PD-L1 Expression in Lung Cancer

doi:10.1016/J.JTHO.2016.04.014

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PD-L1 Expression in Lung Cancer

Journal Article•DOI•

PD-L1 Expression in Lung Cancer

Hui Yu¹, Theresa A. Boyle¹, Caicun Zhou, David L. Rimm², Fred R. Hirsch¹ - Show less +1 more•Institutions (2)

University of Colorado Denver¹, Yale University²

01 Jul 2016-Journal of Thoracic Oncology (Elsevier)-Vol. 11, Iss: 7, pp 964-975

TL;DR: The challenges remaining to harmonize PD‐L1 detection and interpretation for best patient care are described and described.

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About: This article is published in Journal of Thoracic Oncology.The article was published on 2016-07-01 and is currently open access. It has received 270 citations till now. The article focuses on the topics: Biomarker (medicine) & Immunotherapy.

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Journal Article•DOI•

PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples: Results of Blueprint Phase 2 Project.

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Ming-Sound Tsao¹, Keith M. Kerr², Mark M. Kockx, Mary Beth Beasley³, Alain C. Borczuk⁴, Johan Botling⁵, Lukas Bubendorf⁶, Lucian R. Chirieac⁷, Gang Chen⁸, Teh Ying Chou⁹, Jin Haeng Chung¹⁰, Sanja Dacic¹¹, Sylvie Lantuejoul, Mari Mino-Kenudson¹², Andre L. Moreira¹³, Andrew G. Nicholson¹⁴, Masayuki Noguchi¹⁵, Giuseppe Pelosi¹⁶, Claudia Poleri, Prudence A. Russell, Jennifer L. Sauter¹⁷, Erik Thunnissen¹⁸, Ignacio I. Wistuba¹⁹, Hui Yu²⁰, Murry W. Wynes, Melania Pintilie¹, Yasushi Yatabe, Fred R. Hirsch²⁰ - Show less +24 more•Institutions (20)

Princess Margaret Cancer Centre¹, University of Aberdeen², Mount Sinai Hospital³, Cornell University⁴, Science for Life Laboratory⁵, University Hospital of Basel⁶, Brigham and Women's Hospital⁷, Fudan University⁸, Taipei Veterans General Hospital⁹, Seoul National University Bundang Hospital¹⁰, University of Pittsburgh¹¹, Harvard University¹², New York University¹³, National Institutes of Health¹⁴, University of Tsukuba¹⁵, University of Milan¹⁶, Memorial Sloan Kettering Cancer Center¹⁷, VU University Medical Center¹⁸, University of Texas MD Anderson Cancer Center¹⁹, Anschutz Medical Campus²⁰

01 Sep 2018-Journal of Thoracic Oncology

TL;DR: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L 1 immunohistochemical assays.

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550 citations

Cites background from "PD-L1 Expression in Lung Cancer"

...Food and Drug Administration and the European Medicines Agency, PD-L1 IHC has also been established as a complementary diagnostic for nivolumab and atezolizumab to determine NSCLC patient eligibility, respectively.(4,5)...
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Journal Article•DOI•

Multiplex digital spatial profiling of proteins and RNA in fixed tissue.

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Chris Merritt¹, Giang T. Ong¹, Sarah E. Church¹, Kristi Barker¹, Patrick Danaher¹, Gary K. Geiss¹, Margaret L. Hoang¹, Jaemyeong Jung¹, Yan Liang¹, Jill McKay-Fleisch¹, Karen Nguyen¹, Zach Norgaard¹, Kristina Sorg¹, Isaac Sprague¹, Charles Warren¹, Sarah Warren¹, Philippa J. Webster¹, Zoey Zhou¹, Daniel R. Zollinger¹, Dwayne Dunaway¹, Gordon B. Mills², Joseph M. Beechem¹ - Show less +18 more•Institutions (2)

NanoString Technologies¹, Oregon Health & Science University²

11 May 2020-Nature Biotechnology

TL;DR: DSP may be used to profile not only proteins and RNAs in biobanked samples but also immune markers in patient samples, with potential prognostic and predictive potential for clinical decision-making.

