Many patients with non-small cell lung cancer (NSCLC) derive poor benefit from immunotherapy (IO). For some of them, adding chemotherapy (CT) can improve the outcomes, but the reliability of ...programmed death-ligand 1 (PD-L1) expression as the only biomarker to distinguish these patients is unsatisfactory. We sought to detect clinicopathological and molecular predictive factors of survival that might be added to PD-L1 expression in the selection of patients who should receive IO alone or chemoimmunotherapy (CIT).
We conducted a systematic search of randomized controlled clinical trials investigating IO, alone or with CT, vs CT alone in treatment-naïve advanced NSCLC patients. Meta-analyses and meta-regression analyses were performed to investigate IO alone vs CT, CIT vs CT, and IO alone vs CIT.
A total of 14 367 patients with advanced NSCLC across 25 randomized controlled clinical trials were included. Squamous histology, male sex, current and former smoker status, PD-L1 expression of 50% or more, and high tumor mutational burden (TMB) correlated with improved survival with IO alone compared with CT. Conversely, female sex, no smoking history, negative PD-L1 expression, and low TMB correlated with unsatisfactory outcomes with IO alone vs CT but not with CIT vs CT. CIT improved survival vs IO alone in female patients, never smokers, those having a PD-L1 expression of 1% or more (but not with a PD-L1 of ≥ 50%) or a low TMB and in patients with central nervous system metastasis.
These findings suggest some clinicopathological and molecular features that, added to PD-L1 expression, could help in the selection of the most appropriate first-line IO-based treatment for advanced NSCLC patients.
The Xhaul architecture presented in this article is aimed at developing a 5G integrated backhaul and fronthaul transport network enabling flexible and software-defined reconfiguration of all ...networking elements in a multi-tenant and service-oriented unified management environment. The Xhaul transport network vision consists of high-capacity switches and heterogeneous transmission links (e.g., fiber or wireless optics, high-capacity copper, mmWave) interconnecting remote radio heads, 5G points of attachment (5GPoAs, e.g., macro- and small cells), centralized- processing units (mini data centers), and points of presence of the core networks of one or multiple service provider(s). This transport network shall flexibly interconnect distributed 5G radio access and core network functions, hosted on network centralized nodes, through the implementation of a control infrastructure using a unified, abstract network model for control plane integration (Xhaul Control Infrastructure, XCI); and a unified data plane encompassing innovative high-capacity transmission technologies and novel deterministic-latency switch architectures (Xhaul packet Forwarding Element, XFE). Standardization is expected to play a major role in a future 5G integrated front haul/backhaul architecture for multi-vendor interoperability reasons. To this end, we review the major relevant activities in the current standardization landscape and the potential impact on the Xhaul architecture.
Purpose of Review
In this review, we analyzed the current landscape of non-PD-(L)1 targeting immunotherapy.
Recent Findings
The advent of immunotherapy has completely changed the standard approach ...toward advanced NSCLC. Inhibitors of the PD-1/PD-L1 axis have quickly taken place as first-line treatment for NSCLC patients without targetable “driver” mutations. However, a non-negligible portion of patients derive modest benefit from immune-checkpoint inhibitors, and valid second-line alternatives are lacking, pushing researchers to analyze other molecules and pathways as potentially viable targets in the struggle against NSCLC.
Summary
Starting from the better characterized CTLA-4 inhibitors, we then critically collected the actual knowledge on NSCLC vaccines as well as on other emerging molecules, many of them in their early phase of testing, to provide to the reader a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 inhibitors.
Immune checkpoint inhibitors (ICIs), either alone or combined with chemotherapy, represent the cornerstone of the treatment of advanced non-small cell lung cancer (NSCLC) without targetable gene ...alterations. Programmed death ligand-1 expression currently represents the only available biomarker to predict response to ICI, although its reliability is debated. However, most patients still do not derive benefit from immunotherapy, making the identification of further predictive biomarkers extremely needed. Serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) and Kelch-like ECH-associated protein 1 (KEAP1) mutations occur in 25–30% and 11–27% of advanced NSCLC, respectively. Several studies associated their presence with poor outcomes in patients treated with ICI. However, more recent evidence showed poor outcomes among NSCLC with STK11/LKB1 and/or KEAP1 mutations regardless of the treatment received. We reviewed the literature to provide a comprehensive, timely and structured overview of the role of STK11/LKB1 and KEAP1 mutations in NSCLC. Although conflicting outcomes have been reported by studies evaluating their impact in KRAS wild-type patients or regardless of KRAS mutation, the correlation between STK11/LKB1 and KEAP1 mutations and poor outcomes with ICI appears to be consistent in presence of concurrent KRAS mutations. The main limitations of most studies are represented by the inclusion of other gene mutations (e.g. TP53) together with STK11 and KEAP1 mutations as a group and by the lack of comparison arms including patients who received other treatments (e.g. chemotherapy). Studies evaluating the impact of STK11 and KEAP1 mutations on the outcomes with ICI and other therapies showed a similar effect regardless of the treatment received, suggesting a prognostic, rather than predictive, value.
