No abstract

clinicaltrials.gov Identifier: NCT00446225.

BackgroundThe increasing incidence and poor outcome associated with MPM requires finding effective treatment for this disease. PD1/PD-L1 pathway plays a central role in tumor immune evasion and appears to be predictive and prognostic marker. PD-L1 is expressed in many different human cancers but its role in MPM has yet to be established. The aim of this study is to evaluate the expression of PD-L1 in MPM.Methods119 MPM patients (p) from two institutions between November 2002 and February 2014 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained with anti-PD-L1 (clone E1L3N). Cases showing more than 1% of tumor cells expression of PD-L1 were considered positive.ResultsPD-L1 was analyzed in 77 p with tumor tissue available and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 4 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was a significant relationship between PD-L1 expression and histology (PD-L1 expression 37.5% in no-epithelioid tumor and 13.2% in epithelioid; p=0.033). The median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012).ConclusionsWe have shown PD-L1 is expressed in 20% of patients, associated with no epithelioid histology and poor prognostic in MPM. Our results suggest PD-L1 warrants further exploration in selecting p for immunotherapy.

Introduction: There is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. Methods:We performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line-and patientderived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti-EGFR therapy-treated adenocarcinoma. Results:We have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor-treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line-and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. Conclusion:These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.

BackgroundThe immune surveillance reactivator lefitolimod (MGN1703), a DNA-based TLR9 agonist, might foster innate and adaptive immune response and thus improve immune-mediated control of residual cancer disease. The IMPULSE phase II study evaluated the efficacy and safety of lefitolimod as maintenance treatment in extensive-stage small-cell lung cancer (ES-SCLC) after objective response to first-line chemotherapy, an indication with a high unmet medical need and stagnant treatment improvement in the last decades.Patients and methods103 patients with ES-SCLC and objective tumor response (as per RECIST 1.1) following four cycles of platinum-based first-line induction therapy were randomized to receive either lefitolimod maintenance therapy or local standard of care at a ratio of 3 : 2 until progression or unacceptable toxicity.ResultsFrom 103 patients enrolled, 62 were randomized to lefitolimod, 41 to the control arm. Patient demographics and response patterns to first-line therapy were balanced. Lefitolimod exhibited a favorable safety profile and pharmacodynamic assessment confirmed the mode-of-action showing a clear activation of monocytes and production of interferon-gamma-induced protein 10 (IP-10). While in the intent-to-treat (ITT) population no relevant effect of lefitolimod on progression-free and overall survival (OS) could be observed, two predefined patient subgroups indicated promising results, favoring lefitolimod with respect to OS: in patients with a low frequency of activated CD86+ B cells (hazard ratio, HR 0.53, 95% CI: 0.26–1.08; n = 38 of 88 analyzed) and in patients with reported chronic obstructive pulmonary disease (COPD) (HR 0.48, 95% CI: 0.20–1.17, n = 25 of 103).ConclusionsThe IMPULSE study showed no relevant effect of lefitolimod on the main efficacy end point OS in the ITT, but (1) the expected pharmacodynamic response to lefitolimod, (2) positive OS efficacy signals in two predefined subgroups and (3) a favorable safety profile. These data support further exploration of lefitolimod in SCLC.