MEETING INFO FACULTY...MEETING INFO Tele ECHO Series – July 2020 FACULTY Barbara Ann Burtness, MD Professor of Medicine (Medical Oncology) Disease Aligned Research Team Leader,a

MEETING INFO Tele ECHO Series – July 2020

FACULTY Barbara Ann Burtness, MD Professor of Medicine (Medical Oncology) Disease Aligned Research Team Leader, Head and Neck Cancers Program Co-Director, Developmental Therapeutics Research Program Yale University School of Medicine and Yale Cancer Center New Haven, CT

PROGRAM AGENDA

I.Inhibition of Immunosurveillance – Immune System and Carcinogenesis of SCCHN a. Maintenance of self-tolerance – co-inhibitory pathway b. Tumor microenvironment – immune dysfunction

i. T cell type and function ii. Cytokine makeup and associated functions

II. Immuno-oncology Agents in Recurrent/Metastatic SCCHN

a. Rationale for targeting immune checkpoint receptors in oncology b. Review of clinical trial data

i. Pembrolizumab – Efficacy and safety ii. Nivolumab – Efficacy and safety

iii. Other investigational agents and combinations iv. 3D video: Depiction of the PD-1 agents, their site of action and anti-tumor effects

c. Application of treatment guidelines in clinical practice i. Sequencing and combining therapies

ii. Place of immuno-oncology across lines of therapy III. The Safety Profile of Immune Checkpoint Inhibitors in SCCHN

a. Recognition of immune-related adverse events b. PD-1 inhibitors and irAEs in patients with advanced SCCHN c. Guideline recommendations for the management of common irAEs

IV. Immune Checkpoint Proteins and Other Biomarkers in SCCHN

a. The need for predictive biomarkers in SCCHN b. Clinical trial biomarker data and its interpretation

i. PD-L1 expression, mutational load, HPV status ii. Predictive and prognostic utility – ready for prime time?

c. Review of the utility of investigated biomarkers VI Case studies VII. Conclusions/ Questions and answers

ECHO Series: Challenges and Opportunities in Care: Maximizing Treatment of Head and Neck Cancer

Chair

Barbara Ann Burtness, MD

Professor of Medicine (Medical Oncology)

Disease Aligned Research Team Leader, Head and Neck Cancers Program

Co-Director, Developmental Therapeutics Research Program

Yale University School of Medicine and Yale Cancer Center

New Haven, CT

Learning Objectives

• Evaluate clinical trial data on the use of biomarkers to predict response to immunotherapy in head and neck squamous cell carcinoma (SCCHN)

• Utilize current treatment guidelines and clinical trial data to appropriately sequence and combine therapies in the management of SCCHN

• Develop strategies to identify and manage immune-related adverse events associated with immune checkpoint inhibitors

Target Audience

This activity is designed to meet the educational needs of medical oncologists, surgical oncologists, and other healthcare professionals who manage patients with head and neck squamous cell carcinoma.

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Purpose: This program would be beneficial for nurses involved in the care of patients with head and neck cancer.

Credits: 1.0 ANCC Contact Hour(s)

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Challenges and Opportunities in Care: Maximizing Treatment of Head and Neck Cancer

Barbara Burtness, MDProfessor of Medicine (Medical Oncology)

Disease Aligned Research Team Leader, Head and Neck Cancers Program

Co‐Director, Developmental Therapeutics Research Program

Yale University School of Medicine and Yale Cancer Center

New Haven, CT

Disclosures

• Dr. Burtness discloses that she has received consulting fees from Aduro, Alligator Biosciences, Rakuten, Marerick, Debio Pharma, Celegene, CUE Biopharma, GSK, Nanobiotix and Merck & Co., Inc.

• During the course of this lecture, the faculty may mention the use of medications for both FDA‐approved and non‐approved indications.

This activity is supported by an educational grant from Merck & Co., Inc.

2

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Learning Objectives

• Evaluate clinical trial data on the use of biomarkers to predict response to immunotherapy in head‐and‐neck squamous cell carcinoma (SCCHN)

• Utilize current treatment guidelines and clinical trial data to appropriately sequence and combine therapies in the management of SCCHN

• Develop strategies to identify and manage immune‐related adverse events associated with immune checkpoint inhibitors

SCCHN = squamous cell carcinoma of the head and neck.

