PD-L1 Expression, Role, and Significance in Lung Pathology. Ross A Miller, MD FACP FASCP
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1 PD-L1 Expression, Role, and Significance in Lung Pathology Ross A Miller, MD FACP FASCP
2 Background information
3 PD-1 and PD-L1 expression in tissues PD-L1 Ligand to PD-1 (PD-1 on T cells) Rarely expressed during physiologically normal states Also known as CD274 Encoded by the CD274 gene on chromosome 9 Messenger RNA (mrna) for PD-L1 Near ubiquitous expression in human tissues, with some exceptions PD-L1 expression on cells is induced by proinflammatory states Most notable inducer of PD-L1 expression: interferon gamma (IFN- γ) produced by activated T-cells PD-1: expressed on T cells, binds to its ligand (PD-L1) PD-1 expression on Helper CD4+ T cells and CD8+ T lymphs Tonsil crypt epithelium When PD-1 (expressed on T-cells), binds to its ligand (PD-L1) the immune response is dampened (anergic) T-cell proliferation and cytokine production decreases
4 T-cells Activated T-cells PD-L1 Antigen IFN- γ, and other cytokines PD-1 PD-L1 Cell Death!!! Decreased immune response Cell survival Cell lacking PD-L1 Physiologic goal: prevent overactivation of the immune system and excessive tissue destruction
5 Exploitation of the PD-1/PD-L1 pathway Malignant cells can take advantage of the PD-1/PD-L1 Express PD-L1 on their cell surface PD-L1 expression in malignancies often associated with a poor outcome PD-1 Malignant cell Decreased immune response Cell survival
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7 How does PD-L1 become expressed in Tumor cells???
8 Expression of PD-L1 in tumor cells Inducible PD-L1 expression Pro-inflammatory microenvironment Proposed mechanisms for PD-L1 expression seen in tumors with tumor infiltrating lymphocytes Molecular alterations Independent of inflammatory states So called noninducible or innate expression Examples: loss of PTEN Associated with PD-L1 expression
9 Expression of PD-L1 in tumor cells Regardless of the underlying mechanism (inducible or non-inducible) Malignant cells over expressing PD-L1 seemingly have a propensity to escape the immune system Cell survival and Propagation This process is sometimes referred to as adaptive resistance and this is the basis behind therapy targeting the PD-1/PD-L1 pathway
10 Basis of PD-1/PD-L1 therapy Ab blocking the PD-1/PD- L1 interaction Cell Death!!! However.it is not that simple.
11 T Cell Immune modulation Pardoll DM Nature Rev Cancer 12, 252, 2012
12 Immune modulation Immune system Continuous state of balance Recognizing self Attacking non-self Disruption Autoimmune or immune deficiency states In the normal state Immune checkpoints Activate the immune response Inhibitory feed back to prevent over activation
13 T Cell Immune modulation T cell activation: 2 step process 1 st step: APCs presenting antigens via MHC CD4 + T-cells recognize antigens from MHC class II Helper T cells Th1 (enhance cytotoxic T-cells, Th2 (B cell response), Th17 (autoimmunity and tissue regulation), Treg (suppression of immunity) CD8 + T-cells recognize antigens from MHC class I Cytotoxic T- cell Th1 cells, when activated produce: IL-2 TNF-alpha IFN- γ : Most notable inducer of PD-L1 expression 2nd step: activation of B7/CD28 family of receptors B7/CD28 family of receptors Stimulatory B7-1, B7-2 Some are inhibitory PD-1, PD-L1, DP-L2, CD80, CTLA-4 Pardoll DM Nature Rev Cancer 12, 252, 2012
14 Hiding from the immune system How do cancer cells survive in the immune competent individual? Tumor derived Tregs tend to have higher suppressive activity than Tregs in normally physiologic states Cytotoxic T lymphs have difficulty recognizing Ag on cancer cells via impaired MHC1 pathway mechanisms Cancer cells/the tumor microenvironment tends to produce immunosuppressive cytokines Stimulatory molecules tend to be down regulated Suppressive molecules tend to be up regulated
15 Potential for treatment How do cancer cells survive in the immune competent individual? Tumor derived Tregs tend to have higher suppressive activity than Tregs in normally physiologic states Cytotoxic T lymphs have difficulty recognizing Ag on cancer cells via impaired MHC1 pathway mechanisms Cancer cells/the tumor microenvironment tends to produce immunosuppressive cytokines Stimulatory molecules tend to be down regulated Suppressive molecules tend to be up regulated We could get the patients own immune cells act on the malignant cells Treating the cancer without the harsh side effects of traditional chemotherapy AND If we could stimulate the immune system to recognize malignant cells..
