Search

Introduction Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC). Methods Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response. Results High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P Conclusion Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are the standard treatment for advanced ALK-positive non-small cell lung cancer (NSCLC) allowing survivals up to 5 years. However, duration of responses is limited by the almost certain occurrence of drug resistance. Here, we report a case of a never smoker, 59-year-old female with metastatic ALK-positive adenocarcinoma, solid and signet ring patterns, who developed resistance to alectinib, a second-generation ALK-TKI, mediated by HER2 gene amplification. The patient received 22 months of crizotinib as first-line and subsequently 1-year of alectinib therapy. A study of resistance mechanism was performed with next generation sequencing (NGS) on tissue re-biopsy. A HER2-amplified emerging clone was identified by NGS in a liver metastasis and confirmed by fluorescent in situ hybridization (FISH) analysis. The resistant clone was detectable 2 months before disease progression in plasma cell-free DNA (cfDNA) using digital droplet PCR (ddPCR) copy number variation (CNV) assay and it was retrospectively traced in rare cells of the lung primary by FISH. To our best knowledge, this is first evidence of HER2 gene amplification as a resistance mechanism to ALK-TKI in a NSCLC. Future strategies against oncogene-addicted NSCLC might benefit of combined drug treatments, such as ALK and HER2 inhibition.

Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation in advanced EGFR-mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance.Forty patients with advanced NSCLC receiving osimertinib for T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed.Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA [2200 copies/mL or allele frequency (AF)6.1%] showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable EGFR mutations in plasma (shedders) presented worse outcome than negative subjects (non-shedders). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation.The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms.

Aim: This prospective study aimed to envisage the putative prognostic significance of clinical and hematologic parameters in advanced non-small-cell lung cancer patients treated with nivolumab. Materials & methods: Correlations of several parameters with disease control and survival outcomes were provided. Results: A total of 54 patients were included. An ECOG performance status 0–1, the lack of liver and bone metastases and a timeframe from the last systemic treatment ≥4 months correlated with better disease control. The same was observed for baseline low levels of white blood cells and neutrophils, for high levels of NK cells and a neutrophil/lymphocyte ratio

50 Background: hypovitaminosis D is frequent in renal diseases but it was never reported in metastatic renal cell carcinoma (mRCC). The interaction between vitamin D and its receptor (VDR) has a key role for T-cell activation. Naïve T-cells do not express VDR and had very low expression of phospholipase C-γ1 (PLC-γ1), with low responsiveness to T-cell receptor (TCR). Initial TCR signaling induces VDR expression and upregulates PLC-γ1 via the kinase p38 pathway. VDR interaction with high concentrations of vitamin D and PLC-γ1 increase are required to trigger classical TCR signaling, increasing T-cell responsiveness. On these basis, we hypothesized that hypovitaminosis D could contribute to lower responsiveness to immune-checkpoint inhibitors (CKI). Methods: we assessed vitamin D levels of mRCC patients undergoing therapy with CKI, with the aim to reveal hypovitaminosis D, evaluate its prevalence and hypothesize its potential role in the outcome of treatment with CKI. Results: of 10 mRCC patients pretreated with tyrosine-kinase inhibitors, vitamin D levels assessed before the first treatment with nivolumab (anti-PD1 CKI) revealed deficiency in 80% of cases (8 patients). Hypovitaminosis D was severe ( < 20 ng/ml) in 7 cases and moderate ( < 30 ng/ml) in one. The 2 patients without deficiency (20%), had vitamin D values near to the lower limit of normality. Oral supplementation with cholecalciferol was given when necessary, likely confounding the possible influence of vitamin D deficiency on the outcome of CKI treatment. Vitamin D normal values after two months of therapy were recovered in the great majority of cases. Interestingly, the only patient who achieved a good objective response to treatment had normal values of vitamin D before therapy. Conclusions: hypovitaminosis D could have a relevant prevalence in mRCC patients. Considering the role of vitamin D in T-cell activation, assessment of its levels and initiation of a supplementation before immunotherapy should be considered to enhance responsiveness. On the basis of these observations, we are planning a perspective multicenter study to investigate the role of hypovitaminosis D in mRCC patients treated with CKI (PRoviDenCe study).