SCCHN Background

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Head and Neck Cancer: Disease Background

• Head‐and‐neck cancer (HNC) is sixth most common cancer worldwide; >53,000 new cases per year in the United States

• HPV is involved in the etiology of ~60–80% of oropharyngeal HNC in the US

• HPV(–)/tobacco‐related HNC and HPV(+) HNC are distinct clinical entities

• Risk factors

Siegel RL, et al. CA Cancer J Clin. 2020;70:7‐30. Union for International Cancer Control. 2014 (www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf). Centers for Disease Control and Prevention (CDC) 2018 (www.cdc.gov/cancer/hpv/statistics/headneck.htm). American Cancer Society (ACS). Risk factors for oral cavity and oropharyngeal cancers 2018 (www.cancer.org/cancer/ oral‐cavity‐and‐oropharyngeal‐cancer/causes‐risks‐prevention/risk‐factors.html). National Cancer Institute (NCI). Oral cavity, pharyngeal and laryngeal cancer prevention (PDQ®). (www.cancer.gov/types/head‐and‐neck/hp/oral‐prevention‐pdq). NCI. Head and neck cancers. (www.cancer.gov/types/head‐and‐neck/head‐neck‐fact‐sheet#how‐common‐are‐head‐and‐neck‐cancers). CDC. HPV and cancer (www.cancer.gov/about‐cancer/causes‐prevention/risk/infectious‐agents/hpv‐and‐cancer). All URLs accessed 6/15/2020.

– Age (majority of patients >50 years) – Viral (~25–35% of patients with SCC) • EBV (nasopharynx) • HPV (oropharynx)

– Chinese/Asian ancestry (nasopharynx)

– Tobacco

– ETOH (absolute alcohol)

HPV = herpes papillomavirus; EBV = Epstein‐Barr virus.

Sub‐sites of SCCHN

ACS. About oral cavity and oropharyngeal cancer.(www.cancer.org/content/dam/CRC/PDF/Public/8763.00.pdf). Accessed 6/15/2020. Kim K, et al. Head Neck Oncol. 2011;3:47.

• Heterogeneous group of cancers of varying primary sites

• >90% are SCCHN

– Oral cavity

– Oropharynx/hypopharynx

– Larynx

– Nasopharynx

– Paranasal sinuses

– Lip

– Salivary glands

SCCHN = squamous cell carcinoma of the head and neck.

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The HPV “Epidemic”

Chaturvedi AK, et al. J Clin Oncol. 2011;29:4294‐4301.

Calendar yearsCalendar yearsCalendar years

Rates per 100,000

Rates per 100,000

Annual number of cases

Oropharynx (overall)HPV‐positive oropharynx HPV‐negative oropharynx

CervixOropharynx (overall)Oropharynx (men)Oropharynx (women)

CervixOropharynx (overall)Oropharynx (men)Oropharynx (women)

2010

10

1

0.11988–1990

1990 1995 2010 20252003–2004

1999–2000

1995–1996

1991–1992

100

0.1 0

5000

10,000

15,000

20,000

2010 2020 2030

10

1

PIK3CAmut/amp

TSC1/2mut

INPP4Bmut

HPV E6/E7exp

RB1mut

CDKN2Awt p16

NF1/2mut

E2F1amp

TP53wt

HLA A/B, B2Mmut

NOTCH1/2/3mut

TP63/SOX2amp

PTENmut/del

FGFR2/3mut/fus

TRAF3mut/del

CYLDmut

RTKs HLA / Inflammation NOTCH/Differentiation

PI3K signaling RAS signaling NF-kB

Cell Cycle

Presumed effectson immunogenicity

Other RTK alt. are uncommon

Inflammation /effects on Immune Function

Proliferation andSurvival

ImpairedDifferentiation

100100

event rate activatinginactivating

A. HPV-Positive

KRASmut PIK3CA

mut/amp

TSC1/2mut

INPP4Bmut

MYCamp

RB1mut

CDKN2Amut/del

NF1/2mut

CCND1amp

TP53mut

HLA A/B, B2Mmut

NOTCH1/2/3mut

TP63/SOX2amp

PTENmut/del

FGFR1/2/3mut/amp

RTKs HLA / Inflammation NOTCH/Differentiation

PI3K signaling RAS signalingFADDamp

CASP8mut

Cell Death

Cell Cycle

Presumed effectson immunogenicity

Inflammation /effects on

Immune Function

Proliferation andSurvival

ImpairedDifferentiation

B. HPV-negative

EGFRmut/amp

MET

DDR2

EPHA2

IGF1R

ERBB2

HRASmut

FAT1/AJUBAmut

NFE2L2mut

CULmut

KEAP1mut

mu

t/am

p

Oxidative Stress

050 % altered50

*

Hayes DN, et al. J Clin Oncol. 2015;33:3227‐3234.

1. HPV(+) and HPV(–) tumors are distinct BIOLOGIC entities

2. High mutational burden (both)

SCCHN Has Distinct Molecular SubtypesHVP‐positive HVP‐negative

Amp = amplification; del = deletion; HLA = human leukocyte antigen; mut = mutation; fus = fusion/translocation; wt = wild type.

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Tumor Microenvironment: HPV+ vs HPV– SCCHN

Chaudhary S, et al. J Natl Cancer Inst. 2019;111:233‐244.

Tumor microenvironment

COX5B = cytochrome C oxidase subunit 5B; GLUT1 = glucose transporter type 1; CD = cluster of differentiation; Th = T helper (cell); Foxp3 = forkhead box P3.