16 Immune modulation Cytokines and immunotherapy IL-2 (produced by activated Th1 cells) Primarily stimulates T cell proliferation discovered by Morgan in 1976 One of the first attempted immunotherapies: IL-2 administered exogenously Expected to result in tumor regression Effective in murine models Some response noted with high-dose therapies (1985): Renal cell carcinomas (14% RR), Melanoma(16% RR) Major toxicity! IL-2 INF-γ and TNF-α capillary leak syndrome and decreased systemic vascular resistance IFN-alpha and imiquimod therapy Limited effectiveness... Some benefit in a limited number of cancers
17 CTLA-4 therapy Anti-CTLA-4: first immune checkpoint inhibitor approved by the FDA (2011) Blocking CTLA-4 prevents downregulation in early stages of T- cell activation 20% of melanoma patients better long term survival Studies in NSCLC (Phase II trail) Slightly longer progression-free survival Chemo only: 4.6 months Chemo plus phased ipilimumab: 5.7 months Tended to be longer in squamous NSCLC (now in Phase III trials) Chemo plus concurrent ipilimumab: 5.5 months Side effects! Rash, colitis, thyroiditis, hepatitis, other auto-immune like reactions
18 Additional stimulatory agents not shown on diagram 4-1BB: Utomilumab (Phase I) and Urelumab (Phase I-II) GITR: MK-4166 (Phase I) Potentials for treatment NSCLC Inhibitory agents PD-L1 inhibitory agents Atezolizumab: approved by FDA Durvalumab: Phase III trial complete Avelumab: Phase III PD-1 inhibitory agents Nivolumab: approved by FDA Pembrolizumab: approved by FDA Pidilizumab: Phase I-II PDR001 Phase I-II Inhibitory agents CTLA-4 inhibitory agents Ipilimumab: Phase III trails Tremelumumab: Phase III trials Inhibitory agent KIR inhibitory agent Lirilumab: Phase I-II Inhibitory agent LAG3 inhibitory agent LAG525: Phase I-II Stimulatory agents OX40 Stimulatory agents MEDI0562: Phase I MEDI6353: Phase I MOXR0916: Phase I
19 PD-1/PD-L1 therapy PD-1 inhibitory agents Nivolumab: approved by FDA Pembrolizumab: approved by FDA Pidilizumab: Phase I-II PDR001 Phase I-II Nivolumab Initial FDA approval was for melanoma Currently, Nivolumab plus ipilimumab is first line therapy, regardless of BRAF V600E mutation status Various studies showed efficacy in NSCLC Some studies showed better responses with increasing PD-L1 expression, some responses were independent of PD-L1 expression FDA approved for the management of advanced NSCLC (and advanced RCC / classical Hodgkin lymphoma Small cell lung cancer Shown effective, PD-L1 expression was not associated with responses in the Checkmate 032 study
20 PD-1/PD-L1 therapy Pembrolizumab Shown active in a variety of solid tumors Melanoma, MMT deficient colorectal cancer, NSCLC, head and neck squamous cell carcinoma Again, numerous studies have showed efficacy in NSCLC Many of these studies were on patients with some PD-L1 expression or showed greater responses with higher levels of PD-L1 expression Small cell carcinoma Phase Ib trials have shown responses in PD-L1 previously treated patients
21 PD-1/PD-L1 therapy PD-L1 inhibitory agents Block PD-1/PD-L1 interactions leaving the PD-1/PD-L2 pathway intact Atezolizumab: approved by FDA Durvalumab: Phase III Avelumab: Phase III Atezolizumab FDA approved for advanced urothelial carcinoma ImVigor 210 trial: slightly better responses with PD-L1 expressin greater than 5% Various studies show efficacy in NSCLC (POPLAR, BIRCH, OAK trials) FDA approved for second-line therapy of NSCLC
22 Side effects of PD-1/PD-L1 therapy Common Fatigue, cough, shortness of breath, nausea, itching, rash, vitiligo, decreased appetite, headache, constipation, joint pain, back pain, diarrhea Others: anemia, cellulitis, lymphocytopenia, sepsis, SJS-TEN, high blood sugar, rhabdomyolysis, others Patients can have immune mediated reactions Pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, skin reacions
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24 Rational for PD-L1 assessment
25 Conceptually Tumors devoid of PD-L1 Use of PD-1/PD-L1 blockade would be irrelevant as use of blocking agents could not block the pathway. IHC was used to look for PD-L1 + tumors to select patients for blocking agents