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Abstract: Digital Spatial Profiling (DSP) is a method for highly multiplex spatial profiling of proteins or RNAs suitable for use on formalin-fixed, paraffin-embedded (FFPE) samples. The approach relies on (1) multiplexed readout of proteins or RNAs using oligonucleotide tags; (2) oligonucleotide tags attached to affinity reagents (antibodies or RNA probes) through a photocleavable (PC) linker; and (3) photocleaving light projected onto the tissue sample to release PC oligonucleotides in any spatial pattern across a region of interest (ROI) covering 1 to ~5,000 cells. DSP is capable of single-cell sensitivity within an ROI using the antibody readout, with RNA detection feasible down to ~600 individual mRNA transcripts. We show spatial profiling of up to 44 proteins and 96 genes (928 RNA probes) in lymphoid, colorectal tumor and autoimmune tissues by using the nCounter system and 1,412 genes (4,998 RNA probes) by using next-generation sequencing (NGS). DSP may be used to profile not only proteins and RNAs in biobanked samples but also immune markers in patient samples, with potential prognostic and predictive potential for clinical decision-making. A turnkey system allows for spatial profiling of proteins and RNA in fixed tissues, providing a window on cellular heterogeneity.

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388 citations

Journal Article•DOI•

Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer.

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Natasha B. Leighl¹, Ray D. Page, Victoria M. Raymond, Davey B. Daniel, Stephen G. Divers, Karen L. Reckamp², Miguel A. Villalona-Calero, Daniel Dix, Justin I. Odegaard, Richard B. Lanman, Vassiliki A. Papadimitrakopoulou³ - Show less +7 more•Institutions (3)

Princess Margaret Cancer Centre¹, City of Hope National Medical Center², University of Texas MD Anderson Cancer Center³

15 Apr 2019-Clinical Cancer Research

TL;DR: In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotypesing.

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Abstract: Purpose: Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non–small cell lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC. Patients and Methods: Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360). Results: Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%; P 98.2% with 100% positive predictive value for cfDNA versus tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days; P Conclusions: In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping. See related commentary by Meador and Oxnard, p. 4583

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356 citations

Journal Article•DOI•

Regulation of PD-L1 expression in the tumor microenvironment.

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Ming Yi¹, Mengke Niu², Mengke Niu¹, Linping Xu², Suxia Luo², Kongming Wu², Kongming Wu¹ - Show less +3 more•Institutions (2)

Huazhong University of Science and Technology¹, Zhengzhou University²

07 Jan 2021-Journal of Hematology & Oncology

TL;DR: In this paper, the authors focused on PD-L1 regulators at the levels of transcription, post-transcription, and post-translation, and discussed potential applications of these laboratory findings in the clinic.

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Abstract: Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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196 citations

Journal Article•DOI•

Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study

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Anish Thomas, Rasa Vilimas, Christopher Trindade, Rebecca A. Erwin-Cohen¹, Nitin Roper, Liqiang Xi, Venkatesh Krishnasamy², Elliot Levy², Andy Mammen², Samantha Nichols, Yuanbin Chen³, Vamsidhar Velcheti⁴, Faye Yin, Eva Szabo, Yves Pommier, Seth M. Steinberg, Jane B. Trepel, Mark Raffeld, Howard A. Young¹, Javed Khan, Stephen M. Hewitt, Jung-Min Lee - Show less +18 more•Institutions (4)

National Cancer Research Institute¹, National Institutes of Health², Western Michigan University³, New York University⁴

01 Aug 2019-Journal of Thoracic Oncology

TL;DR: Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations, and the predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.

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123 citations

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Journal Article•DOI•

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

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Suzanne L. Topalian¹, F. Stephen Hodi², Julie R. Brahmer¹, Scott N. Gettinger³, David Smith⁴, David F. McDermott², John D. Powderly, Richard D. Carvajal⁵, Jeffrey A. Sosman⁶, Michael B. Atkins², Philip D. Leming, David R. Spigel⁷, Scott J. Antonia⁸, Leora Horn⁶, Charles G. Drake¹, Drew M. Pardoll¹, Lieping Chen³, William H. Sharfman¹, Robert A. Anders¹, Janis M. Taube¹, Tracee L. McMiller¹, Haiying Xu¹, Alan J. Korman⁹, Maria Jure-Kunkel⁹, Shruti Agrawal⁹, Dan McDonald⁹, Georgia Kollia⁹, Ashok Kumar Gupta⁹, Jon M. Wigginton⁹, Mario Sznol³ - Show less +26 more•Institutions (9)

Johns Hopkins University¹, Harvard University², Yale University³, University of Michigan⁴, Memorial Sloan Kettering Cancer Center⁵, Vanderbilt University⁶, Sarah Cannon Research Institute⁷, University of South Florida⁸, Bristol-Myers Squibb⁹

27 Jun 2012-The New England Journal of Medicine

TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.

