Role of the Pathologist in Guiding Immuno-oncological Therapies Scott Rodig MD, PhD Department of Pathology, Brigham & Women s Hospital Center for Immuno-Oncology, Dana-Farber Cancer Institute Associate Professor of Pathology, Harvard Medical School
Role of the Pathologist in Guiding Immunooncological Therapies Scott Rodig MD, PhD Department of Pathology, Brigham & Women s Hospital Center for Immuno-Oncology, Dana-Farber Cancer Institute Associate Professor of Pathology, Harvard Medical School
Disclosure of Relevant Financial Relationships Research Funding: Bristol Myers Squibb, Affimed Pharmaceuticals, Kite Pharmaceuticals Scientific Advisory Board: Perkin Elmer Inc.
Disclosure of Relevant Financial Relationships Dr. Rodig declares affiliations with Bristol Myers Squibb, Affimed Pharmaceuticals, Kite Pharmaceuticals, and Perkin Elmer Inc.
PD-1 :PD-L1 Signaling
PD-1 :PD-L1 Signaling T Cell T-cell Activation Antigen Presenting Cell (APC) Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 :PD-L1 Signaling T Cell T-cell Activation Tumor Cell Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 :PD-L1 Signaling T Cell Antigen Presenting Cell (APC) Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 :PD-L1 Signaling T Cell T-cell Activation Antigen Presenting Cell (APC) Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 :PD-L1 Signaling T Cell T-cell Activation Tumor cell Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 :PD-L1 Signaling T Cell T-cell Activation Nivolumab (Opdivo) Pembrolizumab (Keytruda) Atezolizumab; anti-pdl1 (Tecentriq) PD-L1 PD-L2 Tumor cell Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 :PD-L1 Signaling T Cell T-cell Activation Nivolumab (Opdivo) Pembrolizumab (Keytruda) Atezolizumab; anti-pdl1 (Tecentriq) PD-L1 PD-L2 Tumor cell Adapted from: Freeman G et al., Proc Natl Acad Sci 2008
PD-1 Blockade in Patients with Cancer The Beginning
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer Design: Phase I Patients: 296 patients with advanced melanoma, NSCLC, prostate cancer, renal cell cancer, colon cancer Drug: Single agent nivolumab (anti-pd1) Outcomes: Objective responses among patients with melanoma (28%), NSCLC (18%), renal cell cancer (27%). 20 of 31 responses were durable (>1 year) with one year follow-up. Topalian et al., NEJM, 2012
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer Topalian et al., NEJM, 2012
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer Histopathological correlates: Melanoma RCC Lung Cancer PD-L1 IHC with clone 5H1 PD-L1 IHC negative (<5% tumor PD-L1 expression)= 0/17 responses PD-L1 IHC positive (>5% tumor PD-L1 expression)= 9/25 responses Topalian et al., NEJM, 2012
Tissue-based Biomarkers of Clinical Response to PD-1 Blockade Cellular/ protein biomarkers that correlate with positive response to PD-1 blockade (results of many trials): 1. PD-L1 expression by malignant cells 2. PD-L1 expression by tumor associated inflammatory cells 3. Number of PD-1+ tumor infiltrating lymphocytes 4. Number of CD8+ tumor infiltrating lymphocytes Topalian et al., NEJM, 2012 Tumeh et al., Nature, 2014 Herbst et al., Nature, 2014 Powles et al., Nature, 2014
Tissue-based Biomarkers of Clinical Response to PD-1 Blockade Genetic biomarkers that correlate with response to PD-1 blockade: 1. PD-L1/ PD-L2/ JAK2 co-amplification (chromosome 9p24.1) 2. Total tumor genomic mutation burden 3. Predicted, expressed tumor neoantigens 4. Select somatic mutations (PTEN) Ansell et al., NEJM, 2015 Gubin et al., Nature, 2014 Yadav et al., Nature, 2014 Peng et al., Cancer Disc, 2015
Tissue-based Biomarkers of Clinical Response to PD-1 Blockade Other biomarkers that are associated with clinical response 1. Viral antigens (HPV)/ endogenous retroviruses 2. T-cell receptor diversity/ clonality 3. Transcriptional signatures of the inflamed tumor microenvironment
Tissue-based Biomarkers of Clinical Response to PD-1 Blockade Cancers can be cold warm hot Immunohistochemistry: CD8
Tissue-based Biomarkers of Clinical Response to PD-1 Blockade Non-inflamed Tumor: Low mutation burden Non-immunogenic neoantigens Low PD-L1 expression No or Incorrect immune response Inflamed Tumor: High mutation burden Immunogenic antigens (incl. viral) PD-L1/PD-L2 amplification Tumor PD-L1 expression Correct, but attenuated, immune response
Classical Hodgkin Lymphoma- An Ineffective Anti-tumor Immune Response Rare Hodgkin Reed-Sternberg cells (1-5% of the cellularity) within a very cellular tumor microenvironment composed of T-cells, macrophages, plasma cells, eosinophils.
