Emerging Concepts on PD-L1: Immune Check Point Blockade in Cancer - PowerPoint Presentation

Emerging Concepts on PD-L1: Immune Check Point Blockade in Cancer Short Presentations on Emerging Concepts(SPEC) Version 1.0, rev. 9/7/2016

© 2018 College of American Pathologists (CAP). All rights reserved.The CAP does not permit reproduction of any substantial portion of CAP’s Short Presentations on Emerging concepts (SPECs) without its written authorization. The CAP hereby authorizes use of its SPECs by pathologists for local educational purposes such as when presenting to: 1) other pathologists for educational purposes and 2) local clinicians for tumor boards, grand rounds, and individual discussions. This authorization does not extend to reproduction or other use of any substantial portion of the SPECs for commercial purposes without the written consent of the CAP. To request the CAP’s approval for reproductions other than those described in this paragraph, write to spec@cap.org. About these slides SPEC – Short Presentation on Emerging Concepts © 2018 College of American Pathologists. All rights reserved.

The CAP also authorizes pathologists to make modified versions of the SPECs solely for their individual use when presenting to 1) other pathologists for educational purposes and 2) local clinicians for tumor boards, grand rounds, and individual discussions. To request the CAP’s approval for modifications other than those described in this paragraph, write to spec@cap.org.Any and all third party content is expressly excluded from the permissions described above. For all third party content, eg, figures/tables credited to a source other than the CAP, you will need to obtain permission from the copyright holder before making any use of the material. About these slides SPEC – Short Presentation on Emerging Concepts © 2018 College of American Pathologists. All rights reserved.

The information presented herein is reflective of the original author's opinion of current subject matter. Neither the original author nor CAP is responsible for any additional, altered or misinterpreted information that may arise from a third party presenter. The CAP offers the SPECs as information about emerging molecular tests and developed them as an educational tool to assist pathologists in their discussions with local clinical colleagues. It did not issue the SPECs for use in litigation, reimbursement, or other contexts. Nevertheless, the CAP recognizes that the SPECs might be used by physicians and others. At the same time, the CAP cautions that use of the SPECs other than for their intended educational purpose may involve additional considerations that are beyond their scope. About these slides SPEC – Short Presentation on Emerging Concepts © 2018 College of American Pathologists. All rights reserved.

The inclusion of a product name or service in a CAP publication should not be construed as an endorsement of such product or service, nor is failure to include the name of a product or service to be construed as disapproval. Version 1.0, rev. 9/7/2016About these slides SPEC – Short Presentation on Emerging Concepts © 2018 College of American Pathologists. All rights reserved.

Emerging Hallmark of Cancer The immune system plays a fundamental role in the cancer pathophysiology and the ability to avoid immune destruction has been recognized as an emerging hallmark of cancer. © 2018 College of American Pathologists. All rights reserved. Reprinted from Cell, 144(5), Hanahan D, Weinberg RA., Hallmarks of Cancer: The Next Generation.,646-74, 2011, with permission from Elsevier.

Your Immune System has two main ways to respond to foreign invaders: Innate versus adaptive Innate Immunity (rapid response) Adaptive Immunity (slower response) © 2018 College of American Pathologists. All rights reserved. Reprinted by permission Macmillan Publishers Ltd: Nature Reviews Cancer Dranoff G., Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004;4(1): 11-22, 2004.

The cancer-immunity cycle Accessing the tumor Active T cell TUMOR MICROENVIRONMENT 3 Priming and activation 2 Cancer antigen presentation 1 Release of cancer cell antigens 7 Killing of cancer cells 6 Recognition of cancer cells by T cells 5 Infiltration of T cells into tumors 4 Trafficking of T cells to tumors BLOOD VESSELS LYMPH NODE Apoptotic tumor cell Cancer-cell recognition and initiation of cytotoxicity Antigens Initiating and propagating anti-cancer immunity Dendritic cell Active T cell Tumor cell Reprinted from Immunity , 39(1), Chen DS, Mellman I., Oncology Meets Immunology: The Cancer-Immunity Cycle.,1-10, 2013, with permission from Elsevier. © 2018 College of American Pathologists. All rights reserved.

