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Non─small cell lung cancer (NSCLC) presents different druggable genetic abnormalities, including ROS1 and ALK rearrangements, which share relevant clinical features and therapeutic strategies. The homology between the tyrosine kinase domains of ROS1 and ALK defines unique subsets of patients highly sensitive to targeted tyrosine kinase inhibitors (TKIs). Genomic profiling in advanced NSCLC is standard, immunohistochemistry and fluorescence in situ hybridization being the main techniques used to detect genomic rearrangements. Personalized treatment with TKIs in ROS1- and ALK-positive NSCLC patients has dramatically improved patients' outcomes. Crizotinib has been the first-line standard of care treatment in ALK-rearranged NSCLC patients for a long time, while crizotinib still represents the best upfront therapeutic option in ROS1-positive NSCLC patients, followed by next-generation TKIs at the time of disease progression. However, the improved intracranial efficacy of next-generation TKIs has led to these drugs becoming first-line options, widening treatment opportunities for these patients. Since all patients will develop disease progression under TKI therapy, understanding the mechanisms of acquired resistance is crucial to define the optimal sequential therapeutic strategy. Despite the positive correlation between personalized treatment and patients' outcome, access to next-generation TKIs and genomic profiling at the time of disease progression are major challenges to achieving this goal. In this review, we present updated evidence on ROS1- and ALK-rearranged NSCLC regarding epidemiology and diagnostics, current therapies and the most suitable sequential treatment approaches, as well as mechanisms of acquired resistance and strategies to overcome them.

Giving the potential contribute in cancer initiation and progression, lung microbiota represents a promising topic in cancer research, although still unexplored. We performed a systematic literature search to identify clinical studies evaluating lung microbiota composition, its correlation with lung cancer patients' clinico-pathological features and prognosis. Of the identified 370 studies, 21 were eligible and included. Although studies were heterogeneous, lung cancer resulted to be enriched in peculiar microbial communities, with differences in composition and diversity according to clinico-pathological parameters. Few studies explored how lung microbiota influences cancer outcome. In light of these findings and borrowing the suggestions coming from gut microbiota, we speculate that respiratory microbiome may influence pathogenesis, progression and outcome of lung cancer. Taking advantage of the experience of chronical lung diseases, prospective studies should be designed to evaluate lung microbiota changes throughout any phase of lung cancer course, particularly with the advent of immunotherapy as pivotal treatment.

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.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.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%).Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking.

Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4–6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castration-resistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on new-generation hormonal therapies. Severalin vitrostudies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.

Objectives We previously reported that quality of life (QoL) is not included among trial endpoints and QoL results are underreported in a significant proportion of phase III oncology trials. Here we describe QoL adoption, reporting and methodology of QoL analysis in lung cancer trials. Materials and methods We selected all primary publications of lung cancer phase III trials assessing anticancer drugs published between 2012 and 2018 by 11 major journals. Results 122 publications were included. In 39 (32.0%) publications, QoL was not listed among endpoints: in 10/17 (58.8%) early stage/locally advanced NSCLC, in 15/54 (27.8%) first-line of advanced NSCLC; in 10/41 (24.4%) second and further lines of advanced NSCLC, in 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012–2015 vs. 30.6% in 2016–2018. Out of 83 trials including QoL among endpoints, QoL results were absent in 36 primary publications (43.4%). Proportion of trials without QoL results in primary publication increased over time (30.6% 2012–2015 vs. 61.8% 2016–2018, p = 0.005). Overall, QoL data were not available in 75/122 (61.5%) primary publications, due to the absent endpoint or unpublished results. QoL data were lacking in 48/68 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement comparing 2012–2015 vs. 2016–2018. Conclusion QoL is not assessed or published in many phase III lung cancer trials, a setting where QoL value should be highly considered, due to high symptom burden and generally limited life expectancy. Timely inclusion of results in primary publications is worsening in recent years.

Background In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. Methods We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. Results Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. Conclusions QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.