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Abstract: Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

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10,674 citations

"PD-L1 Expression in Lung Cancer" refers background or methods in this paper

..., which described a higher frequency of response to anti–PD-1 therapy in patients with tumors that were positive versus negative for PD-L1 protein expression, used a threshold of 5% for positivity, and many subsequent studies have also used a 5% threshold for positivity.(1) Although the rationale for selection of 5% as a cutoff...
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...In a follow-up multidose, phase I nivolumab trial, nine of 25 patients with PD-L1–expressing tumors responded to treatment versus no response in any of 17 patients with tumors that lacked PD-L1 expression (nine of 25 versus none of 17).(1) Although in subsequent...
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...A study by Toplian et al.1 in 2012 compared the performance of two anti–PD-L1 human antibodies, the clone 5H1 (noncommercial, from L. Chen, John Hopkins University, Baltimore, MD) and the clone 28-8....
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...A study by Toplian et al.(1) in 2012 compared the performance of two anti–PD-L1 human antibodies, the clone 5H1 (noncommercial, from L....
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Journal Article•DOI•

Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

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Hossein Borghaei¹, Luis Paz-Ares¹, Leora Horn¹, D. R. Spigel¹, M. Steins¹, Neal Ready¹, L.Q. Chow¹, Everett E. Vokes¹, Enriqueta Felip¹, Esther Holgado¹, F. Barlesi¹, M. Kohlhufl¹, Oscar Arrieta¹, Marco Angelo Burgio¹, J. Fayette¹, H. Lena¹, Elena Poddubskaya¹, David E. Gerber¹, Scott N. Gettinger¹, Charles M. Rudin¹, Naiyer A. Rizvi¹, L. Crina¹, G. R. Blumenschein¹, Scott J. Antonia¹, C. Dorange¹, C. T. Harbison¹, F. Graf Finckenstein¹, Julie R. Brahmer¹ - Show less +24 more•Institutions (1)

Fox Chase Cancer Center¹

21 Oct 2015-The New England Journal of Medicine

TL;DR: Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1, ≥5%, and ≥10%) of the PD-1 ligand.

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Abstract: BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...

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7,474 citations

Additional excerpts

...Clinical Trials with PD-L1 Protein Expression as a Biomarker by IHC Analysis Reference Drug Phase Tumor Type Sample Size Antibody (IHC Platform) Cell Location Cutoff Prevalence Objective Response Rate Clinical Trial ID PD-L1– Positive PD-L1– Negative Borghaei et al.3 Nivolumab III Stage IIIB or IV squamous cell NSCLC 117 28-8 (Dako automated Link48) TC membrane 1% 5% 10% 54% 36% 31% 17% 21% 19% 17% 15% 16% NCT01683867 Rizvi et al.20 Nivolumab II Stage IIIB or IV squamous cell NSCLC 117 28-8 (Dako) TC membrane 1% 5% 10% 59% 33% 33% 42% 48% 48% 32% 33% 33% NCT01721759 Gettinger et al.21 Nivolumab I Pretreated advanced NSCLC 68 28-8 (Dako) TC membrane 5% 49% 17% (22 of 129) 15% 14% NR Gettinger et al.22 Nivolumab I Chemotherapy-naive advanced NSCLC 47 Not reported (NR) TC 5% 55% 31% 10% NCT01454102 Rizvi et al.23 Nivolumab I Chemotherapy-naive advanced NSCLC 17 28-8 (Dako) TC 5% 59% 50% 0% NR Antonia et al.24 Nivolumab + ipilimumab I Chemotherapy-naive advanced NSCLC 38 28-8 (Dako) TC 5% 42% 19% 14% NR Ramalingam et al.25 Nivolumab II, singlearm study Advanced refractory squamous NSCLC 76 NR NR 5% 33% 20% 10% NR Garon et al.4 Pembrolizumab I Advanced NSCLC 325 22C3 (Dako) TC membrane 50% 23 % 41% 13% NCT01295827 1% 61% 26% 10% Herbst et al.26 Pembrolizumab II/III Previously treated NSCLC and enrolled 1034 22C3 (Dako) TC 1% 1-49% 66% 38% 18% NR NR NR NCT01905657 50% 28% 30% NR Herbst et al.27 Atezolizumab I Locally advanced or metastatic solid tumor 184 SP142 (Ventana) Tl TI 5% 5% 24% 26% 46% 18% NCT01375842 Spira et al.28 Atezolizumab II Previously treated NSCLC 287 SP142 (Ventana) TC and/or TI TC0 and IC0a TC1/2/3 or IC1/2/3 TC2/3 or IC2/3 TC3 or IC3 32% 68% 37% 16% 8% 18% 22% 38% NCT01903993 Spigel et al.29 Atezolizumab II Chemotherapy-naive stage IIIB/IV NSCLC 2 lines of therapy with no brain metastasis 2 lines of therapy with treated asymptomatic brain metastasis 31 71 12 SP142 (Ventana), in archival or fresh tumor biopsy specimens (required for the latter 2 cohorts) TC and/or TI TC3 or IC3a TC3 or IC3 TC3 or IC3 23% 37% 67% 29% 17% 17% NCT01846416 (continued) 9 6 6 Yu et a l Journa l of T hora cic O ncology V ol....
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...Borghaei et al.(3) Nivolumab III Stage IIIB or IV squamous cell NSCLC 117 28-8 (Dako automated Link48) TC membrane 1% 5% 10% 54% 36% 31% 17% 21% 19% 17% 15% 16% NCT01683867...
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Journal Article•DOI•

