Pembrolizumab, an inhibitor of programmed cell death 1 (PD-1), produced responses in 24% of patients with non–small-cell lung cancer, with a median overall survival of 16.2 months. The response rate ...increased to 45% if more than 50% of tumor cells expressed the PD-1 ligand.
Lung cancer is the leading cause of cancer-related death worldwide.
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Platinum-based chemotherapy, with or without maintenance therapy and subsequently followed by second-line cytotoxic chemotherapy, is standard treatment for most patients with advanced non–small-cell lung cancer, with a median survival of approximately 1 year.
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One hallmark of cancer is immune evasion, in which the immune system does not mount an effective antitumor response.
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Programmed cell death 1 (PD-1) is a negative costimulatory receptor expressed primarily on the surface of activated T cells.
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The binding of PD-1 to one of its ligands, PD-L1 or PD-L2, can inhibit a cytotoxic . . .
Summary Background Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of ...pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. Methods We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0·00825 (one-sided) for the analysis of overall survival and a threshold of p<0·001 for progression-free survival. This trial is registered at ClinicalTrials.gov , number NCT01905657. Findings Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10·4 months with pembrolizumab 2 mg/kg, 12·7 months with pembrolizumab 10 mg/kg, and 8·5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio HR 0·71, 95% CI 0·58–0·88; p=0·0008) and for pembrolizumab 10 mg/kg versus docetaxel (0·61, 0·49–0·75; p<0·0001). Median progression-free survival was 3·9 months with pembrolizumab 2 mg/kg, 4·0 months with pembrolizumab 10 mg/kg, and 4·0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0·88, 0·74–1·05; p=0·07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0·79, 95% CI 0·66–0·94; p=0·004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14·9 months vs 8·2 months; HR 0·54, 95% CI 0·38–0·77; p=0·0002) and with pembrolizumab 10 mg/kg than with docetaxel (17·3 months vs 8·2 months; 0·50, 0·36–0·70; p<0·0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5·0 months vs 4·1 months; HR 0·59, 95% CI 0·44–0·78; p=0·0001) and with pembrolizumab 10 mg/kg than with docetaxel (5·2 months vs 4·1 months; 0·59, 0·45–0·78; p<0·0001). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 13% of 339 patients given 2 mg/kg, 55 16% of 343 given 10 mg/kg, and 109 35% of 309 given docetaxel). Interpretation Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection. Funding Merck & Co.
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the ...relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.
Address correspondence to Leonard P. Freedman, Global Biological Standards Institute, 1020 19th Street, NW, Suite 550, Washington, DC, 20036. E-mail: lfreedman@gbsi.org.
To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients.
...Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression.
The maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients.
The addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.
- With the abundance of therapeutics targeted against programmed death receptor-1 and its ligand (PD-L1) that are currently approved or in clinical development, there is interest in identifying those ...patients most likely to respond to these drugs. Expression of PD-L1 may be an indicator of an initial and robust inflammatory response to the presence of tumor cells. Therefore, tumors that express PD-L1 may be the most likely to respond to therapies that interrupt the negative feedback mechanism that leads to PD-L1 upregulation.
- To develop a prototype immunohistochemistry assay using the anti-PD-L1 antibody clone 22C3.
- The assay was developed and optimized using commercially available reagents and archival tumor-bank tissue.
- The optimized immunohistochemistry method had high precision and reproducibility. Using the prototype assay in 142 non-small cell lung cancer and 79 melanoma archival tumor-bank tissue samples, PD-L1 staining was observed at the plasma membrane of nucleated tumor and nontumor cells and, in some cases, as a distinct lichenoid pattern at the tumor-stroma border. Using a preliminary scoring method, 56% (80 of 142) of non-small cell lung cancer and 53% (42 of 79) of melanoma samples were defined as PD-L1
based on a modified H-score of 1 or more or the presence of a distinctive staining pattern at the tumor-stroma interface.
- The immunohistochemistry assay using the anti-PD-L1 antibody 22C3 merits further investigation in clinical trials and prevalence assessments to further understand the prognostic and predictive value of PD-L1 expression in cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
It has become increasingly apparent that one of the major hurdles in the genomic age will be the bioinformatics challenges of next-generation sequencing. We provide an overview of a general framework ...of bioinformatics analysis. For each of the three stages of (1) alignment, (2) variant calling, and (3) filtering and annotation, we describe the analysis required and survey the different software packages that are used. Furthermore, we discuss possible future developments as data sources grow and highlight opportunities for new bioinformatics tools to be developed.
ATR and Chk1 are two key protein kinases in the replication checkpoint. Activation of ATR-Chk1 has been extensively investigated, but checkpoint termination and replication fork restart are less well ...understood. Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. The protein levels of Chk1 and Fbx6 showed an inverse correlation in both cultured cancer cells and in human breast tumor tissues. Further, we show that low levels of Fbx6 and consequent impairment of replication stress-induced Chk1 degradation are associated with cancer cell resistance to the chemotherapeutic agent, camptothecin. We propose that Fbx6-dependent Chk1 degradation contributes to S phase checkpoint termination and that a defect in this mechanism might increase tumor cell resistance to certain anticancer drugs.
Traditional pathology approaches as well as molecular‐based assays are being used to identify tissue of origin of carcinoma of unknown primary. Cutting edge pathologists will maintain their critical ...position in analysis of patient samples by embracing new approaches such as next‐generation sequencing for optimizing patient outcomes beyond a focus on tumor type diagnosis alone.
Abstract BACKGROUND: Recent clinical trial results have suggested that programmed cell death ligand 1 (PD-L1) expression measured by immunohistochemistry may predict response to anti–programmed cell ...death 1 (PD-1) therapy. Results on the association between PD-L1 expression and survival among patients with advanced non–small cell lung cancer (NSCLC) treated with chemotherapy are inconsistent. MATERIAL AND METHODS: We evaluated the relationship between PD-L1 expression and overall survival (OS) among 204 patients with advanced NSCLC treated at Aarhus University Hospital, Aarhus, Denmark, from 2007 to 2012. PD-L1 expression was measured using a prototype immunohistochemistry assay with the anti–PD-L1 22C3 antibody (Merck). PD-L1 strong positivity and weak positivity were defined to be traceable to the clinical trial version of the assay. RESULTS: Twenty-five percent of patients had PD-L1 strong-positive tumors, and 50% had PD-L1 weak-positive tumors. No statistically significant association was found between PD-L1 expression and survival; adjusted hazard ratio of 1.34 (95% confidence interval, 0.88-2.03; median OS, 9.0 months) for the PD-L1 strong-positive group and 1.07 (0.74-1.55; median OS, 9.8 months) for the PD-L1 weak-positive group compared with the PD-L1–negative group (median OS, 7.5 months). No association was seen between PD-L1 expression and OS when PD-L1 expression levels were stratified by median or tertiles. CONCLUSIONS: In concordance with previous studies, we found PD-L1 measured by immunohistochemistry to be frequently expressed in patients with advanced NSCLC. However, PD-L1 expression is not a strong prognostic marker in patients with advanced NSCLC treated with chemotherapy.
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![[Letter to the Editor] The ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0736-6205_1940-9818/small "[Letter to the Editor] The need for improved education and training in research antibody usage and validation practices")