•STK11 and KEAP1 mutations were described as predictors of poor outcomes with ICI.•Poor outcomes are consistent among patients with concurrent KRAS mutation.•Less consistency exists if STK11 and KEAP1 are not associated with KRAS mutation.•Studies evaluating outcomes with ICI and other treatments showed a similar effect.•STK11 and KEAP1 mutations might be prognostic, not predictive, factors in NSCLC.
Background
The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer ...(NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting.
Objective
We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC.
Patients and methods
We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO–UMC system, a standardized probabilistic algorithm.
Results
Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizotinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as
highly probable
and 69.5% as
probable
. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%).
Conclusion
Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs.
Background
Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association ...of irAEs with outcomes in NSCLC treated with nivolumab are limited.
Methods and objectives
We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival.
Results
33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS 6.1 vs. 3.1 months, HR 0.68 95% CI (0.55–0.85);
p
= 0.001 and OS 14.9 vs. 7.4 months, HR 0.66 95% CI (0.52–0.82);
p
< 0.001) compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS HR 0.69, 95% CI (0.55–0.87);
p
= 0.002 and a trend for better OS HR 0.62, 95% CI (0.55–1.03);
p
= 0.057. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS 2.3 vs. 6.6 months, HR 1.74 95% CI (1.06–2.80);
p
= 0.02 and median OS 3.6 vs. 17.6 months; HR 2.61 95% CI (1.61–4.21);
p
< 0.001 compared to those that did not have permanent ICI discontinuation.
Conclusions
Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
This article proposes an innovative architecture design for a 5G transport solution (dubbed 5G-Crosshaul) targeting the integration of existing and new fronthaul and backhaul technologies and ...interfaces. At the heart of the proposed design lie an SDN/NFV-based management and orchestration entity (XCI), and an Ethernet-based packet forwarding entity (XFE) supporting various fronthaul and backhaul traffic QoS profiles. The XCI leverages widespread architectural frameworks for NFV (ETSI NFV) and SDN (Open Daylight and ONOS). It opens the 5G transport network as a service for innovative network applications on top (e.g., multi-tenancy, resource management), provisioning the required network and IT resources in a flexible, cost-effective, and abstract manner. The proposed design supports the concept of network slicing pushed by the industry for realizing a truly flexible, sharable, and cost-effective future 5G system.
Epidermal growth factor receptor (EGFR) gene mutations identify a molecularly defined subset of non-small cell lung cancer (NSCLC) patients who display an excellent sensitivity to EGFR tyrosine ...kinase inhibitors (TKIs). First-generation reversible EGFR TKIs, gefitinib and erlotinib have been proven to improve the objective response rate and to prolong the progression-free survival compared with standard chemotherapy in large phase III trials. Unfortunately, virtually all patients develop resistance to treatment, usually within 9–12 months. Afatinib is an irreversible ErbB family inhibitor initially designed to overcome the development of resistance. Compared with gefitinib in a first-line setting, afatinib prolonged progression-free survival and time to treatment failure, without impacting on overall survival in the general population of EGFR-mutant patients. However, afatinib has been shown to prolong overall survival in the subset of patients with an EGFR exon 19 deletion compared with chemotherapy. The aim of this review is to summarize the clinical evidence available to date and to critically discuss the place in therapy of afatinib in the rapidly expanding landscape of EGFR-mutant NSCLC first-line therapy.
Precision medicine has revolutionized the therapeutic management of cancer patients with a major impact on non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, where advances have ...been remarkable. Tissue biopsy, required for tumor molecular testing, has significant limitations due to the difficulty of the biopsy site or the inadequacy of the histological specimen. In this context, liquid biopsy, consisting of the analysis of tumor-released materials circulating in body fluids, such as blood, is increasingly emerging as a valuable and non-invasive biomarker for detecting circulating tumor DNA (ctDNA) carrying molecular tumor signatures. In advanced/metastatic NSCLC, liquid biopsy drives target therapy by monitoring response to treatment and identifying eventual genomic mechanisms of resistance. In addition, recent data have shown a significant ability to detect minimal residual disease in early-stage lung cancer, underlying the potential application of liquid biopsy in the adjuvant setting, in early detection of recurrence, and also in the screening field. In this article, we present a review of the currently available data about the utility and application of liquid biopsy in lung cancer, with a particular focus on the approach to different techniques of analysis for liquid biopsy and a comparison with tissue samples as well as the potential practical uses in early and advanced/metastatic NSCLC.
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