HPV Status Influences PrognosisEven in Recurrent/Metastatic Disease

Argiris A, et al. Ann Oncol. 2014;25:1410‐1416.

Progression‐free survival Overall survival

HPV ORR

p16 ORR

• HPV negative = 19%• HPV positive = 55%

• p16 negative = 19%• p16 positive = 50%

ORR = overall/objective response rate.

HPV+HPV–

HPV+HPV–

p16+p16–

p16+p16–

Log‐rank P= .056

Log‐rank P= .096

Log‐rank P= .014

Log‐rank P= .027

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Cytokines in SCCHNCytokine Function Key points

Transforming growth factor β (TGF-β)

• Suppresses NK and T-cell activation • Key cytokine in Treg differentiation

Interleukin-6 (IL-6) • Inhibits dendritic cell maturation • Inhibits NK-cell, T-cell, neutrophil and

macrophage activation

• Correlated with recurrence and survival in SCCHN

Signal transducer and activator of transcription 3 (STAT3)

• Transcription factor • Involved in other immunosuppressive pathways, including IL-10 signaling, dendritic cell suppression, IL-12 downregulation, and Treg generation

Prostaglandin E2 • Proangiogenic molecule • Produced by SCCHN

Vascular endothelial growth factor (VEGF)

• Promoter of angiogenesis• Increases the ratio of immature to

mature dendritic cells in tumor microenvironment

• Overexpressed in 90% of SCCHN• Increase in immature dendritic cell

ratio thought to lead to T-cell dysfunction and inactivation

Toll-like receptors (TLRs)

• Stimulate production of proinflammatory cytokines, including TNF-α and IFN-𝛾

• Induces a T-cell stimulating effect

• Results in a type 1 helper response

Ferris RL. J Clin Oncol. 2015;33:3293‐3304.

NK = natural killer (cell): TNF = tumor‐necrosis factor; IFN = interferon: Treg = regulatory T cell.

Immune Components of Tumor Microenvironment

Ferris RL. J Clin Oncol. 2015;33:3293‐3304.

Cellular immune component

Function Key points

Myeloid-derived suppressor cells (MDSCs)

• Inhibit activated T-cells• Produce nitric oxide and reactive oxygen species,

causing T-cell receptor nitration, inhibiting T-cell receptor and HLA interaction, signaling, and activation

• Basal MDSC levels increase with age

Suppressive regulatory T cells (Tregs)

• Secrete suppressive cytokines, including TGF-β and IL-10

• Treg subset also expresses cytotoxic T lymphocyte-associated protein 4 (CTLA-4), CD25, and CD39

• Promote cancer progression by anergy, apoptosis, and cell cycle arrest of activated T cells

• Can inhibit the action of dendritic cells, NK cells, and B cells

Tumor associated macrophages (TAMs)

• May have M1 phenotype, characterized by IFN-𝛾 and other type 1 cytokine production

• Alternatively activated (M2) macrophages force Th2 cytokine response, producing tumor growth by promoting interleukins such as IL-4 and IL-13

• M2 phenotype produces EGF, IL-6 and IL-10

• Correlate with worse clinical outcome• Close association with M2 phenotype• M2 phenotypes have been associated

with angiogenesis, local tumor progression and metastasis

SCCHN induces immunosuppressed state through multiple mechanisms, creating a barrier to effective cancer therapy

EGF = epidermal growth factor.

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Cancer Is Highly Immunosuppressive

• Reduced antigen processing and presentation (signal 1)

• Anergic T cells (signal 2)

– ↑ Co‐inhibitory receptors: CTLA‐4, PD‐1

– ↓ Co‐stimulatory receptors: CD137, OX40

• Tumor‐permissive cytokine profile (signal 3)

PD‐1 = programmed (cell) death (protein) 1; APC = antigen‐presenting cell; TCR = T‐cell receptor; MHC = major histocompatibility complex.

Ferris RL. J Clin Oncol. 2015;33:3293‐3304. Agrawal L, et al. Postgrad Med. 2020; 132:206‐214. Gaspar M, et al. Cancer Immunol Res. 2020;8:781‐793.

SCCHN: Immunotherapy Data

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FDA Approvals for PD‐1 Inhibitors: Nivolumab

FDA = US Food and Drug Administration; IPI = ipilimumab; CRC = colorectal cancer; dMMR = mismatch repair deficiency; NSCLC = non‐small cell lung cancer; SCLC = small cell lung cancer; MSI‐H = microsatellite instability‐high; RCC = renal cell carcinoma; LN = lymph node; SCT = stem cell transplant.

