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Background: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. Methods: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. Results: PD-1 positive (+) was significantly associated with current smoking status ( P =0.02) and with the presence of KRAS mutations ( P =0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology ( P =0.005) and with presence of EGFR mutations ( P =0.001). In patients treated with EGFR tyrosine kinase inhibitors ( N =95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P =0.01) time to progression (TTP: P <0.0001) and survival (OS: P =0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative ( P =0.01). Conclusions: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Background: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. Methods: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. Results: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model ( n =4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%). Conclusion: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

The efficacy of temozolomide strongly depends on O 6 -alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m 2 /daily for 21 days every 28 days until disease progression. O 6 -methyl-guanine-DNA-methyl-tranferase ( MGMT ) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31–71) with a median KPS of 90 (range 60–100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18–51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.

Background: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). Methods: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. Results: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. Conclusion: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mgday −1 ) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1–36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2–104+) weeks and PFS-6 was 14.3% (95% CI 4.0–32.7%). The median overall survival was 24.6 weeks (range 4–104+). No grade 3–4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

High levels of serum and/or plasma circulating DNA (cDNA) have been described in patients with systemic autoimmune diseases (SADs). However, the role of this molecule has not been clarified. Our aim was to evaluate plasma cDNA levels in 48 systemic lupus erythematosus (SLE) and 44 primary Sjögren’s syndrome (SS) patients, as compared with healthy and rheumatoid arthritis (RA) subjects, and to analyse their correlation with disease activity, disease damage and clinical manifestations. Plasma DNA was extracted using Qiagen columns and quantified by real-time quantitative PCR. Disease activity and damage were evaluated in both diseases by analysis of clinical and laboratory findings. Our results showed that plasma cDNA levels were significantly higher in patients with SS (mean ± SE: 32.0 ± 7.3 ng/ml) and with SLE (35.0 ± 9.0 ng/ml) than in controls (5.1 ± 1.1 ng/ml) (p < 0.0001 for both). Disease activity index correlated with cDNA levels in SS (p = 0.02), but not in SLE, and SS subjects with active disease displayed significantly higher cDNA levels with respect to inactive patients (p < 0.05). No correlation was found between plasma cDNA levels and disease damage indexes in either SLE or SS. These results indicate that increased plasma cDNA levels can been demonstrated in SLE and in SS patients with respect to healthy subjects. Interestingly, although cDNA levels did not correlate with indexes of disease damage in these disorders, a significant correlation between cDNA concentrations and disease activity was observed in SS, but not in SLE, suggesting a possible role of cDNA as non-invasive marker of disease activity. The different results obtained in these SADs may be explained by distinct disease pathogenesis or the influence of immunosuppressive and corticosteroid therapy that, unlike in SS, is usually employed in SLE.

Background We present a comprehensive analysis of KRAS , PIK3CA , MET, and non-sensitizing EGFR mutations in advanced non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs), with the aim of clarifying the relative contribution of these molecular alterations to resistance. Patients and methods One hundred and sixty-six patients with advanced NSCLC treated with EGFR-TKIs with available archival tissue specimens were included. EGFR (exons 18–21), KRAS (exons 2, 3), PIK3CA (exons 9, 20), and MET (exons 14, 15) mutations were analyzed using PCR-based sequencing. Among all the mutations evaluated, only KRAS , PIK3CA , MET, and non-sensitizing EGFR mutations, defined as “TKI non-sensitizing mutations” were used for response, time to progression (TTP), and overall survival (OS) analysis. Results TKI non-sensitizing mutations were associated with disease progression ( p  = 0.001), shorter TTP ( p  < 0.0001), and worse OS ( p  = 0.03). Cox’s multivariate analysis including histology and performance status showed that TKI non-sensitizing mutations were independent factors for shorter TTP ( p  < 0.0001) and worse OS ( p  = 0.01). Conclusions When KRAS , PIK3CA , MET, and non-sensitizing EGFR mutations are concomitant, up to 96.0% of NSCLC patients unlikely to respond to TKIs can be identified, and they represented independent negative prognostic factors. Comprehensive molecular dissection of EGFR signaling pathways should be considered to select advanced NSCLC patients for TKIs therapies.