Classical Hodgkin Lymphoma- An Ineffective Anti-tumor Immune Response PAX5/ PD-L1 PDL1/ PDL2/ CEN9 In 90% of classical Hodgkin lymphomas, the Hodgkin Reed-Sternberg cells express high levels of the PD-1 ligands which is attributed to amplification of PD- L1/PD-L2 on chromosome 9p24. Roemer et al., JCO, 2016
PD-1 Blockade in Patients with Relapsed or Refractory Hodgkin s Lymphoma Design: Phase I Patients: 23 patients with multiply relapsed chl Drug: Single agent nivolumab (anti-pd1) Ansell et al., NEJM, 2015
PD-1 Blockade in Patients with Relapsed or Refractory Hodgkin s Lymphoma Outcomes: Overall response rate 87% PFS 86% at 24 weeks Ansell et al., NEJM, 2015
PD-1 Blockade in Patients with Relapsed or Refractory Hodgkin s Lymphoma The Reed-Sternberg cells had gains of PD-L1/PD-L2 and express the PD-1 ligands in all cases. Ansell et al., NEJM, 2015
PD-1 Blockade in Patients with Mismatch Repair Deficiency 5000 P=0.007 Somatic mutations per tumor 4000 3000 2000 1000 0 MMR-deficient tumors MMR-proficient tumors Le DT et al., NEJM, 2015
PD-1 Blockade in Patients with Mismatch Repair Deficiency Design: Phase II Patients: 41 patients with metastatic carcinoma and with or without MMR deficiency Drug: Single agent pembrolizumab (anti-pd1) Le DT et al., NEJM, 2015
PD-1 Blockade in Patients with Mismatch Repair Deficiency Outcomes: Overall response for MMR-deficient = 40% ORR for MMR proficient = 0% 20 week PFS for MMR-deficient = 78% 20 week PFS for MMR proficient = 11% Le DT et al., NEJM, 2015
PD-1 Blockade in Patients with Mismatch Repair Deficiency Le DT et al., NEJM, 2015
PD-1 Blockade in Patients with Mismatch Repair Deficiency 5000 P=0.02 Somatic mutations per tumor 4000 3000 2000 1000 0 Objective Response Stable Disease Progressive Disease Le DT et al., NEJM, 2015
Pembrolizumab for the Treatment of Non- Small-Cell Lung Cancer Design: Phase I Patients: 495 patients Drug: Single agent pembrolizumab (anti-pd1) Outcomes: Overall response rate = 19% Median Duration of response = 12.5 months Median PFS = 3.7 months Garon EB et al., NEJM, 2015
Pembrolizumab for the Treatment of Non- Small-Cell Lung Cancer PD-L1 IHC <1% 1-49% >50% Garon EB et al., NEJM, 2015
Pembrolizumab for the Treatment of Non- Small-Cell Lung Cancer PD-L1 IHC Outcomes for patients with >50% Tumor cells with PD-L1: ORR= 45.2% PFS= 6.3 months Median survival= not reached Garon EB et al., NEJM, 2015
Pembrolizumab for the Treatment of Non- Small-Cell Lung Cancer PFS OS Garon EB et al., NEJM, 2015
Pembrolizumab versus Chemotherapy for PD-L1 Positive Non-Small-Cell Lung Cancer Design: Phase III Patients: 305 untreated patients with NSCLC showing >50% PD-L1 expression Drugs: anti-pd1 vs. chemo Outcomes: Pembro (anti-pd1): ORR= 45%; PFS= 10.3 months, OS at 6 mo= 80.2% Chemotherapy: ORR= 28%; PFS= 6 months, OS at 6 mo= 74% Reck et al., NEJM, 2016
Pembrolizumab versus Chemotherapy for PD-L1 Positive Non-Small-Cell Lung Cancer Reck et al., NEJM, 2016
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma Design: Phase III Patients: 945 patients; previously untreated stage 3 or 4 melanoma Drug: anti-pd1 vs. anti-ctla4 vs combination Larkin et al., NEJM, 2015
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma Outcomes: Nivolumab (anti-pd1): Ipilimumab (anti-ctla4): PFS= 6.9 months PFS= 2.9 months Nivo + Ipi: PFS= 11.5 months Larkin et al., NEJM, 2015
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma For tumors >5% PD-L1 Nivolumab (anti-pd1): Ipilimumab (anti-ctla4): PFS= 14 months PFS= 2.9 months Nivo + Ipi: PFS= 14 months Larkin et al., NEJM, 2015
