optimizing the treatment of metastatic merkel cell carcinoma with immune checkpoint inhibitors

Optimizing the Treatment of Metastatic

Merkel Cell Carcinoma With Immune

Checkpoint Inhibitors

Paul Nghiem, MD, PhD

George F. Odland Endowed Chair in Dermatology

Professor & Head, University of Washington Dermatology

Affiliate Investigator, Fred Hutchinson Cancer Research Center

Disclosures

Dr. Nghiem discloses the following commercial

relationships:Consultant: EMD Serono

Grant/Research Support: Bristol-Myers Squibb

Non-FDA approved use of drugs or products

referenced in this presentation:Pembrolizumab

Nivolumab

Ipilimumab

FDA = Food and Drug Administration.

Learning Objectives

Learning objectives apply to physicians and nurses:

Describe the pathophysiology of MCC and the scientific foundation for immune checkpoint inhibitorsApply emerging data on immune checkpoint inhibitors in treatment planning for patients with metastatic MCCAssess strategies to manage immune-related adverse events associated with immune checkpoint inhibitors

MCC = Merkel cell carcinoma.

Agenda

MCC overview

Pathophysiology

Diagnosis, work-up, and

initial therapy

Immunotherapy for

metastatic MCC

Case discussions

Merkel Cell Carcinoma: Overview

More lethal than melanoma~40% mortality (~15% for

melanoma)

Reported incidence

increasingQuintupled since 1986

Currently ~2,500 new

cases/year in the US

Risk factorsFair skin (98% white), prolonged

sun exposure,

age >50 yr, immune

suppression (HIV, SOTR, CLL)

HIV = human immunodeficiency virus; SOTR = solid organ transplant recipient;

CLL = chronic lymphocytic leukemia.

Paulson et al, 2017; ACS, 2016; Heath et al, 2008; Miller et al, 1999.

Biopsy of primary lesion shows MCC

Nodes clinicallynegative

Excision of the primary lesion &

typically, sentinel lymph

node biopsy

Nodes clinically positive

Fine needle aspiration, core or

excisional biopsy of lymph node & excision

of the primary site

Baseline imaging in most

cases

MCC: Initial Work-Up

NCCN, 2017.

7th Edition AJCC Staging for MCC

AJCC = American Joint Committee on Cancer.

Edge et al, 2010; Harms et al, 2016.

Disease Extent

(% of initial presentation)Stage

Local (65%)

Stage I: Primary tumor ≤2 cm

Ia: Nodes negative by pathological exam

Ib: Nodes not clinically detectable

Stage II: Primary tumor >2 cm

IIa: Nodes negative by pathological exam

IIb: Nodes not clinically detectable

IIc: Primary tumor invading

bone/muscle/fascia/cartilage

Nodal (26%)

Stage III: Regional nodal disease

IIIa: Nodes positive by pathological exam

and not clinically detectable

IIIb: Nodes clinically detectable; in-transit

metastasis

Distant (8%) Stage IV: Distant metastatic disease

8th Edition AJCC Staging for MCC

Harms et al, 2016.

Stage Primary Tumor Lymph Node Metastasis

0 In situ (within epidermis only) No regional lymph node metastasis No distant metastasis

I Clinical ≤ 2 cm maximum tumor dimensionNodes negative by clinical exam

(no pathological exam performed)No distant metastasis

I Pathological ≤ 2 cm maximum tumor dimension Nodes negative by pathologic exam No distant metastasis

IIA Clinical > 2 cm tumor dimensionNodes negative by clinical exam


IIA Pathological > 2 cm tumor dimension Nodes negative by pathologic exam No distant metastasis

IIB ClinicalPrimary tumor invades

bone, muscle, fascia, or cartilage

Nodes negative by clinical exam


IIB PathologicalPrimary tumor invades

bone, muscle, fascia, or cartilageNodes negative by pathologic exam No distant metastasis

III Clinical Any size / depth tumor Nodes positive by clinical exam


IIIA Pathological

Any size / depth tumor Nodes positive by pathological exam only

(nodal disease not apparent on clinical exam)No distant metastasis

Not detected ("unknown primary")Nodes positive by clinical exam,

and confirmed via pathological examNo distant metastasis

IIIB Pathological Any size / depth tumor Nodes positive by clinical exam, and confirmed via

pathological exam OR in-transit metastasis***No distant metastasis

IV Clinical Any +/- regional nodal involvementDistant metastasis

detected via clinical exam

IV Pathological Any +/- regional nodal involvementDistant metastasis

confirmed via pathological exam

Local (65%)