Agent Target Approved Indications*Nivolumab (Nivo)

IgG4 Fully human

PD-1

high affinity

• Bladder cancer (advanced/metastatic, 2nd line)

• Head and neck (recurrent/metastatic, 2nd line)

• Hepatocellular carcinoma (2nd line)

• Hodgkin lymphoma (relapsed/progressed after SCT or 4th line)

• Melanoma (metastatic and adjuvant)

• MSI-H/dMMR CRC (2nd line)

• NSCLC (metastatic, 2nd line)

• RCC (advanced, 2nd line), in combo w/IPI (intermediate or poor risk)

• SCLC (metastatic, 3rd line)

• Esophageal SCC (advanced, recurrent, metastatic (2nd line)

Nivolumab (Opdivo®) PI 2020 (https://packageinserts.bms.com/pi/pi_opdivo.pdf). Accessed 6/15/2020. InvivoGen. Anti‐hPD1‐Ni‐hlgG4 (https://www.invivogen.com/anti‐hpd1‐higg4s228p). Accessed June 24, 2020.

*See prescribing information for complete detailing of approved indications

FDA Approvals for PD‐1 Inhibitors: Pembrolizumab

CPS = combined positive score.

Agent Target Approved Indications*Pembrolizumab (Pembro)

IgG4Humanized

PD-1

high affinity

• Bladder cancer (1st and 2nd line)

• Cervical cancer (2nd line)

• Cutaneous squamous cell carcinoma (recurrent or metastatic not curable by surgery or radiation)

• Endometrial carcinoma (advanced, not MSI-H or dMMR, 2nd line)

• Esophageal (recurrent locally advanced or metastatic, 2nd line)

• Gastric cancer (3rd line)

• Head and neck − metastatic and unresectable, recurrent—

1st-line/combo therapy

− metastatic and unresectable, recurrent w/ PD-L1 expression ≥1 (by CPS)—1st-line/single agent

− recurrent or metastatic (2nd line)

• Hepatocellular carcinoma (2nd line)

• Hodgkin lymphoma (4th line)

• Melanoma (all metastatic and adjuvant)

• Merkel cell carcinoma (recurrent locally advanced or metastatic)

• MSI-H tumors (1st and 2nd line)

• NSCLC (1st and 2nd line)

• Primary mediastinal large B-cell lymphoma (3rd line)

• RCC (advanced, 1st-line/combo therapy)

• SCLC (metastatic, 2nd line)

• TMB-H tumors (2nd line)

Pembrolizumab (Keytruda®) PI, 2020 (www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf). Accessed 6/24/2020. InvivoGen. Anti‐hPD1‐Pem‐hlgG2 (https://www.invivogen.com/anti‐hpd1‐pem‐higg2). Accessed June 24, 2020.

*See prescribing information for complete detailing of approved indications

NL1NL2

Slide 16

NL1 slide updated for endometrial carcinoma and esophageal cancer Nicole Longo, 9/17/2019

NL2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/12551Nicole Longo, 9/17/2019

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SCCHN Cohorts of Nonrandomized Patients Phase 1b, Multi‐Cohort KEYNOTE‐012 Trial

• Patients: recurrent or metastatic SCCHN patients who have good performance status with PD‐L1 positive tumors

• Initial cohort: 60 patients to receive weight‐based pembrolizumab every 2 weeks

• Expansion cohort: 132 patients to receive fixed‐dose pembrolizumab every 3 weeks

• Study endpoints: ORR, safety

Seiwert TY, et al. Lancet Oncol. 2016;17:956‐965. Chow LQ, et al. J Clin Oncol. 2016;34:3838‐3845.

Chan

ge from baselin

e in

tumor size (%)

20% increase

30% decrease

Weeks

HPV‐positiveHPV negative

100

–100

80

60

40

20

0

–20

–40

–60

–80

40 50 60100 20 30

Research Concepts: Chemo‐immunotherapy

Chemotherapy + immune therapy

CRT = calreticulin; CRTR = CRT receptor.Kepp O, et al. Cancer Metastasis Rev. 2011;30:61‐69.

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• Gastric• SCCHN• Likely bladder• Lung cancer (TPS) is an “outlier.”

PD‐L1 staining tumor

PD‐L1 non‐staining tumor

PD‐L1 staining mononuclear

inflammatory cell

~CPS 80

~CPS 50

~CPS 30

~CPS 100

Calculate the CPS of the entire tumor area:

Assessment of CPS

(80 + 30 + 50 + 100) / 4 = CPS ~65

Clinical interpretation: PD‐L1 expression

# PD‐L1 staining cells (tumor cells, lymphocytes,

macrophages)

Total # viable tumor cellsCPS = x 100

• With Pembro 1st‐line approval 6/2019, PD‐L1 CPS testing (NOT TPS) is now recommended

• With Pembro 1st‐line approval 6/2019, PD‐L1 CPS testing (NOT TPS) is now recommended

CPS—Combined Positive Score

Burtness B, et al. Ann Oncol. 2018;29(suppl 8):viii729 (abstract LBA8_PR). Burtness B, et al. Lancet. 2019;394:1915‐1928. FDA. (www.fda.gov/drugs/resources‐information‐approved‐drugs/fda‐approves‐pembrolizumab‐first‐line‐treatment‐head‐and‐neck‐squamous‐cell‐carcinoma). URLs accessed 6/15/2020.