Lung Squamous Cell Carcinoma (SCC) is a Non-Small Cell Lung Cancer (NSCLC) subtype with a strong clinical association with smoking habits and a very low incidence in never-smokers. Molecular profiling of SCC in never-smokers could unveil tumor vulnerabilities and new treatment strategies. We considered a patient cohort of 17 former or current smokers (51.5%) and 16 never-smoker SCC patients (48.5%). TruSight Oncology 500, investigating hotspots in 523 cancer-related genes, Tumor mutation burden (TMB) and microsatellite instability (MSI), and RNA sequencing was performed on tumor tissue. Genomic and transcriptomic profiles were compared between smokers and never-smoker patients. The most frequently altered genes were (67%), (20%) and (17%), with no substantial differences between groups, except for which was more frequently mutated in smokers (86.7% vs 46.7%, p = 0.05), who also showed a higher TMB with respect to non-smokers (median 11 mut/Mb vs 5.5 mut/Mb, p = 0.028); all patients were stable for MSI score (median 1.87 vs 1.82, p = 0.87). Activating mutations in and were found in one and two never-smokers, respectively. Three smoker patients had simultaneous amplifications in and . Enrichment analyses showed that cyclin-dependent protein Ser/Thr kinase activity and PI3K signaling pathways were affected in both groups, while cellular damage response was exclusively altered in never-smokers. Unsupervised hierarchical clustering on transcriptomes effectively identified different specific transcriptional subtypes between smokers and never-smokers. Gene set enrichment analysis highlighted that tumors from never-smokers are characterized by dysregulation in cell membrane potential and ion homeostasis across cell membrane pathways. Genomic and transcriptomic profiles deeply differentiate SCC occurring in never-smokers with respect to SCC in smoker patients. Moreover, SCC could carry canonical NSCLC) activating mutations. Our data suggest that deep molecular analyses resolve tumor heterogeneity and may help with new algorithm-based treatment strategies for SCC.

Everolimus, an mTOR inhibitor, which has been demonstrated to induce anti‐tumour effects in different types of neuroendocrine tumours, has never been evaluated in patients with medullary thyroid cancer (MTC). The aim of this study was to evaluate the in vitro and in vivo effects of everolimus in combination with octreotide in MTC. Two patients with progressive metastatic MTC and high calcitonin levels were treated with everolimus 5–10 mg/day. Both patients were under treatment with octreotide LAR at the study entry. An in vitro study was also performed to assess everolimus effects on MTC cell lines (TT and MZ‐CRC‐1 cells). A tumour response was observed in both patients. Serum calcitonin decreased by 86% in patient 1 and by 42% in patient 2. In TT and MZ‐CRC‐1 cells, everolimus induced a significant dose‐dependent inhibition in cell proliferation. This effect seems to be related to a cell cycle arrest in G0/G1 phase in both cell lines and to the induction of cellular senescence in TT cells. Everolimus in combination with octreotide may be active as anti‐tumour therapy in patients with progressive metastatic MTC, suggesting to further evaluate this agent in MTC patients in a large prospective study.

Extensive stage Small-Cell Lung Cancer (ES-SCLC) is the most lethal lung cancer, and the addition of immunotherapy conferred a slight survival benefit for patients. Extensive molecular profiling of patients treated with chemotherapy (CT) or chemotherapy plus immunotherapy (CT+IO) would be able to identify molecular factors associated with patients' survival. In this retrospective study, 99 ES-SCLC patients were considered. Of the 79 includible patients, 42 received CT (median age 71 y/o, I-IIIQ: 65-76), and 37 received CT+IO (median age 71 y/o, I-IIIQ 66-75). The FoundationOne CDx assay was performed on patients' tumor tissues. The most mutated genes were (99%), (78%), (23%) and (20%), with no significant differences between the treatment groups. As a continuous variable, Tumor Mutation Burden (TMB) had an effect on patients' progression-free survival (PFS) by type of treatment (HR 1.81 (95%, CI: 0.99-3.31) and HR 0.84 (95%, CI: 0.56-1.26) for patients treated with CT and CT+IO, respectively). TMB was also computed and dichotomized using two different cut-offs: considering cut-offs of 10 mut/Mb and >16 mut/Mb, 45 patients (57%) and 68 patients (86.1%) had a low TMB, respectively. A high TMB (cut-off 10 mut/Mb) predicted worse PFS in patients treated with CT ( =0.046); even though not statistically significant, a high TMB (cut-off 16 mut/Mb) predicted a better survival in patients treated with CT+IO. Moreover, at univariate analysis, mutations were associated with better prognosis in the overall case series (HR = 0.51, 95% CI: 0.28-0.94), and overall survival (HR = 0.52, 95% CI: 0.28-0.97). In ES-SCLC, TMB is associated with worse survival in patients treated with CT alone, and with better survival in patients treated with CT+IO, whether considered as a continuous or a dichotomized variable, at different cut-offs. Alterations in epigenetic factors are also associated to better patient prognosis.