Role of the Pathologist in Guiding Immuno-oncological...

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

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

Antigen Presenting Cell (APC)

T Cell

Adapted from: Freeman G et al., Proc Natl Acad Sci 2008


T-cell Activation

Tumor Cell

T Cell



T-cell Activation


T Cell




T Cell



T-cell Activation

Tumor cell

T Cell



T-cell Activation

Tumor cell

T Cell



T-cell Activation

Nivolumab(Opdivo)

Pembrolizumab (Keytruda)

Atezolizumab; anti-PDL1 (Tecentriq) PD-L1

PD-L2

PD-1 Blockade in Patients with Cancer… The Beginning

Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer

Topalian et al., NEJM, 2012

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.



Histopathological correlates:

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

Melanoma RCC Lung Cancer

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, 2014Herbst et al., Nature, 2014 Powles et al., Nature, 2014


Ansell et al., NEJM, 2015 Gubin et al., Nature, 2014 Yadav et al., Nature, 2014 Peng et al., Cancer Disc, 2015

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)


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


Cancers can be “cold” “warm” “hot”

Immunohistochemistry: CD8


“Inflamed” Tumor: • High mutation burden • Immunogenic antigens (incl. viral) • PD-L1/PD-L2 amplification • Tumor PD-L1 expression Correct, but attenuated, immune response

“Non-inflamed” Tumor: • Low mutation burden • Non-immunogenic neoantigens • Low PD-L1 expression

No or Incorrect 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.

Roemer et al., JCO, 2016

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.

PDL1/ PDL2/ CEN9 PAX5/ PD-L1

Classical Hodgkin Lymphoma- An Ineffective Anti-tumor Immune Response

PD-1 Blockade in Patients with Relapsed or Refractory Hodgkin’s Lymphoma

Ansell et al., NEJM, 2015

Design: Phase I Patients: 23 patients with multiply relapsed cHL Drug: Single agent nivolumab (anti-PD1)



Outcomes: Overall response rate 87% PFS 86% at 24 weeks



• The Reed-Sternberg cells had gains of PD-L1/PD-L2 and express the PD-1 ligands in all cases.

PD-1 Blockade in Patients with Mismatch Repair Deficiency

Le DT et al., NEJM, 2015

MMR-deficient tumors MMR-proficient tumors

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Design: Phase II Patients: 41 patients with metastatic carcinoma and with or without MMR deficiency Drug: Single agent pembrolizumab (anti-PD1)



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%



Objective Response Stable Disease Progressive Disease

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Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer

Garon EB et al., NEJM, 2015

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



<1% 1-49% >50%

PD-L1 IHC



PD-L1 IHC

Outcomes for patients with >50% Tumor cells with PD-L1: ORR= 45.2% PFS= 6.3 months Median survival= not reached



PFS OS

Pembrolizumab versus Chemotherapy for PD-L1 Positive Non-Small-Cell Lung Cancer

Reck et al., NEJM, 2016

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%

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

Larkin et al., NEJM, 2015

Design: Phase III Patients: 945 patients; previously untreated stage 3 or 4 melanoma Drug: anti-PD1 vs. anti-CTLA4 vs combination



Outcomes: Nivolumab (anti-PD1): PFS= 6.9 months Ipilimumab (anti-CTLA4): PFS= 2.9 months Nivo + Ipi: PFS= 11.5 months



For tumors >5% PD-L1 Nivolumab (anti-PD1): PFS= 14 months Ipilimumab (anti-CTLA4): PFS= 2.9 months Nivo + Ipi: PFS= 14 months


Larkin et al., NEJM, 2015 • If PD-L1+, you did not benefit from Ipilimumab!

Pembrolizumab as Second Line Therapy for Advanced Urothelial Carcinoma

Bellmut et al., NEJM, 2017

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• PD-L1 positive tumor cells + immune cells is >10%

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

Seiwert et al., Lancet Onc, 2016 • Better response among HPV+ tumors

Nivolumab versus Everolimus for Advanced Renal Cell Carcinoma

Motzer et al., NEJM, 2015

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

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.


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.


Additional IHC assays Cell Signaling Technology 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)

Hodgkin Lymphoma

Comparing Commercial IHC Assays

Gaule et al, JAMA Onc, 2017

• 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.

The Future

Lovitch et al, Ann Rev Path, 2016

• 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”

The Future

Lovitch et al, Ann Rev Path, 2016

• New targets, new drugs, new biomarkers….

Important Information Regarding CME/SAMs

The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, 2017.

No claims can be processed after that date!

After September 30, 2017 you will NOT be able to obtain any

CME or SAMs credits for attending this meeting.

Role of the Pathologist in Guiding Immuno-oncological...

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