26 PD-L1 Immunohistochemistry as a Predictive Biomarker MPDL3280A: Atezolizumab
27 N Engl J Med. 2015;372(21): Keynote-001 Phase 1 study PD-L1 clone: 22C3 (Dako) and using the IHC kit protocol PS: Proportion Score (% of tumor cells staining for PD-L1) ORR: Objective response rate: FDA definition (the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period)
28 PD-L1 clone: 22C3 (Dako) and using the IHC kit protocol
29 Phase II/III: Previously treated advanced stage NSCLC Among patients with at least 50% of tumor cells expressing PD-L1, overall survival was significantly longer with pembrolizumab with docetaxel (median 14 9 months vs 8 2 months; HR 0 54, 95% CI ; p=0 0002) KEYNOTE-024 Reck M et al. N Engl J Med. 2016;375(19): Phase III: 305 patients with previously untreated advanced NSCLC with PD-L1 expression in at least 50% of tumor cells No sensitizing EGFR mutations or ALK translocations Conclusions: pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy PD-L1 antibody clone: 22C3 (Merck)
30 October 24 th, 2016 Pembrolizumab became the 1 st immunotherapy drug approved for first line treatment of metastatic NSCLC whose tumor over express PD-L1 (TPS greater than or equal to 50%) Second line with lower levels of PD-L1 expression
31 Nivolumab CheckMate 017 and 057 trials Second-line nivolumab was superior to docetaxel in two subsequent randomized phase III trials of patients with advanced NSCLC who previously received a platinumbased chemotherapy doublet - FDA approval for second line therapy Trails as first line therapy (Nivolumab as a single agent) CheckMate 012: looked at safety and efficacy: 71% had adverse reactions, ORR: 23% CheckMate 026: PD-L1 expression of 5% or greater: the progression-free survival and ORR was longer for the chemotherapy arm but overall survival was better for the nivolumab arm
32 Phase 3 trial comparing nivolumab monotherapy to docetaxel monotherapy in patients with advanced squamous-cell NSCLC in those who had disease progression during or after one prior platinum-containing chemotherapy regimen Patients with stage IIIB or IV Kaplan-Meier curves for progression free survival Time from randomization to the date of first documented tumor progression, death, or last tumor assessment
33 CheckMate 026 ORR Progression free survival Overall Survival Overall Survival at 1 year Nivolumab (months) 14.4 (months) 56.3 Platinum Doublet (months) 13.2 (months) 53.6
34 Bottom line Pembrolizumab was approved for first line therapy (PD-L1 expression greater than 50%) Nivolumab indication: second line therapy Many feel the PD-L1 expression level was set to low in Phase III trial for Nivolumab The goal of a biomarker: Enrich the patient population of who will benefit (select the people most likely to respond) Avoid harm to patients (toxicity) These new drugs are $$$ PD-L1 cutoff for Nivolumab At the time of the study: include as many patients as possible
35 Predictive significance of PD-L1 IHC with nivolumab Checkmate 017: trend toward improved overall survival and overall response rate for patients with PD-L1 expression of 1% or greater Checkmate 057: greater efficacy than docetaxel in subgroups: tumor-membrane expression of PD-L1 (1% or greater, 5% or greater, and 10% or greater) The median overall survival for patients in these subgroups treated with nivolumab was 17.1, 18.2, and 19.4 months, respectively, compared to 9.0, 8.1, and 8.0 months, respectively, with docetaxel Borghaei, NEJM 2015
36 Some of the immunohistochemistry antibody clones and assays for PD-L1 evaluation Drug Antibody Clone Criteria Pembrolizumab PD-1 inhibitory agent Nivolumab PD-1 inhibitory agent 22C3 (Dako) Companion diagnostic (FDA approval) 1st line: PD-L1 at least 50% 2nd Line: PD-L1, 1% or greater 28-8 (Dako) Complementary (FDA approval) 2 nd line: PD-L1 1% or greater Atezolizumab PD-L1 inhibitory agent SP142 (Ventana) Complementary (FDA approval) 2 nd line NSCLC: 50% in tumor cells, or at least 10% in immune cells Durvalumab PD-L1 inhibitory agent SP263 (Ventana) Complementary (FDA Approval) Greater than or equal to 25% Avelumab PD-L1 inhibitory agent (Dako) Greater than or equal to 1% PD-L1 E1L3N: PD-L1 IHC clone: Cell Signaling Technology (Non-FDA approved) ***Laboratory Developed tests (LDTs)*** companion diagnostic: defined as a diagnostic assay required for the use of the associated drug based on clinical efficacy and safety data complementary diagnostic: defined as a diagnostic assay that predicts a favorable outcome of the associated drug by selecting patients based on results of the assay. However, it is not harmful to treat patients with the associated drug in the absence of assay results or if the results are negative. In other words, use of the complementary assay is not required for treatment with the associated drug
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38 Challenges and Caveats
39 PD-L1 as a biomarker Is not binary... Information presented by Dr. K Kerr at 2017 PPS meeting Used with permission
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41 Presented by Dr. K Kerr at 2017 PPS meeting Used with permission
42 Things to keep in mind Absent PD-L1 staining does not mean the patient will not respond Various studies show around 10% of patients with negative PD-L1 tumor staining showed response to PD-(L)1 inhibitors Positive PD-L1 expression does not mean the patients will respond to therapy Up to 60% of patients with PD-L1 expression did not respond to therapy Numbers based on studies from: Borghaei et al, NEJM 2015; Rittmeyer A, et al, Lancet 2017; Brahmer J et al, NEJM 2015; Reck M et al, Lancet 2016; Garassino M et al, JTO WCLC 2016; Herbst RS et al, Lancet 2016 PD-L1 expression is tumors is heterogeneous Is our sample representative of the entire tumor? Small clusters of tumor cells on small bx or cell block Resection specimen
43 Things to keep in mind PD-L1 expression is tumors is heterogeneous Is our sample representative of the entire tumor? Resection specimen Modern Pathology (2017) 30, Immunohistochemical staining for PD-L1 in tissue microarray cores from a series of 79 squamous cell lung cancers and 71 pulmonary adenocarcinomas Substantial inconsistencies for the percentages of cells staining positive for PD-L1 among different tissue microarray cores
44 Some of the immunohistochemistry antibody clones and assays for PD-L1 evaluation Drug Antibody Clone Criteria Pembrolizumab PD-1 inhibitory agent Nivolumab PD-1 inhibitory agent 22C3 (Dako) Companion diagnostic (FDA approval) 1st line: PD-L1 at least 50% 2nd Line: PD-L1, 1% or greater 28-8 (Dako) Complementary (FDA approval) 2 nd line: PD-L1 1% or greater Atezolizumab PD-L1 inhibitory agent SP142 (Ventana) Complementary (FDA approval) 2 nd line NSCLC: 50% in tumor cells, or at least 10% in immune cells Durvalumab PD-L1 inhibitory agent SP263 (Ventana) Greater than or equal to 25% Avelumab PD-L1 inhibitory agent (Dako) Greater than or equal to 1% PD-L1 E1L3N: PD-L1 IHC clone: Cell Signaling Technology (Non-FDA approved) ***Laboratory Developed tests (LDTs)*** companion diagnostic: defined as a diagnostic assay required for the use of the associated drug based on clinical efficacy and safety data complementary diagnostic: defined as a diagnostic assay that predicts a favorable outcome of the associated drug by selecting patients based on results of the assay. However, it is not harmful to treat patients with the associated drug in the absence of assay results or if the results are negative. In other words, use of the complementary assay is not required for treatment with the associated drug
45 Solutions? LDTs and Off-label Screen with LDTs before send-out Select one test based on local oncologists preference Universally accepted, standardized criteria for IHC testing of PD-L1 European approach
46 The French National cancer Institute National validation study of PD-L1 expression using different antibodies and platforms in solid and hematological tumors Not all antibodies and platforms are readily available Provide national guidelines and recommendations regarding antibodies, protocols and scoring systems These studies can only report on technical equivalence there is no guarantee that the same predictive performance will be delivered by an LDT
