New insight on the interaction between the immune system and tumor has identified the programmed death-1/programmed death-1 ligand pathway to be a key player in evading host immune response. The ...immune checkpoint modulator, nivolumab (BMS-936558/ONO-4538), is the first PD-1 inhibitor to gain regulatory approval, for the treatment of patients with unresectable melanoma. This review will discuss results from early phase studies of nivolumab in solid tumors including non-small cell lung cancer (NSCLC) as well as studies of nivolumab in combination with chemotherapy, other immune modulators and molecular targeted therapy in patients with NSCLC.
Highlights • 3rd generation EGFR TKIs are T790M selective with minimal inhibition in WT EGFR. • The 3rd generation EGFR TKIs are highly active and are well tolerated. • Acquired resistance to 3rd ...generation EGFR TKIs include EGFR C797S mutation. • A new class of EGFR TKI has increased CNS penetration with promising CNS activity.
In this study, we report the successful demonstration of an intermediate-frequency-over-fiber (IFoF)-based radio access network (RAN) for 28 GHz millimeter-wave (mmWave)-based 5G mobile ...communication. In order to increase the network coverage of the mmWave-based 5G networks, we propose a distributed antenna system (DAS) that uses the IFoF technology. An IFoF-based DAS with 2 × 2 multiple-input multiple-output (MIMO) configuration was deployed in the PyeongChang area to provide 5G trial demonstration during the Winter Olympics. 5G trial services such as high-speed data transfer and autonomous vehicle driving were offered to the public through the IFoF-based DAS. A downlink throughput of ~1 Gb/s and uplink throughput of ~200 Mb/s were achieved in the DAS-deployed area. We also present an IFoF-based 5G mobile fronthaul that can overcome the bandwidth bottleneck in RANs. We performed real-time transmission of mmWave-based 5G wireless access networks using the IFoF-based mobile fronthaul. The real-time downlink throughput achieved per 5G terminal was approximately 9 Gb/s, when using a 4 × 4 MIMO configuration. An outdoor demonstration was performed to verify the technical feasibility of the 5G fronthaul based on IFoF technology. When moving the 5G terminal between remote radio heads at a speed less than 60 km/h, 5G mobile broadband services could be provided with real-time throughput more than 5 Gb/s. Thus, we confirmed that the IFoF technology was capable of supporting RANs for mmWave-based 5G networks and providing real-time multi-Gb mobile services.
•Acquired resistance to EGFR targeted therapy can be EGFR-dependent or independent.•Third-generation EGFR TKIs are in various stages of clinical development.•Plasma detection of T790M resistance ...mutation enables serial monitoring.•Integration of immune checkpoint inhibitors in EGFR-mutant patients is controversial.
The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research.
We demonstrate 4 × 4 multiple-input and multiple-output (MIMO) supporting mmWave-based indoor 5G mobile network based on a distributed antenna system (DAS) that has over-the-air interface to receive ...the broadband wireless signal from, e.g., remote radio head (RRH) of mobile fronthaul. To realize the cost/bandwidth-efficient and low-latency-inducing indoor 5G DAS network, we exploit the radio-over-fiber (RoF) system that is based on the intermediate frequency-over-fiber (IFoF) technology. To be more specific, we make simultaneous use of wavelength- and frequency-division multiplexing in the IFoF link so as to transport 4 × 4 MIMO 5G signal of which the bandwidth is effectively 3.2 GHz (= 4 × 800 MHz, where each antenna deals with 800 MHz 5G signal). The 4 × 4 MIMO-supporting IFoF link has error vector magnitude (EVM) performance of <; 4.5% at all channels of downlink and uplink for up to 2 km. The whole RoF system, exploiting the IFoF link, mmWave frequency conversion module, and control /management plane, proves itself to meet the 3GPP-defined EVM requirement (i.e., 8%) at all channels. Based on the RoF system, we demonstrate the indoor 5G DAS network in conjunction with Korea Telecom 5G mobile network, i.e., 5G baseband unit and RRH, investigating the downlink and uplink throughputs. We achieve ~4 Gb/s total throughput for end user, where the additional latency induced by the DAS network is only a few hundreds of nanoseconds other than the single mode fiber transmission delay.
Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, ...strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC.
Abstract Advances in the understanding of the role of the immune system in tumor immunosurveillance have resulted in the recognition that tumors can evade immune destruction via the dysregulation of ...co-inhibitory or checkpoint signals. This has led to the development of a generation immunotherapeutic agents targeting the immune checkpoint pathway. Recent early phase studies of immune checkpoint modulators, such as CTLA-4, PD-1 and PD-L1 inhibitors in NSCLC have reported promising results with prolonged clinical responses and tolerable toxicity. This article provides an overview of co-stimulatory and inhibitory molecules that regulate the immune response to tumors, recent therapies that have been developed to exploit these interactions and the role of predictive biomarkers in treatment selection.
The interest in combining radiation therapy (RT) with immunotherapy is increasing. We investigated the significance of lymphopenia in patients receiving immunotherapy for non-small cell lung cancer ...(NSCLC), and the factors associated with treatment-related lymphopenia, with particular emphasis on RT.
In this retrospective single institution study, 268 patients with advanced NSCLC received immunotherapy, of whom 146 received RT. Lymphopenia was defined as an absolute lymphocyte count <1000 cells/mm.
Patients were divided into 2 groups depending on the presence of peri-immunotherapy lymphopenia at the start of immunotherapy or during immunotherapy.
At median 6.4 months of follow-up, patients with peri-immunotherapy lymphopenia (n = 146; 54.5%) showed significantly poorer progression-free survival (PFS) (median PFS: 2.2 vs 5.9 months, P < .001) and overall survival (OS) (median OS: 5.7 vs 12.1 months, P < .001). On multivariate analysis, peri-immunotherapy lymphopenia remained a significant prognostic factor for both PFS and OS. RT significantly increased peri-immunotherapy lymphopenia with an odds ratio (OR) of 1.91 (P = .025). Factors associated with the development of RT-associated lymphopenia included multiple courses (OR, 3.78; P < .001), multiple irradiated sites (OR, 4.77; P = .018), and higher dose (≥50 Gy) (OR, 3.75; P = .004). Conversely, stereotactic body RT/radiosurgery reduced the risk (OR 0.21; P = .002).
Lymphopenia was indicative of poor prognosis in NSCLC patients receiving immunotherapy and was significantly associated with more intensive RT. Choosing appropriate RT regimens and techniques may be essential in reducing lymphopenia. Promising results are expected in the era of precision RT.
Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase ...inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.
At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma ...kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months’ follow-up (cutoff December 1, 2017).
Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant.
Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib.
Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.
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