and controversial topic for clinical lung cancer research. This review describes the current real-word treatment scenario for stage III unresectable NSCLC in Italy, and provides an updated overview of the upcoming therapeutic strategies under clinical investigation, discussing the most relevant challenges and opportunities featuring the post-PACIFIC era., (Copyright © 2021. Published by Elsevier B.V.)

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: Stereotactic ablative body radiation therapy (SBRT) has evolved as the standard treatment for patients with inoperable stage I non-small-cell lung cancer (NSCLC). We report the results of a retrospective analysis conducted on a large, well-controlled cohort of patients with stage I to II NSCLC who underwent lobectomy (LOB) or SBRT., Materials and Methods: One hundred eighty-seven patients with clinical-stage T1a-T2bNoMO NSCLC were treated in 2 academic hospitals between August 2008 and May 2015. Patients underwent LOB or SBRT; those undergoing SBRT were sub-classified as surgical candidates and nonsurgical candidates, according to the presence of surgical contraindications or comorbidities., Results: In univariate analysis, no significant difference was found in local control between patients who underwent SBRT and LOB, with a trend in favor of surgery (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.07-1.01; P < .053). Univariate analysis showed that overall survival (OS) was significantly better in patients who underwent LOB (HR, 0.44; 95% CI, 0.23-0.85) with a 3-year OS of 73.4% versus 65.2% for surgery and radiation therapy patients, respectively (P < .01). However, no difference in OS was observed between operable patients undergoing SBRT and patients who underwent LOB (HR, 1.68; 95% CI, 0.72-3.90). Progression-free survival was comparable between patients who underwent LOB and SBRT (HR, 0.61; P = .09)., Conclusion: SBRT is a valid therapeutic approach in early-stage NSCLC. Furthermore, SBRT seems to be very well-tolerated and might lead to the same optimal locoregional control provided by surgery for patients with either operable or inoperable early-stage NSCLC., (Copyright © 2018 Elsevier Inc. All rights reserved.)