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma If PD-L1+, you did not benefit from Ipilimumab! Larkin et al., NEJM, 2015
Pembrolizumab as Second Line Therapy for Advanced Urothelial Carcinoma PD-L1 positive tumor cells + immune cells is >10% Bellmut et al., NEJM, 2017
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial Better response among HPV+ tumors Seiwert et al., Lancet Onc, 2016
Nivolumab versus Everolimus for Advanced Renal Cell Carcinoma Design: Phase III Patients: 821 Patients failing prior therapies Drugs: anti-pd1 vs. MTOR inhibitor Outcomes: Nivolumab (anti-pd1): ORR= 25%; OS= 25 months Everolimus: ORR= 5%; OS= 19.6 months PD-L1 expression (>1%, >5%) marginally associated with better response Motzer et al., NEJM, 2015
Additional Studies of Importance 1. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck (Ferris et al., NEJM, 2016). 2. Nivolumab versus Everolimus for Advanced Renal Cell Carcinoma (Motzer et al., NEJM, 2015) 3. PD-1 Blockade with Pembrolizumab in Advanced Merkel Cell Carcinoma (Ngheim et al., NEJM, 2016).
FDA Approvals Opidivo (Nivolumab) Advanced melanoma (December, 2014) Advanced lung cancer (May, 2015) Metastatic renal cell carcinoma (Nov, 2015) Unresectable or metastatic melanoma, combined with Yervoy (Ipilumumab; Jan. 2016) Relapsed classical Hodgkin lymphoma (May, 2016) Head and Neck Cancer (November, 2016) Previously treated locally advanced or metastatic urothelial cancer (Feb, 2017)
FDA Approvals Keytruda (Pembrolizumab) Advanced melanoma (Dec., 2015) First line metastatic non-small cell lung cancer (Oct., 2016) Metastatic or recurrent head & neck squamous cell carcinoma (May, 2016)
FDA Approvals Tecentrq (Atezolizumab; anti-pd-l1) Locally advanced or metastatic urothelial carcinoma after failing platinum-based therapy Metastatic or advanced non-small cell lung cancer after failing platinum-based therapy
Commercial Diagnostic Assays DAKO/ Agilent Anti-PD-L1 (22C3): FDA-approved test to identify patients with non-small cell lung cancer who can receive pembrolizumab (>50% tumor positive staining). Anti-PD-L1 (28-8): FDA-approved test to identify patients with non-small cell lung cancer who may benefit from nivolumab. Garon et al., 2015.
Commercial Diagnostic Assays Ventana/ Roche Anti-PD-L1 (SP142): FDA-approved test to identify patients with non-small cell lung cancer and urothelial cancer most likely to gain benefit from atezolizumab. Anti-PD-L1 (SP263): To identify patients with non-squamous NSCLC most likely to gain benefit from nivolumab.
Commercial Diagnostic Assays Additional IHC assays Cell Signaling Technology Hodgkin Lymphoma Anti-PD-L1 (9A11): Assay used in Hodgkin lymphoma studies correlating IHC / 9p24.1 amplification status/ outcomes Anti-PD-L1 (E1L3N) PAX5/ PD-L1 (9A11)
Comparing Commercial IHC Assays IHC-based comparison of anti-pd-l1 clones SP142, E1L3N, 9A11, SP263, 22c3, and 28-8 High concordance in staining across clones on engineered cell lines and tissues on microarrays Conclusion: The IHC assays are highly concordant. Gaule et al, JAMA Onc, 2017
The Future Integration and interpretation of multiple biomarker assays: Quantitative IHC/ multiplex immunofluorescence Transcriptional signatures of the inflammatory tumor microenvironment Genetic/ genomic analyses Computational analysis and a Tumor Immune Score Lovitch et al, Ann Rev Path, 2016
The Future New targets, new drugs, new biomarkers. Lovitch et al, Ann Rev Path, 2016
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