47 Proposal for Companion Diagnostic Comparability Clearly using each of the companion diagnostics to select one of the several available targeted therapies in the same class is not practical and may be impossible Likewise, having a single test or assay as a sole companion test for all of the multiple therapeutic options within a class is also impractical since the individual therapies have differing modes of action, intended use populations, specificities, safety and efficacy outcomes
48 Compared PD-L1 assays and LDTs with 5 PD-L1 antibodies in a 41-case series PD-L1 clones: 28-8, 22C3, E1L3N, SP142, and SP263 IHC platforms: Ventana BenchMark Ultra, Leica Bond or Dako Autostainer Link 48 IHC platforms. To assesse matching platforms: Dako or Ventana assays were performed with clones 22C3, 28-8, SP263 Conclusions: 22C3, 28-8, and SP263 assays were highly concordant amongst several different centers regarding Similar concordance compared to those 3 assays was demonstrated by 14 of 27 (51.8%) LDTs LDTs using clone SP263 achieved the highest concordance rate across all platforms
49 Some studies comparing different PD-L1 IHC assays Blueprint PD-L1 IHC Assay Comparison Project Hirsch FR et al, JTO 2016 Percentage of PD-L1 stained tumor cells was comparable when the 22C3, 28-8, and SP263 assays were used, whereas the SP142 assay exhibited fewer stained tumor cells JAMA Oncol. doi: /jamaoncol Published online March 9, The assay using the SP142 antibody is an outlier that detected significantly less PD-L1 expression in tumor cells and immune cells. The assay for antibody 22c3 showed slight yet statistically significantly lower staining than either 28-8 or E1L3N 3 of the 4 tests are concordant and reproducible JAMA Oncol. 2017;3(2): monoclonal antibodies (SP142, E1L3N, 9A11,SP263, 22c3, and 28-8) Evidence that most antibodies used for PD-L1 studies are highly similar in their ability to bind PDL1
50 Some limitations of these studies Sample selection, were critical samples utilized Those on the threshold of positivity Were assays adjusted in attempt to achieve validation between each other Adjustment of assays in attempts to establish a universal cut off point How does the staining pattern seen relate to patient outcomes? We are really just comparing staining amongst the antibodies, we are not necessarily correlating with patient responses to immunotherapy Diffrent antibodies and different medications bind to different epitopes...
51 Different Epitopes PD-L1 Clone PD-L1 target (immunogen) Drug FDA approval FDA approved indications 22C3 Clone (mouse) 28-8 Clone (rabbit) SP142 Clone (rabbit) SP263 Clone (rabbit) Human extracellular domain (Phe19-Thr239 fused to human IgG1 Purified recombinant human PD-L1, extracellular domain Phe19-Thr239) Synthetic peptide derived from the C- terminus of human PD-L1 Synthetic peptide from the C-terminus of human PD-L1 protein Pembrolizumab Companion Metastaic NSCLC, Metastatic Melanoma, Classical Hodgkin Lymphoma, MSI-H Solid Tumors, Head and Neck Sq cell ca, Urothelial Carcinoma, Gastric Cancer Nivolumab Complementary NSCLC, Melanoma, Classical Hodgkins Lymphoma, Head and Neck Sq cell ca, Urothelial, RCC, HCC previous treated with sorafenib Atezolizumab Complementary Metastatic NSCLC, Metastatic Urothelial Durvalumab Complementary Locally advanced or metastatic Urothelial carcinoma
52 Immunohistochemistry is not a black box Numerous factors Cold ischemia time Fixation time IASLC Atlas for PD-L hrs for bx hrs for resection Antibody target Vendor kit vs. LDT IHC platform Antibody concentration Antibody incubation conditions Detection system Ille M, et al. Virchows Arch. 2016;468(5): Impact of Fixation time (SP142 Ab) And of course other variables
53 Other considerations.
54 The cellular cross-talk between different leukocyte subsets and their predominant contribution to either pro- or antitumor activities, including myeloid lineage leukocytes, tumor-associated macrophages with either protumorigenic (M2) or antitumorigenic (M1) properties, helper T-cell subsets, cytotoxic T cells, regulatory T cells, B cells, dendritic cells and myeloid-derived suppressor cells are shown. R. Salgado et al. Ann Oncol 2015;26: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.