TPS = tissue polypeptide‐specific antigen.

KEYNOTE‐048: OS, Pembro + Chemotherapy vs EXTREME

OS = overall survival; P = Pembrolizumab; C = chemotherapy; mo = month(s); HR = hazard ratio; CI = confidence interval. Data cutoff date: Feb 25, 2019.

Median OS (95% CI)14.7 mo (10.3–19.3)11.0 mo (9.2–13.0)

12‐mo rate57.1%46.1%

24‐mo rate35.4%19.4%

36‐mo rate33.2%8.0%

0 10 20 30 40 500

20

40

60

80

100

MonthsNo. at risk126 102 77 60 50 44 36 21 4 0 0110 91 60 40 26 19 11 4 1 0 0

OS (%

)

Median OS (95% CI)13.6 mo (10.7–15.5)10.4 mo (9.1–11.7)

12‐mo rate55.0%43.5%

24‐mo rate30.8%16.8%

36‐mo rate25.6%6.5%

0 10 20 30 40 500

20

40

60

80

100

MonthsNo. at risk242 197 144 109 84 70 52 29 5 0 0235 191 122 83 54 35 17 5 1 0 0

OS (%

)

Median OS (95% CI)13.0 mo (10.9–14.7)10.7 mo (9.3–11.7)

12‐mo rate53.0%43.9%

24‐mo rate29.4%18.8%

36‐mo rate22.6%10.0%

0 10 20 30 40 500

20

40

60

80

100

MonthsNo. at risk281 227 169 122 94 77 55 29 5 0 0278 227 147 100 66 45 23 6 1 0 0

OS (%

)

Events HR (95% CI) P-value

P+C Extreme

CPS ≥20 population 67% 89% 0.60 (0.45–0.82) .0004

CPS ≥1 population 73% 91% 0.65 (0.53–0.80) <.0001

Total population 76% 89% 0.72 (0.6–0.87)

CPS ≥20 population CPS ≥1 population Total population

Rischin D, et al. J Clin Oncol. 2019;37(suppl): abstract 6000. Burtness B, et al. Lancet. 2019;394:1915‐1928 supplement.

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KEYNOTE‐048: OS, Pembro vs EXTREME

Data cutoff date: Feb 25, 2019.

Events HR (95% CI) P-value

Pembro alone Extreme

CPS ≥20 population 71% 89% 0.58 (0.44–0.78)

CPS ≥1 population 77% 90% 0.74 (0.61–0.90)

Total population 79% 88% 0.83 (0.70–0.99) .0199

Median OS (95% CI)14.8 mo (11.5–20.6)10.7 mo (8.8–12.8)

12‐mo rate56.4%44.9%

24‐mo rate35.3%19.1%

36‐mo rate29.3%9.2%

0 10 20 30 40 500

20

40

60

80

100

MonthsNo. at risk133 107 85 65 57 45 29 15 9 1 0122 100 64 42 28 21 13 6 3 0 0

OS (%

)

CPS ≥20 population CPS ≥1 population Total population

Median OS (95% CI)12.3 mo (10.8–14.3)10.3 mo (9.0–11.5)

12‐mo rate50.4%43.6%

24‐mo rate28.9%17.4%

36‐mo rate22.1%8.0%

0 10 20 30 40 500

20

40

60

80

100

MonthsNo. at risk257 197 152 110 91 70 43 21 13 1 0255 207 131 89 59 40 21 9 5 0 0

OS (%

)

Median OS (95% CI)11.5 mo (10.3–13.4)10.7 mo (9.3–11.7)

12‐mo rate48.7%44.4%

24‐mo rate27.0%18.8%

36‐mo rate19.7%10.0%

0 10 20 30 40 500

20

40

60

80

100

MonthsNo. at risk301 226 172 125 99 75 46 22 13 1 0300 245 158 107 72 51 28 11 6 0 0

OS (%

)

Burtness B, et al. Lancet. 2019;394:1915‐1928.

Assessments and Statistical Analysis• PFS2: time from randomization to objective tumor progression on next‐line therapy or death from any cause

– Exploratory outcome assessed in patients receiving subsequent therapy after 1L therapy

– Estimated using the Kaplan‐Meier method

– HR and 95% CIs based on a Cox regression model with Efron’s method of handling ties with treatment as a covariate

• Stratified by ECOG PS, HPV status, and PD‐L1 for CPS ≥1 and total populations

• Stratified by ECOG PS and HPV status for CPS ≥20 population

Harrington KJ, et al. J Clin Oncol. 2020;38(15 suppl): abstract 6505.

Patients who did not receive 2L therapyor who stopped 2L therapy without PD

and did not start 3L therapy

Patients who stopped2L therapy with PD

Patients who stopped 2L therapywithout PD and started 3L therapy

Counted as an event at the timeof death if the patient died Counted as an event

at the time of PDCounted as an event

at the start of 3L therapyCensored at the time of last knownsurvival if the patient was alive

PD = progressive disease; ECOG = Eastern Cooperative Oncology Group; PS = performance status.