Dampening the Immune Response in Cancer Cytotoxic T cell CTLA-4 B7 Dendritic cell CD28 B7 Priming Phase Negative immune regulators Inhibitory receptors Suppressive cells Suppressive enzymes (IDO, arginase) T reg Tumor PD-L1 Exhaustion MDSC T T PD-1 Cytotoxic T cell Effector Phase © 2018 College of American Pathologists. All rights reserved. Images courtesy of Kenneth J. Bloom, MD, FCAP: Human Longevity, Inc.

Intratumoral PD-L1 Expression: Innate vs Adaptive © 2018 College of American Pathologists. All rights reserved. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer , Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint in cancer therapy. Nat Rev Cancer. 2016; 16(5):275-87, 2016.

PD-L1 expression can be temporal and heterogeneous Tumor cell initially PD-L1 Negative Tumor cell expressed PD-L1 after T-cell activation © 2018 College of American Pathologists. All rights reserved. From Sharma P, Allison JP. The future of immune checkpoint therapy. Science . 2015;348(6230):56-61. Reprinted with permission from AAAS.

Early data suggest that anti-PDL1/-PD1 is active across a wide range of tumor types Hodgkin lymphoma Bladder cancer Colorectal cancer Renal cancer Melanoma Liver cancer Lung cancer Gastric Breast cancer Glioblastoma Pancreatic Head & neck cancer Ovarian Images courtesy of Kenneth J. Bloom, MD, FCAP: Human Longevity, Inc. © 2018 College of American Pathologists. All rights reserved.

Durable responses have been seen across a range of tumor types Nivolumab in RCC 3 0.3mg/kg (n=12) 2mg/kg (n=12) 10mg/kg (n=11) Time to response Ongoing response 0 3 6 9 12 15 18 21 24 27 30 Time (months) Responders Pembrolizumab in UBC 2 Onoing treatment CR PR PD as best response PD after non-PD Last pembrolizumab dose 0 20 40 60 80 Time (weeks) Responders © 2018 College of American Pathologists. All rights reserved. Atezolizumab in UBC 1 Reprinted from The Lancet , 387(10031), Rosenberg JE, Hoffman- censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre , phase 2 trial. The Lancet . 2016;387(10031):1909-20, 2016, with permission from Elsevier. Reprinted from The Lancet Oncology , 18(2), Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non- randomised , open-label, phase 1b study. The Lancet Oncology . 2017 Feb;18(2):212-220, 2017, with permission from Elsevier. Motzer, RJ. Nivolumab for metastatic renal cell carcinoma (mRCC): Results of a randomized, dose-ranging phase II trial. Talk presented at: American Society of Clinical Oncology 2015 Annual Meeting; May 30-June 3, 2014; Chicago, IL. http://meetinglibrary.asco.org/content/94571?media=vm. Accessed February 22, 2017. Reused with author’s permission.

Companion Diagnostics (CDx) in Development for PDL1/aPD1 Immunotherapies Atezolizumab Nivolumab Pembrolizumab Primary antibody Ventana SP142 Dako 28-8 Dako 22C-3 Cells to interpret IC + TC (NSCLC) IC only (UBC) TC only TC only (NSCLC) TC + stromal cells (UBC) Positive result ≥50% TC OR ≥10% IC (IC 3) OR ≥5% IC (IC 2) ≥5% or ≥1% TC in a field of >100 cells ≥50% TC (strong) 1–49% TC (weak) Instrument and detection system OptiView Detection and amplification on Benchmark Ultra EnVision Flex on Autostainer Link 48 EnVision Flex on Autostainer Link 48 Therapeutic developerGenentechBristol-Myers SquibbMerck© 2018 College of American Pathologists. All rights reserved.

Differences in Scoring IHC assays Staining pattern Result <1% of the viable tumor cells exhibit complete circumferential or partial linear plasma membrane staining at any intensityPD-L1 expression <1% >1% of the viable tumor cells exhibit complete circumferential or partial linear plasma membrane staining at any intensity PD-L1 expression ≥1% >5% of the viable tumor cells exhibit complete circumferential or partial linear plasma membrane staining at any intensity PD-L1 expression ≥5% >10% of the viable tumor cells exhibit complete circumferential or partial linear plasma membrane staining at any intensity PD-L1 expression ≥10% Staining pattern Result Partial or complete membrane staining (≥1+) in <1% of viable tumor cells No PD-L1 expression Partial or complete membrane staining (≥1+) in 1-49% of viable tumor cells Low PD-L1 expression Partial or complete membrane staining (≥1+) in ≥50% of viable tumor cells High PD-L1 expression Staining pattern Result IC ≥10% IC3 IC ≥5%and <10% IC2 IC ≥1%and <5% IC1 Staining pattern ResultTC ≥50%TC3TC ≥5%and <50%TC2IC ≥1%and <5%TC1Dako 28-8Dako 22C3Ventana SP142IC = Immune cells TC = Tumor cells© 2018 College of American Pathologists. All rights reserved.