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer

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Julie R. Brahmer¹, Karen L. Reckamp², Paul Baas³, Lucio Crinò, Wilfried Eberhardt⁴, Elena Poddubskaya⁵, Scott J. Antonia⁶, Adam Pluzanski, Everett E. Vokes⁷, Esther Holgado, David M. Waterhouse, Neal Ready⁸, Justin F. Gainor⁹, Osvaldo Arén Frontera, Libor Havel¹⁰, Martin Steins¹¹, Marina Chiara Garassino¹², Joachim G.J.V. Aerts¹³, Manuel Domine¹⁴, Luis Paz-Ares, Martin Reck, Christine Baudelet¹¹, Christopher T. Harbison¹¹, Brian Lestini¹¹, David R. Spigel¹² - Show less +21 more•Institutions (14)

Johns Hopkins University¹, City of Hope National Medical Center², Netherlands Cancer Institute³, University of Duisburg-Essen⁴, Russian Academy⁵, University of South Florida⁶, University of Chicago⁷, Duke University⁸, Harvard University⁹, Charles University in Prague¹⁰, Bristol-Myers Squibb¹¹, Sarah Cannon Research Institute¹², Erasmus University Rotterdam¹³, Autonomous University of Madrid¹⁴

08 Jul 2015-The New England Journal of Medicine

TL;DR: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level.

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Abstract: BackgroundPatients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population. MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 3...

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6,869 citations

Journal Article•DOI•

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

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Dung T. Le, Jennifer N. Uram¹, Hao Wang², Bjarne Bartlett³, Holly Kemberling, Aleksandra Eyring⁴, Andrew D. Skora⁵, Brandon Luber⁶, Nilofer S. Azad, Daniel A. Laheru, Barbara A. Biedrzycki, Ross C. Donehower, Atif Zaheer, George A. Fisher¹, Todd S. Crocenzi, James J. Lee³, Steven M. Duffy, Richard M. Goldberg⁵, Richard M. Goldberg⁴, Albert de la Chapelle⁴, Albert de la Chapelle⁵, Minori Koshiji⁶, Feriyl Bhaijee⁶, Thomas Huebner⁶, Ralph H. Hruban, Laura D. Wood, Nathan Cuka⁶, Drew M. Pardoll, Nickolas Papadopoulos, Kenneth W. Kinzler, Shibin Zhou, Toby C. Cornish, Janis M. Taube, Robert A. Anders, James R. Eshleman, Bert Vogelstein, Luis A. Diaz - Show less +33 more•Institutions (6)

Stanford University¹, Providence Health & Services², University of Pittsburgh³, Ohio State University⁴, Merck & Co.⁵, Johns Hopkins University⁶

24 Jun 2015-The New England Journal of Medicine

TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.

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Abstract: BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

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6,835 citations

Journal Article•DOI•

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

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Julie R. Brahmer¹, Scott S. Tykodi², Scott S. Tykodi¹, Laura Q.M. Chow², Wen-Jen Hwu³, Suzanne L. Topalian¹, Patrick Hwu³, Charles G. Drake¹, Luis H. Camacho⁴, John S. Kauh⁵, Kunle Odunsi⁶, Henry C. Pitot⁷, Omid Hamid, Shailender Bhatia², Renato G. Martins², Keith D. Eaton², Shuming Chen¹, Theresa M. Salay¹, Suresh Alaparthy⁸, Joseph F. Grosso⁸, Alan J. Korman⁸, Susan M. Parker⁸, Shruti Agrawal⁸, Stacie M. Goldberg⁸, Drew M. Pardoll¹, Ashok Kumar Gupta⁸, Jon M. Wigginton⁸ - Show less +23 more•Institutions (8)

Johns Hopkins University¹, University of Washington², University of Texas MD Anderson Cancer Center³, St Lukes Episcopal Hospital⁴, Emory University⁵, Roswell Park Cancer Institute⁶, Mayo Clinic⁷, Bristol-Myers Squibb⁸

28 Jun 2012-The New England Journal of Medicine

TL;DR: Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.

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Abstract: Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...

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6,812 citations