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CPS ≥20 Population Events HR (95% CI)

Pembro + chemo 72.2% 0.63 (0.47–0.84)

EXTREME 90.9%

KEYNOTE‐048: PFS2 in Patients Initially Randomized Pembro + Chemotherapy vs EXTREME

PFS2 analysis involved patients in the ITT population with PD‐L1 CPS≥20 (Pembro + Chemotherapy vs EXTREME)

ITT = intention to treat.

0 5 10 15 20 25 30 35 40 45 500102030405060708090100

Months

PFS2 (%)

(%)

12‐mo rate49.2%34.2%

24‐mo rate28.9%12.0%

Median PFS2 (95% CI)11.3 mo (8.8–14.7)9.7 mo (8.4–11.0)

No. at risk126 98 66 49 41 35 29 17 4 0 0

110 87 53 29 17 12 7 3 0 0 0


Pembro + chemo 78.9% 0.66 (0.54–0.80)

EXTREME 93.2%

0 5 10 15 20 25 30 35 40 45 500102030405060708090100

Months

PFS2 (%)

12‐mo rate45.5%32.3%

24‐mo rate23.7%9.0%

Median PFS2(95% CI)10.3 mo (9.2–12.5)8.9 mo (8.4–9.8)

No. at risk242 190 125 86 64 52 40 22 4 0 0

235 180 101 51 30 19 11 4 1 0 0



Pembro alone 76.7% 0.64 (0.48–0.84)

EXTREME 91.0%

PFS2: Initially Randomized, Pembro vs EXTREME

PFS2 analysis involved patients in the ITT population with PD‐L1 CPS≥20 (Pembro vs EXTREME)

0 5 10 15 20 25 30 35 40 45 500102030405060708090100

Months

PFS2 (%)

Median PFS2 (95% CI)11.7 mo (9.1–14.8)9.4 mo (7.9–10.8)

No. at risk133 102 73 53 40 35 21 11 8 0 0

122 96 56 31 19 14 9 5 1 0 0

12‐mo rate48.1%33.3%

24‐mo rate27.0%12.5%


Pembro alone 80.9% 0.80 (0.66–0.96)

EXTREME 92.5%

0 5 10 15 20 25 30 35 40 45 500102030405060708090100

Months

PFS2 (%)

12‐mo rate37.3%32.9%

24‐mo rate22.0%9.9% Median PFS (95% CI)

9.4 mo (8.3–10.2)8.8 mo (8.3–9.8)

No. at risk257 185 116 77 60 54 31 16 11 0 0

255 196 109 56 35 23 15 8 3 0 0


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First Subsequent Therapy

*A patient is counted only once for each therapy group, but a patient could be counted in more than one therapy group.

n (%)

Pembro Monotherapy

n = 301

Pembro + Chemotherapy

n = 281EXTREME

n = 300

Any new anticancer treatment* 148 (49) 115 (41) 159 (53)

Chemotherapy 135 (44.9) 88 (31.3) 102 (34.0)

EGFR inhibitor 59 (19.6) 37 (13.2) 19 (6.3)

Immune checkpoint inhibitor 6 (2.0) 12 (4.3) 50 (16.7)

Other immunotherapy 1 (0.3) 0 (0.0) 6 (2.0)

Kinase inhibitor 1 (0.3) 7 (2.5) 1 (0.3)

Other 2 (0.7) 1 (0.4) 2 (0.7)


CHECKMATE 141: OS Nivolumab vs IC

Ferris RL, et al. N Engl J Med. 2016;375:1856‐1867.

Patientsn

mOSmo (95% CI)

Nivolumab 240 7.5 (5.5–9.1)

Investigator’s choice 121 5.1 (4.0–6.0)

HR = 0.70 (97.73% CI, 0.51–0.96); P= .01

Response rate was only 13%, but it had a major impact on SURVIVAL

0 3 6 9 12 15 18

Months

Nivolumab 240 167 109 52 24 7 0IC 121 87 42 17 5 1

No. at risk

0

0

10

20

30

40

50

60

70

80

90

100

OS (%

)

1‐year OS36.0% (95% CI, 28.5–43.4)

16.6% (95% CI, 8.6–26.8)

Nivolumab

Investigator’s choice

IC = investigator’s choice; mOS = median OS.

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CHECKMATE 141: OS by Tumor HPV

Ferris RL, et al. Oral Oncol. 2018;81:45‐51.

Long‐term OS benefit was observed irrespective of HPV status.