Nodal (26%)

Distant (8%)

Current Management and Limitations

Local disease:Surgery and radiation○ >95% of patients “free of detectable disease” but nearly half

experience recurrence

Metastatic or locally advanced disease:(Used to be) chemotherapy (“small cell regimen”) ○ Shrinks MCC in most cases, but more than half progress by 3

months

Need more effective therapies

Recent successful trials of PD-1 axis blockade and

FDA approval of avelumab

PD-1 = programmed cell death protein 1.

Iyer et al, 2016; NCCN, 2017.

Immune Suppression and MCC

90% of patients with MCC do not have immune suppression

Early studies in HIV in 2002: 13-fold increased risk of MCC

Immune suppression is a (major) risk factor for MCC

Intensive search for pathogen

Paulson et al, 2013; Heath et al, 2008; Engels et al, 2002.

80% of MCCs Are Associated With

Merkel Cell Polyomavirus

MCC’s similarities to Kaposi’s sarcoma (caused by KSHV) raised

the possibility that MCC may have an infectious origin

MCPyV present in 8/10 MCCs

Validated in dozens of studies

KSHV = Kaposi’s sarcoma-associated herpes virus; MCPyV = Merkel cell polyomavirus.

Feng et al, 2008; Chun et al, 2013; Becker et al, 2009.

Merkel Cell Polyomavirus Genome

Feng et al, 2008.

Virus-Negative Tumors (~20%) Have

High Mutational Burden

NSCLC = non-small cell lung cancer; UV = ultraviolet; TIL = tumor-infiltrating lymphocytes; PD-L1 = programmed-death ligand 1.

Goh et al, 2016; Harms et al, 2015; Wong et al, 2015.

Virus-negative MCC tumors

have more tumor

neoantigens than melanomas

or NSCLC

Characterized by a prominent

UV-signature pattern

Subset of virus-negative

MCC tumors exhibit high TIL

and PD-L1 expression

Genetics of Virus-Positive vs

Virus-Negative MCC

Goh et al, 2015.

“MCC-high”

virus negative

“MCC-low”

virus positive

Exome sequenced tumor mutations

49 MCCs

To make an MCC:

Multiple UV mutations OR polyomavirus

Both “visible” to

immune system!

Seronegative

Virus-Positive vs Virus-Negative MCC at

Extremes of TCGA Mutation Spectrum

TCGA = The Cancer Genome Atlas.

Goh et al, 2015.

Both can be

immunogenic

UV mutations

Virus Positive Virus Negative

How Do CD8 T Cells

Recognize Their Target?

MCPyV-specific T cells

exist in blood & tumors

MCC-specific T cells

often “exhausted”

Target with PD-1 pathway

blockade?

Lyngaa et al, 2014; Iyer et al, 2014; Afanasiev & Nghiem, 2013.

Killer CD8 T cell

MCC cell expressing

MCPyV protein

Why Do Tumors Grow If Patients Have

(Virus-Specific) T Cells?

Photo Credit: Jim Dowdalls/Photo Researchers.

Virus infected cell

CD8

T cell

Are those T cells

dysfunctional?

T-Cell Surface Receptor Phenotype

Reveals Functional Profile

TNF = tumor necrosis factor; PD-L2 =

programmed death ligand 2

Afanasev & Nghiem, 2013.

Activated cells, characterized by expression of:

CD28 Costimulatory receptor (ligand: B7); required for T-cell activation

CD69 Earliest inducible cell surface glycoprotein during T-cell activation;

plays a role in T-cell proliferation

CD137

(4-1BB)

Member of TNF-receptor family; induced by T-cell activation;

important in T-cell proliferation, cytokine secretion, and cytotoxicity

CD38 Cyclic ADP ribose hydrolase; marker of T-cell activation; functions in

cell adhesion, signal transduction, and calcium signaling

HLA-DR MHC class-II surface receptor that is upregulated with T-cell

activation

Recently activated T cells, characterized by expression of:

Combination of activation and inhibition markers via appropriate

immunoregulatory feedback mechanisms

Exhausted T cells, characterized by prolonged expression of:

PD-1

Programmed death 1; inhibitory T-cell receptor (ligands: PD-L1

[B7-H1], PD-L2 [B7-DC]); reduces T-cell proliferation and

effector functions

CTLA-4

(CD152)

Cytotoxic T-lymphocyte antigen 4; inhibitory receptor (ligand: B7);

effectively competes for ligands with CD28 (which has lower avidity

than CTLA-4), preventing T-cell activation

Tim-3T-cell immunoglobulin mucin domain 3; inhibitory T-cell receptor

(ligand: galectin-9); leads to decrease in effector T-cell function

Acute antigen

exposure

T cell

Chronic antigen

exposure

Are the “Brakes” on in MCC-Specific

T Cells (vs Other Viral Responses)?

Tet = tetramer; CMV = cytomegalovirus; EBV = Epstein-Barr virus.

Afanasiev et al, 2013.

Detected “exhausted” PD-1+/Tim-3+ cells

using “tetramers” to isolate specific cells

(Data From 4–7 MCC Patients)

PD

-1+

Tim

-3+

(%

Po

sit

ive

Ce

lls

)

PD-1Tim-3

Target PD-1

and PD-L1?

Brakes and Accelerators of the

T-Cell Response

Drake et al, 2014.

MCC Immunotherapy Clinical Trials

Clinicaltrials.gov, 2017a; Clinicaltrials.gov, 2017b; Clinicaltrials.gov, 2017c.

Clinical Trial Indication Patient Characteristic

PD-1 (pembrolizumab)

NCT02267603Metastatic 1st line No prior systemic therapy

PD-L1 (avelumab)

NCT02155647

Metastatic 2nd line Progressed after

chemotherapy

Metastatic 1st line No prior systemic therapy

PD-1 ± CTLA-4 inhibitor

(nivolumab ± ipilimumab)

NCT02488759

Metastatic ≥1st line

Metastatic 1st line No prior systemic therapy

Stage IIA-IV,

resectable diseaseNeoadjuvant

Response Rates for Chemotherapy

vs PD-1 Axis Blocking Agents

ORR = overall response rate; NCCN = National Comprehensive Cancer Network.

Iyer et al, 2016; Kaufman et al, 2016; Nghiem et al, 2016; Topalian et al, 2017; NCCN, 2017.

Agents Response Study Status in MCC

Chemotherapy 55% ORR

1st-line treatment,

retrospective study for 62

patients, Iyer et al, 2016

Included in NCCN

guidelines based on

historical/clinical

experiences



1st-line treatment,



Included in NCCN

guidelines based on

historical/clinical

experiences

Avelumab 32% ORR≥2nd-line trial,

Kaufman et al, 2016

FDA-approved: 1st

and ≥ 2nd line, 3/2017



1st-line treatment,



Included in NCCN

guidelines based on

historical/clinical

experiences

Avelumab 32% ORR≥2nd-line trial,

Kaufman et al, 2016

FDA-approved: 1st

and ≥ 2nd line, 3/2017

Pembrolizumab 56% ORR1st-line trial, Nghiem et al,

2016

NCCN guideline for

MCC, 2017


Chemotherapy 55% ORR1st-line retrospective study

(N=62), Iyer et al, 2016

Included in NCCN

guidelines based on

historical/clinical

experiences

Avelumab 32% ORR≥2nd-line trial (N=88),

Kaufman et al, 2016

FDA-approved:

1st and ≥2nd line,

3/2017

Pembrolizumab 56% ORR1st-line trial (N=25),

Nghiem et al, 2016

NCCN guideline for

MCC, 2017

Nivolumab 73% ORR

1st- and ≥2nd-line trial

(N=25), Topalian et al,

2017

Public efficacy data

Unclear whether agents differ in response rate.

PFS Across Trials: 1st and 2nd Line

PFS = progression-free survival.

Iyer et al, 2016; Kaufman et al, 2016; Nghiem et al, 2016; Topalian et al, 2017.

Pembrolizumab 1st-line trial (n=26)

Avelumab ≥2nd-line trial (n=88)

FDA

approval

data…

Nivolumab 1st- and ≥2nd-line trial

(n=25)

PD-1 axis blockade agents

50-70% durable response

(1st line)

20-40% durable response (≥2nd

line)

45%

70%

55%

67%

84%

75% 75% 75%

52%X

25%X

13%X

6%X

Chemotherapy 1st-line data (n=62)X

100

80

90

70

Pro

gre

ss

ion

-Fre

e S

urv

iva

l, %

Months From Start of Systemic Therapy

60

50

40

30

20

10

0

0 2 4 6 8 10 12 14

Checkpoint Inhibitors: A New Standard

of Care for Advanced MCC?