Background aMM still represents a hard-to treat disease, due to its rarity and to the modest activity of standard chemotherapy. Recently, ICIs directed against PD-1/PD-L1 have been tested in clinical trials in chemotherapy pre-treated aMM patients, but their efficacy is still debatable. Methods We searched PubMed and proceedings of major meetings, to perform a systematic review and meta-analysis (updated at September 30th 2019) of clinical trials testing ICIs in this setting, describing activity in terms of Objective Response Rate (ORR) and Disease Control Rate (DCR). To explore the potential predictive role of PD-L1 expression, we also collected the ORR in subgroups of patients selected for PD-L1 expression (based on the highest cut-off used in each study). Results 8 studies were selected (1 phase III, 4 phase II, 2 phase IB, 1 real-world EAP data study), including 405 patients, most with pleural MM; 1 registry study was excluded due to inclusion of treatment-naive patients, 1 due to unclear inclusion criteria. 352 patients (87%) were treated with anti-PD-1 (nivolumab [N] or pembrolizumab [P]), 53 (13%) with anti-PD-L1 (avelumab [A]). Overall, ORR was 19.6% (95% CI, 16.0-23.8%) with no significant difference among drugs (N 20.0%, P 22.6%, A 9.4%; p = 0.11); DCR was 56.5% (95% CI, 51.6-61.3%) with no significant difference among drugs (N 54.0%, P 58.7%, A 58.5%; p = 0.66). When restricting the analysis to patients selected for PD-L1 expression (n evaluable=91, based on cut-offs ranging from 1% to 50% in different trials), ORR was 34.1% (95% CI, 25.2-44.3%), ranging from 18.8% to 71.4% in different trials. In unselected patients, median progression-free survival ranged from 2.5 to 6.1 months, and median overall survival ranged from 6.36 to 17.3 months. Conclusion To our knowledge, this is the first meta-analysis synthesizing the evidences of activity of PD-1/PD-L1 ICIs in pre-treated aMM. ORR and DCR in unselected patients are encouraging compared to historical results with second-line chemotherapy. Selection based on PD-L1 expression could increase the activity of immunotherapy, but trials were heterogeneous for test and cut-off. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Tagliamento: Travel / Accommodation / Expenses: Takeda, Bristol-Myers Squibb, Roche. P. Bironzo: Honoraria (self): Bristol-Myers Squibb, BI, AstraZeneca. E. Capelletto: Advisory / Consultancy: BI, AstraZeneca. S. Novello: Speaker Bureau / Expert testimony: AstraZeneca, Abbvie, Celgene, BI, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, Roche. M. Di Maio: Honoraria (self): Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Janssen, Takeda, Pfizer; Honoraria (institution): Tesaro. All other authors have declared no conflicts of interest.

Quality of life (QoL) is a relevant end point and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an end point in cancer phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of under-reporting and delay of publication. All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about end points was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed. In total, 446 publications were eligible. In 210 (47.1%), QoL was not included among end points. QoL was not an end point in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory end point, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as end point or with missing QoL results was relevant in all tumor types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years, respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials. QoL is not included among end points in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant under-reporting and delay in publication.

Androgen deprivation therapy (ADT) is the mainstay of treatment of patients with relapsed or metastatic hormone-sensitive prostatic carcinoma. The dramatic reduction of serum testosterone levels induced by ADT produces multiple side effects as vasomotor flushing, sexual dysfunction, fatigue, impairment of cognitive function, reduced quality of sleep, gynecomastia and anemia, that are able to decrease health-related quality of life (QoL). In addition, hormonal therapy can interfere with bone metabolism and induce metabolic and cardiovascular complications. Recently, new-generation hormonal therapies, such as abiraterone and enzalutamide, have been tested and approved in castration resistant prostatic cancer patients and current studies are moving forward to the earlier use of these two drugs. In this evolving scenario, the management of hormonal therapy toxicity, given the long duration of treatment and the potentially high impact of side effects on patients' functional status and quality of life, is a critical challenge for clinicians. A correct information of patients before the initiation of treatment, together with the adoption of preventive measures, could help to ameliorate their quality of life. The aim of this review is to describe the impact on quality of life of endocrine treatment side effects and analyze possible interventions to alleviate them.

Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy-induced neutropenia and survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line docetaxel.Metastatic castration-resistant prostate cancer patients treated with first-line docetaxel, with known neutrophils value 10 days after first administration, were included in this retrospective analysis. Neutropenia was categorized in Grade 0 to 1 (G0-1), Grade 2 to 3 (G2-3), and Grade 4 (G4). Outcome measures were progression-free survival (PFS) and overall survival (OS).Eighty patients were analyzed. Median PFS was 5.4 months in patients with G0-1 neutropenia, 6.9 months with G2-3 neutropenia (hazard ratio [HR] vs. G0-1, 0.69; 95% confidence interval [CI], 0.35-1.35; P = .27) and 9.5 months with G4 neutropenia (HR vs. G0-1, 0.30; 95% CI, 0.16-0.57; P .0001). Median OS was 11.6 months in patients with G0-1 neutropenia, 25.5 months in patients with G2-3 neutropenia (HR vs. G0-1, 0.36; 95% CI, 0.16-0.80; P = .012) and 39.3 months in patients with G4 neutropenia (HR vs. G0-1, 0.19; 95% CI, 0.09-0.41; P .0001). In multivariate analysis, the occurrence of severe neutropenia showed a statistically significant association with OS (HR G4 vs. G0-1, 0.14; 95% CI, 0.03-0.67; P = .013; HR G2-3 vs. G0-1, 0.42; 95% CI, 0.11-1.57; P = .20) and PFS (HR G4 vs. G0-1, 0.28; 95% CI, 0.09-0.86; P = .03; HR G2-3 vs. G0-1, 1.07; 95% CI, 0.38-2.96; P = .90).Docetaxel-induced neutropenia is associated with better survival of mCRPC.

In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials. Simultaneously other therapeutic strategies which recruit an adaptive immune response against tumoral antigens or employ externally manipulated tumor infiltrating lymphocytes might change the natural history of bladder cancer in the near future. This review describes the rationale for the use of immunotherapy in bladder cancer and discusses recent and ongoing clinical trials with checkpoint inhibitors and other novel immunotherapy agents.

219 Background: We previously reported that QoL is not included among endpoints and QoL results are significantly underreported in a high proportion of recently published phase III trials in oncology. In this study our aim was to describe QoL prevalence and heterogeneity in QoL reporting in prostate cancer (PC) phase III trials. Methods: Whole database included all primary publications (P) of phase III trials evaluating anticancer drugs published between 2012 and 2016 by 11 major journals. For this analysis, we extracted the subset of PC trials. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis. Results: 35 P were identified (21 in castration-resistant [CRPC], 9 in advanced hormone sensitive [aHSPC], incl. both metastatic and biochemical relapsed, and 5 in earlier stages). In 13 (37.1%) QoL was not listed among study endpoints: 7/21 (33.3%) in CRPC, 3/9 (33.3%) in aHSPC, and 3/5 (60%) in earlier stages. Out of 22 primary P of trials including QoL among endpoints, QoL results were not reported in 9 (40.9%). Overall, no QoL data were available in 22/35 (62.9%) primary P (61.9% in CRPC, 44.4% in aHSPC and 100% in earlier disease). QoL data were not available in 15/25 (60%) trials with overall survival (OS) as primary endpoint, and in 7/10 (70%) trials with other primary endpoints. QoL data were not available in 7/16 (43.8%) trials with a positive result (25% in CRPC, 40% in aHSPC, 100% in earlier stages). In 18 trials with available QoL results (incl. secondary publications), most common QoL tools were FACT-P (11, 61.1%) and EORTC QLQ-C30 (6, 33.3%). Common methods of analysis were mean changes (6, 33.3%), mean scores over time (6, 33.3%), time to deterioration (6, 33.3%) and proportion of responders (3, 16.7%). QoL analysis was focused on the impact of toxicity in 10 cases (mostly in earlier stages), and on disease symptoms in 10 cases (mostly in CRPC). Conclusions: QoL is absent in a high proportion of recently published phase III trials in PC, although presence of QoL results is better in positive trials, especially in CRPC. Methodology of QoL analysis is heterogeneous in terms of type of instruments, analysis and presentation of results.

The increasing knowledge of the genomic landscape of hepatocellular carcinoma (HCC) and the development of molecular targeted therapies are a promising background for increasing the number of effective drugs for HCC patients. In recent years, many new drugs have been tested as an alternative to sorafenib or after sorafenib failure.In this review, our aim is to describe the randomized trials recently conducted in HCC patients, in order to understand the main reasons potentially related to the failures of many drugs. In addition, we briefly describe the main ongoing trials, that could potentially change the scenario of HCC treatment in the next years. Expert commentary: Heterogeneity of study populations, lack of understanding of critical drivers of tumor progression, risk of liver toxicity associated with experimental agents, flaws in trial design and marginal antitumoral potency can be considered the main reasons for failure of phase III clinical trials in HCC. Most ongoing trials are conducted without any molecular selection criteria, although many drugs could be probably better tested in a molecularly selected population. The knowledge of potential predictive factors for drug efficacy in patients with advanced HCC could improve the chance of obtaining positive results in clinical trials.

e18719Background: QoL assessment is relevant to evaluate benefit/risk ratio of cancer therapies and it is formally included in ASCO and ESMO scales of treatment value. However, its use as an endpoi...