HPV positive mOS, mo (95% CI) HR (95% CI)

Nivolumab (n = 64) 9.1 (6.5–11.8) 0.60 (0.37–0.97)

IC (n = 29) 4.4 (3.0–9.8)

HPV negative mOS, mo (95% CI) HR (95% CI)

Nivolumab (n = 56) 7.7 (4.8–13.0) 0.59 (0.38–0.92)

IC (n = 37) 6.5 (3.9–8.7)

Nivolumab


OS (%

)

Months

OS (%

)

Months

HPV‐positive HPV‐negative100

90

80

70

60

50

40

30

03924 27 30 33 36211815129630

012 11 7 6 3131617233140506401 1 1 1 012489132029

No. at risk

NivoIC

20

10

100

90

80

70

60

50

40

30

03924 27 30 33 36211815129630

013 8 4 2 0151619222434385602 1 0 0 0344511182837

No. at risk

NivoIC

20

10

Nivolumab


CHECKMATE 141: OS by Tumor PD‐L1

Ferris RL, et al. Oral Oncol. 2018;81:45‐51.

Long‐term OS benefit was observed irrespective of PD‐L1 expression.

PD-L1 expressors mOS, mo (95% CI) HR (95% CI)

Nivolumab (n = 96) 8.2 (6.7–9.5) 0.55(0.39–0.78)

IC (n = 63) 4.7 (3.8–6.2)

PD-L1 non-expressors mOS, mo (95% CI) HR (95% CI)

Nivolumab (n = 76) 6.5 (4.4–11.7) 0.73 (0.49–1.09

IC (n = 40) 5.5 (3.7–8.5)

PD‐L1 expressors

OS (%

)

Months

OS (%

)

Months

100

90

80

70

60

50

40

30

03924 27 30 33 36211815129630

016 11 8 5 1192225304259749602 2 0 0 03461014244563

No. at risk

NivoIC

20

10

Nivolumab


24.0%18.5%

13.7%

PD‐L1 non‐expressors

OS (%

)

Months

OS (%

)

Months

100

90

80

70

60

50

40

30

03924 27 30 33 36211815129630

015 11 5 4 3171920293239547604 1 0 0 04571014193040

No. at risk

NivoIC

20

10

26.2%20.7%

11.2%

Nivolumab


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CHECKMATE 141: OS by Tumor p16 Status

Ferris RL, et al. N Engl J Med. 2016;375:1856‐1867 supplement.

Months0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

OS (%

)

Nivolumab


50 32 25 12 136 26 13 7

63 1

00

p16‐negative

OS (%

)

Months0 3 6 9 12 15 18

0

10

20

30

40

50

60

70

80

90

100

Nivolumab


NivolumabIC

No. at risk63 49 35 18 10 3 029 20 11 4 1 0 0

p16‐positive

p16-positive mOS, mo (95% CI) HR (95% CI)

Nivolumab (n = 63) 9.1 (7.2–10.0) 0.56(0.32–0.99)

Standard Tx (n = 29) 4.4 (3.0–9.8)

p16-negative mOS, mo (95% CI) HR (95% CI)

Nivolumab (n = 50) 7.5 (3.0–NA) 0.73(0.42–1.25)

Standard Tx (n = 36) 5.8 (3.8–9.5)

EAGLE: OS by Treatment Arm (ITT Population)

Licitra LF, et al. J Clin Oncol. 2019;37(15 suppl): abstract 6012.

• Primary OS endpoint was not statistically significant for D+T or D vs SoC

• OS rate for D at 12 to 24 months was numerically higher than SoC

Time from randomization (months)

Probab

ility of OS

D+T (n = 247) SoC (n = 249) D (n = 240)Median overall survival, mos (95% Cl) 6.5 (5.5–8.2) 8.3 (7.3–9.2) 7.6 (6.1–9.8)Hazard ratio (95% Cl)(compared with SOC)

1.04 (0.85–1.26) 0.88 (0.72–1.08)

P-value .76 .20Survival at 12 mos, % (95% Cl) 30.4 (24.7–36.3) 30.5 (24.7–36.4) 37.0 (30.9–43.1)Survival at 18 mos, % (95% Cl) 21.0 (15.9–26.5) 17.8 (13.1–23.2) 25.4 (19.9–31.3)Survival at 24 mos, % (95% Cl) 13.3 (8.9–18.6) 10.3 (5.7–16.5) 18.4 (13.3–24.1)

mAb = monoclonal antibody; D = anti‐PD‐L1 mAb; T = anti‐CTLA4 mAb; SoC = standard of care.

D+T

SoC

D

+ Censored

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Investigational Trials for SCCHNSTUDY STUDY CONDITION STUDY AGENT(S)/PROTOCOL PHASE

PATHWayNCT02841748

SCCHN Adjuvant pembrolizumab x 1 year vs placebo 2

E3161NCT03811015

Intermediate risk HPV+ SCCHN, locally advanced

Weekly cisplatin and radiation followed by 1 year of nivolumab or observation

2/3

HN004NCT03258554

Locally advanced cisplatin‐ineligible SCCHN

Radiation with weekly cetuximab vs radiation with durvalumab every 4 weeks

2/3

KEYNOTE‐412NCT03040999

High‐risk locally advanced SCCHN

Radiation with high‐dose cisplatin with pembrolizumab or placebo—completed accrual