October 2016: Anti–PD-1 (pembrolizumab) listed in

NCCN guidelines for MCC

March 2017: Anti–PD-L1 (avelumab) FDA approved for

MCC

“Taken together, these reports strongly suggest

that checkpoint blockade is the best option to treat

patients with advanced Merkel cell carcinoma…”

– Axel Hauschild & Dirk Schadendorf

Hauschild & Schadendorf, 2016; NCCN, 2017.

PD-1 Axis Blockade for MCC

Metastatic MCC

Most responses by 8‐12 weeks

Optimal duration of therapy is not known1-2 years after best response?

Restarting PD-1 blocking agents for progression after treatment

completed

Kaufman et al, 2016.

Case 1: PD-1 Axis Blockade for MCC

55-year-old woman

History:5/2014 – Patient noticed a 1-cm growing nodule on the

left chest skin

7/2014 – Skin biopsy showed MCC

8/2014 – PET/CT showed FDG-avid liver lesions

8/2014 – Liver biopsy showed metastatic MCC

Diagnosis: Stage IV metastatic MCC involving liver

(2 x 11 cm) and left chest

PET/CT = positron emission tomography/computed tomography; FDG = fluorodeoxyglucose.

Case 1 (cont.)

Treatment course:9/2014 – Cisplatin and etoposide x 4, discontinued due to

progressive disease

1/2015 – Avelumab trial; durable PR for more than 2 years

Scan every 3 months

PR = partial response.

After 4 Weeks (2 Doses) of PD-L1 After 20 Months of PD-L1What do you recommend?

Radiation vs more chemo vs avelumab (trial)?Progression After Chemo

Case 2: PD-1 Axis Blockade Combined

With Pain Management

56-year-old woman

History:9/2013 – Stage IB MCC of the right calf with clinically negative

LN, s/p WLE

11/2016 – Metastatic MCC of the right kidney, s/p right

nephrectomy

1/2017 – Patient developed worsening right-sided abdominal

pain

2/2017 – PET/CT showed enlarged retroperitoneal LN adjacent

to the nephrectomy bed

3/2017 – Biopsy of the LN showed MCC

Diagnosis: Metastatic MCC involving retroperitoneal LN

LN = lymph node; s/p = status post; WLE = wide local excision.

Case 2 (cont.)

Treatment course:3/2017 – Single fraction radiation treatment (8 Gy) to

symptomatic lesion

3/2017 – Pembrolizumab with CR on 6/2017 scan

Scan every 3 months

CR = complete response.

Iyer et al, 2015.

Iyer and colleagues (2015): Single-fraction

radiation therapy in patients with

metastatic Merkel cell carcinoma.

Challenges:

1. Acute severe pain due to a small

metastasis

2. Uncertainty whether PD-1 alone

will work

3. High risk of metastasis to other

sites

Our decision through

multidisciplinary discussion…

3/2017 – Painful Metastasis

Case 3: PD-1 Axis Blockade and IRAEs

69-year-old man with

metastatic MCC,

s/p 23 doses of avelumab

(9 months) with CR

URI with cough for 2 weeks

Exam: crackles on bilateral

lower lung fields

CT of chest: bilateral basilar

predominant consolidations

and multiple other areas of

patchy consolidations

IRAE = immune-related adverse event; URI = upper respiratory infection.

Case 3 (cont.)

Function deteriorated despite empiric antibiotics for

presumed aspiration pneumonia (dyspnea, unable

to walk through grocery store)

TreatmentHold avelumab

Admission, high-dose systemic steroids and empiric antibiotics

Bronchoscopy with lavage and tissue biopsies

Patient subsequently improved; presumed pneumonitis

Pneumonia vs Pneumonitis

Adverse Events Can Be Significant

Common:Fatigue (50%)

Musculoskeletal pain (32%)

Diarrhea (23%)

Infusion-related reactions (22%)

Rash (22%)

Abnormal CBC (~49%), LFT (~34%)

CBC = complete blood count; LFT = liver function test.

Bavencio® prescribing information, 2017.