55 Other factors and immune regulatory mechanisms are involved Immune interaction looks more like this Not quite this simple and there may be more Pardoll DM Nature Rev Cancer 12, 252, 2012
56 TC negative and IC+ have similar leukocyte infiltrates to TC+ tumors Both had similar expression of PD-1 and other immune checkpoints Suggest patients who score as PD-L1 by many IHC tests may be immunologically indistinguishable from PD-L1+ patients. Conclusions Relying only on PD-L1 IHC scoring to predict sensitivity to PD-1/PD-L1 blockade may exclude some patients who may respond to anti PD-1 therapy. Defined hot and cold tumors Hot tumors (likely to respond) contain CD8+ T cells expressing PD-1 and TIM3 PD-L1 tumor cells Correlate with high mutational load, smoking history, squamous morphology If the critical factor underlying the response to checkpoint blockade is presence of leukocytes: hybrid IHC/flow cytometry may improve (only) PD-L1 IHC as an immune biomarker More studies needed.
57 Tumor mutational burden and MSI-H/MMR-D Note: FDA is not clearly defined which test/s should be run.i.e PCR based MSI testing, IHC MMR testing, both??? Questions still remain for pathologists FDA News Release: May 23, 2017 Pembrolizumab: FDA approval for patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dmmr) Based on data from KEYNOTE 016, 164, 012, 028, 158 Trials July 31, 2017 FDA grants nivolumab accelerated approval for MSI-H or dmmr colorectal cancer Approval based on Checkmate 142 Trial
58 Tumor Mutational Burden The CheckMate 026 trial Compared the treatment efficacy of nivolumab versus chemotherapy in first line therapy of advanced nonsmall cell lung cancer (NSCLC) based on the programmed death-ligand 1 (PD-L1) expression. However, there was no strong correlation between treatment response and PD-L1 expression. Subanalysis: Question; could tumor mutation burden (TMB) determine nivolumab treatment response? 312 patients with evaluable TMB data: patients with a high mutation burden had a better progression free survival (9.7 vs 5.8 months; HR,0.62) and objective response rate (46.8% vs 28.3%) compared with the control arm. These findings imply that tumor mutation burden may be considered as a biomarker for nivoluamb in the first line treatment of advanced NSCLC AACR annual meeting 2017: CT082 - Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage IV or recurrent nonsmall cell lung cancer: An exploratory analysis of CheckMate 026
59 Plotted objective response rate for anti-pd-1 or anti-pd-l1 therapy against the median tumor mutational burden Literature review, identified 27 tumor types (meta-analysis study) Observed a significant correlation between tumor mutational burden and objective response rate
60 Accelerated Approval based on the Phase II clinical Trial: KEYNOTE-021 ORR was conducted in subgroups defined by PD-L1 tumor expression (TPS: <1% and 1%) TPS <1% subgroup: ORR was 57% in the pembrolizumab plus PC ORR was 13% in the PC alone arm TPS 1% subgroup: ORR was 54% pembrolizumab plus PC ORR was 38% and in the PC alone arm
61 September 8 th, 2017 Phase 3 (PACIFIC study) Comparing durvalumab as consolidation therapy with placebo in patients with stage III, locally advanced, unresectable NSCLC that had not progressed after platinum-based chemoradiotherapy No significant (P<0.05) between-group differences were noted in either PD-L1 expression or EGFR mutation status
62 PD-L1 on cytology samples Various trials looking at therapeutic response and PD-L1 expression were not done or validated in cytology material PD-L1 evaluation is often requested on cytology specimens Appl Immunohistochem Mol Morphol ;25(7): Used 28-8 and 22C3 kits used 85-95% concordance between histology and cytology specimens Limited studies...
