The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an ...issue for clinical research.
Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed.
Twenty trials (1,475 patients) were identified. A significant interaction (p<0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% (95% CI 27.6-41.3%) in the PD-L1 positive and 19.9% (95% CI 15.4-25.3%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4% and 19.5%, respectively. A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer.
Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.
Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, ...but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% 95·9% CI 21·9–43·1) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Funding Merck KGaA, Darmstadt, Germany.
The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In ...recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME's elements and their implications in cancer immunotherapy.
Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, ...recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.
In this review, we highlighted and discussed current knowledge about the role of Rictor in development and progression of cancer focusing on the major mechanisms that drive its dysregulation in ...malignancies.
Abstract
Genomic alterations affecting components of the mechanistic target of rapamycin (mTOR) pathway are found rather frequently in cancers, suggesting that aberrant pathway activity is implicated in oncogenesis of different tumor types. mTOR functions as the core catalytic kinase of two distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which control numerous vital cellular processes. There is growing evidence indicating that Rictor, an essential subunit of the mTORC2 complex, is inappropriately overexpressed across numerous cancer types and this is associated with poor survival. To date, the candidate mechanisms responsible for aberrant Rictor expression described in cancer are two: (i) gene amplification and (ii) epigenetic regulation, mainly by microRNAs. Moreover, different mTOR-independent Rictor-containing complexes with oncogenic role have been documented, revealing alternative routes of Rictor-driven tumorigenesis, but simultaneously, paving the way for identifying novel biomarkers and therapeutic targets. Here, we review the main preclinical and clinical data regarding the role of Rictor in carcinogenesis and metastatic behavior as well as the potentiality of its alteration as a target.
To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).
We conducted a systematic review and meta-analysis of the prevalence ...of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (
,
,
,
,
,
,
, and the
genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline
mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813).
Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was
: 0.9%,
: 3.5%,
: 0.2%,
: 2.2%,
: 0.3%,
: 0.5%,
: 0.0%, and
: 0.1%. Prevalence of germline mutations was
: 0.9% (2.4% in AJ),
: 3.8% (8.2% in AJ),
: 0.2%,
: 2%,
: 0.3%, and
: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD).
Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.
Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic ...approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker.
The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and ...pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.
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