Response Rate by PD-L1 Status © 2018 College of American Pathologists. All rights reserved . Reprinted from Current Opinion in Pharmacology , 23, Sunshine J, Taube JM., Association of PD-L1 expression in treatment tumor specimens with objective response to anti-PD-L1 therapy, 32-38, 2015, with permission from Elsevier. Association of PD-L1 expression in pre-treatment tumor specimens with objective response to anti-PD-1/PD-L1 therapy

Stronger expression of PD-L1 is associated with improved survival Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre , open-label, phase 2 randomised controlled trial. Lancet . 2016;387(10030):1837-46. Borghaei H, Paz-ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-39. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50. OS in KEYNOTE-010 (2L+ NSCLC; pembrolizumab) 2 OS in POPLAR (2L+ NSCLC; atezolizumab) 1 OS in CheckMate 057 (2L Non-Squamous NSCLC; nivolumab) 3 n (%) HR* 95% Cl p value TC3 or IC3 47 (16%) 0.49 0.22 –1.07 0.068 TC2/3 or IC2/3 105 (37%) 0.54 0.33 –0.89 0.014 TC1/2/3 or IC1/2/3 195 (68%) 0.59 0.40 –0.85 0.005 TC0 and IC0 92 (32%) 1.04 0.62–1.750.871Intention to treat2870.730.53–0.990.040FavoursatezolizumabDocetaxel0.2 12Favourspembrolizumab Favours docetaxel0.1110 PD-L1 expressionlevelNivolumabnDocetaxelNUnstratified HR(95% Cl)Interaction P-value≥1%1231230.59 (0.43–0.82) 0.06<1%1081010.90 (0.66–1.24)≥5%95860.43 (0.30–0.63)<0.001 <5%1361381.01 (0.77–1.34)≥10%86790.40 (0.26–0.59)<0.001 <10%451451.00 (0.76–1.31)Events/patients (n)HR95% Cl≥50%204/442 0.530.40–0.70 1–49% 317/591 0.760.60–0.96 0.212 0.5 Nivolumab © 2018 College of American Pathologists. All rights reserved .

PD-L1 confusion Different drugsDifferent assays Clones Staining protocols Platforms and scoring methods Clinical decision points Tumor indications The use of tumor cells or TILs or both Different tissues Different cut-offs in the same tissue for first- and second-line indications PD-L1 biomarker is dynamic and heterogeneous both spatially and temporally © 2018 College of American Pathologists. All rights reserved .

Factors in Addition to PD-L1 Expression May Predict Response to PD-L1 Therapy © 2018 College of American Pathologists. All rights reserved. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer , Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275-87, 2016.

SPEC Author/Editor InformationAuthors: Kenneth J Bloom, MD – Human Longevity , Inc.Editors: Matthew W. Anderson, MD, PhD – BloodCenter of WisconsinPranil K. Chandra, DO – PathGroup Jessica Crothers, MD – University of Vermont Medical Center Michael J. Misialek, MD – Newton-Wellesley Hospital Gail H. Vance, MD – Indiana University Mary M. Zutter, MD – Vanderbilt Medical Center© 2018 College of American Pathologists. All rights reserved.

Selected Resources Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39(1): 1-10.Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial." Lancet. 2016;387(10030): 1837-46.Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387(10027): 1540-1550. © 2018 College of American Pathologists. All rights reserved.

Selected Resources (continued) Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012; 366(26): 2517-2519.Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015; 348(6230): 56-61. Spranger S, Gajewski T. Rational combinations of immunotherapeutics that target discrete pathways. J Immunother Cancer. 2013; 1: 16. Topalian SL, Taube JM, Andres RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016; 16(5): 275-287. © 2018 College of American Pathologists. All rights reserved.

Selected Resources (continued) Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4): 450-461. © 2018 College of American Pathologists. All rights reserved.