63 Primary endpoints (Keynote-061) were OS and PFS in PD-L1 positive patients Secondary outcome measures included OS, PFS, and overall response rate (ORR) regardless of PD-L1 expression Accelerated approval (based on Keynote-059) is contingent on confirmatory trials Ongoing phase III KEYNOTE-062 trial is evaluating pembrolizumab alone and in combination with chemotherapy in the frontline setting for PD-L1 positive advanced gastric or GEJ cancer; phase III KEYNOTE-585 trial is studying the combination of pembrolizumab and chemotherapy in the neoadjuvant and adjuvant settings. However, TPS is not used. So when evaluating PD-L1 we need to know what type of tumor we are evaluating for
64
65 Future Directions
66 The state of current immuotherpaies Lasting and significant responses are only occurring in a subset of patients As we have already discussed, there is far more going on than a single molecule ligand interaction
67 Used CRISPR-Cas9 technology CRISPR: clustered, regularly interspaced, palindromic repeats Exploits a bacterial host defense system and uses the DNA-cutting enzyme Cas9 bound to a RNA guide strand that targets a specific genetic sequence
68 CRISPR-Cas9 Cell transfected with a DNA plasmid wit Cas9protein and guide RNA to target the gene of interest Cas9 cuts the DNA sequence of interest (both strands) A modified portion of DNA can be inserted to insert or replace a DNA sequence Known as homology directed repair (HDR)
69
70 Applied this technology to melanoma cells Used ~123K guide RNA sequences targeting thousands of protein coding genes Looked to see which genetically altered cells could escape the immune system Numerous genes identified that may potentially influence T-cell susceptibility When these genes were silenced -> cells survived after being exposed to T-cells conditioned to respond to tumor antigens Genes most influential had roles in antigen presentation and IFN- γ signaling pathways Correlated with patient tumors Many of these genes were altered in patient tumors
71 Correlated with patient tumors Many of these genes were altered in patient tumors, particularly ones immune to cytotoxic T-cell activity One gene: APLNR Codes for apelin receptor: involved in the JAK-STAT signaling pathway and IFN- γ Melanomas known to be resistant to immunotherapies were sequenced, 7 different mutations were found in the APLNR gene
72 Relevance??? PD-L1 is likely a small piece of the immune therapy puzzle 19 genes were found whose activity correlated cytolytic T-cell activity in 36 human cancer types
73 Conclusions PD-L1 expression is only a piece of the puzzle As more is learned, other or additional tests may be used to help select patients for PD-(L)1 therapies MSI/MMR Mutational profile, tumor immune profiles, etc PD-L1 expression may be very heterogeneous Expression seen in a small sample may not reflect expression in the entire tumor There are many different antibodies and assays, a clinically validated assay should be used and the pathologist should be trained on how to interpret the stain they are using Know what the type of tumor you are scoring!
74 Guideline??? There is a CAP/IASLC/AMP consensus guideline on molecular testing for lung cancer Future: separate guideline focused on PD-L1 expression testing in lung cancer is on the way
75 Dynamic and rapidly evolving area in Medicine! Currently Six different anti PD-1 or PD-L1 drugs in use More that 20 agents are in clinical testing Several hundred ongoing clinical trials exploring PD-1/PD-L1 inhibitors in combination with other checkpoint antibodies, vaccines, other therapeutics, surgery, and/or radiation therapy. Be willing to adapt accordingly!
76 Continually evolving field So what should we do??? The best we can while providing the information we know in a concise fashion Talk with your oncology colleagues PD-L1 expression (evaluated by immunohistochemistry) - Tumor cells: No membranous staining versus membranous staining in _% of cells - Associated inflammatory cells: no staining versus positive staining in % of cells Please note: PD-L1 is often heterogeneously expressed in tumors. As such, the PD-L1 expression observed in this particular specimen may not reflect the expression in all portions of the patient s malignancy. There are a number of PD-L1 antibodies and assays available. The assay used to evaluate PD-L1 expression in this sample is a laboratory developed test validated at the Houston Methodist Histology Laboratory using the Ventana SP142 antibody.
77 Sincere thanks to Dr. Cagle, the programming committee and the TSP!, Thanks for your attention Enjoy the meeting!
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