IRAEs Can Affect Any Organ System

Hypophysitis

Thyroiditis

Adrenal insufficiency

Diabetes mellitus

Enterocolitis

Dermatitis

Arthritis

Pneumonitis

Hepatitis/

pancreatitis

Nephritis

Neuropathies

And many

more…

Laboratory Monitoring

Prior to each dose:Careful clinical evaluation – Assess for immune-mediated

adverse events

CBC with differential, CMP, TFTs, cortisol, lipase

Cannot predict who will experience IRAEs

Radiologic assessment prior to start of therapy and:As needed to evaluate for IRAEs (eg, pneumonitis)

Approximately every 8-12 weeks thereafter

CMP = comprehensive metabolic panel; TFT = thyroid function test.

Approach to Potentially

Immune-Mediated Symptoms

Drug-induced until proven otherwise; often

diagnosed by exclusionOther causes must be ruled out (infections, reactions to

other medications, metabolic causes, neoplasm)

Educate the entire team!Any organ system can be affected

Early recognition, evaluation, and treatment are critical

for patient safety

IRAEs can occur ~2 years even after the

discontinuation of medication

General Toxicity Management

Discontinuation favored over dose reduction

Steroids often indicated and do not reverse antitumor effects in most

patients

Min et al, 2015; Abdel-Wahab et al, 2016.

Grade Recommendation

1 (mild) Supportive care; may or may not withhold therapy

2 (moderate) Withhold therapy; may consider restarting therapy in future

if resolves to grade ≤ 1

Low-dose corticosteroids (prednisone 0.5 mg/kg/d or

equivalent) given if symptoms do not resolve in 1 wk

3/4 (severe)

Discontinue therapy, consider permanent discontinuation

Use high-dose corticosteroids (prednisone 1-2 mg/kg/d or

equivalent) tapered SLOWLY over ≥1 mo once toxicity

resolves to grade ≤1



2 (moderate)

Withhold therapy; may consider restarting therapy in future

if resolves to grade ≤1

Low-dose corticosteroids (prednisone 0.5 mg/kg/d or

equivalent) given if symptoms do not resolve in 1 wk



IRAEs Associated With Avelumab

PFT = pulmonary function test; Cr = creatinine; CCr = creatinine clearance rate; DM = diabetes mellitus; DKA =

diabetic ketoacidosis.

Bavencio® prescribing information, 2017.

IRAE Freq. Detection Onset (mo)Duration

(median)Note

Thyroid

disorders6% Exam, TFT

2.3

(2 wk – 13 mo)

Often

permanent

Colitis 1.5%Exam,

colonoscopy

2.1

(2 d - 11 mo)6 wk

Pneumonitis 1.2% Exam, CT, PFT2.5

(3 d - 11 mo)7 wk

Hepatitis 0.9% Exam, LFT3.2

(1 wk - 15 mo)2.5 mo

Adrenal

insufficiency0.5% Exam, cortisol

2.5

(1 d - 8 mo)n/a

Nephritis 0.1% Exam, Cr, CCr n/a n/a

Type 1 DM 0.1% Exam, blood n/a n/aPossible

DKA

Controversies Surrounding

PD-1 Blockade in MCC

How long to treat?6-12 months after complete/deep-stable disease response?

Until IRAE develops?

Refractory disease…Combination therapies?

Follow-up?

Follow-Up

No data to guide recommendations for surveillance in

patients with recurrence/metastasis

Follow-up as high-risk patients?

NCCN, 2017.

Future Directions

Combinations with anti–PD-1 therapy under

investigation:CTLA-4 blockade (ipilimumab)

MCPyV-specific T cells○ Transgenic T-cell receptors

Natural killer cells with IL-15

T-VEC

CD47

Many more

Adjuvant immunotherapy?Avelumab (US trial)

Ipilimumab (EU trial)

IL-15 = interleukin-15; T-VEC = talimogene laherparepvec; CD47 = cluster of differentiation 47.

Key Takeaways

PD-1 pathway blockade preferred over

chemotherapy in 1st line for MCC due to improved

chance for durable response

Avelumab is approved based on ≥2nd-line data

Publicly available data support the use of

pembrolizumab and nivolumab

A multidisciplinary approach is essential for

optimal MCC management

Careful monitoring for adverse events is critical

Questions?

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optimizing the treatment of metastatic merkel cell carcinoma with immune checkpoint inhibitors

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