3

JAVELINNCT02952586

High‐risk locally advanced SCCHN

Avelumab + SoC CRT (cisplatin plus definitive radiation) or SoC CRT—completed accrual and reported negative

3

KEYNOTE 689NCT03765918

Resectable SCCHN Neoadjuvant pembrolizumab followed by surgery + pembrolizumab and risk‐adjusted post‐operative therapy vs surgery and risk‐based post‐operative therapy

3

LEAP‐10NCT04199104

Met/rec SCCHN in 1st line Lenvatinib daily + pembrolizumab every 3 weeks vs placebo + pembrolizumab every 3 weeks

3

INDUCE‐3NCT04128696

Met/rec SCCHN in 1st line Pembrolizumab + GSK3359609 vs pembrolizumab + placebo 2/3

Met = metastatic; rec = recurrent; GSK3359609 = ICOS (inducible T‐cell co‐stimulatory) agonist antibody.

Immune‐Related Adverse Events in SCCHN

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Time of Onset of irAEs With ICIs

Sznol M, et al. J Clin Oncol. 2017;35:3815‐3822. Postow MA, et al. N Engl J Med. 2018;378:158‐168. Weber JS, et al. J Clin Oncol. 2012;30:2691‐2697. Pallin DJ, et al. Acad Emerg Med. 2018;25:819‐827.

• IrAEs can emerge weeks to months after therapy

• A patient’s history of treatment with ICI agents may be relevant in the emergency setting

Time to onset of grade 3/4

treatment‐related AEs

GI = gastrointestinal; IQR = interquartile range.

Time since study initiation (weeks)

Skin(n = 33)

Renal(n = 7)

GI(n = 73)

Hepatic(n = 76)

Endocrine(n = 21)

Pulmonary(n = 6)

3.1 (IQR = 1.0–8.0; min‐max = 0.1–55.0)

16.3 (IQR = 4.1–23.7; min‐max = 3.3–29.0)

7.1 (IQR = 4.3–10.6; min‐max = 0.6–48.9)

8.4 (IQR = 5.2–12.1; min‐max = 2.1–48.0)

11.4 (IQR = 6.7–13.6; min‐max = 2.9–19.1)

9.4 (IQR = 3.7–19.9; min‐max = 3.7–20.6)

6050403020100

Adverse Events Pembrolizumab vs Nivolumab

Burtness B, et al. Lancet. 2019;394:1915‐1928. Ferris RL, et al. Oral Oncol. 2018;81:45‐51

All AEsP

(n = 300)EXTREME (n = 287)

Any grade 97% 100%

Grade 3–5 55% 83%

Led to death 8% 10%

Led to discontinuation 12% 28%

All‐Cause Adverse Events, KEYNOTE‐048

All AEsNivolumab

(n = 236)IC

(n = 111)

Any grade 61.9% 79.3%

Grade 3–4 15.3% 36.9%

Led to death n = 2 n = 1

Led to discontinuation 4.2% 9.0%

AE = adverse event.

All‐Cause Adverse Events, CHECKMATE 141

*IC = methotrexate, docetaxel, or cetuximab

Common AEs for pembrolizumab

Grade 1–2 Grade 3–5

• Fatigue• Constipation• Nausea

• Fatigue• Anemia• Constipation

Common AEs for Nivolumab

Any Grade Grade 3–4

• Dermatologic• Fatigue• Nausea

• Fatigue• Anemia• Asthenia

* Grade 5 = death

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Grade Steroids Study Treatment Persistent/Recurring

1Treat symptomatically; no

systemic steroidsContinue

2Steroids for

selected AEsWithhold for most AEs

Systemic steroids; discontinue for selected AEs

3 Systemic steroids Withhold or discontinueSystemic steroids and

discontinue

4 Systemic steroidsDiscontinue

(unless endocrine irAEs)

Systemic steroids (by mouth or IV): 1–2 mg/kg/day prednisone or equivalent • Slow taper over ≥4 weeks is recommended• Several courses may be necessary if symptoms worsen when dose is decreased

Management of irAEs*

*Endocrine irAEs are treated differently. Steroids are not needed except for physiologic replacement in adrenal insufficiency.

IV = intravenous; irAE = immune‐related adverse event.

Brahmer JR, et al. J Clin Oncol. 2018;36:1714‐1768. Puzanov I, et al. J Immunother Cancer. 2017;5:95.

General Approach to Immune‐Mediated Symptoms

Can affect any organ system

irAE is always included in differential and is often diagnosed by exclusion

Early recognition, evaluation, and treatment are critical for patient safety

Rule out other etiologies(eg, infection, other drugs, neoplasm, metabolic causes)

Brahmer JR, et al. J Clin Oncol. 2018;36:1714‐1768. Puzanov I, et al. J Immunother Cancer. 2017;5:95.

Pretreatment patient education on potential irAE development

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Take‐Home Messages

• Immunotherapy is active in SCCHN (HPV+ and HPV–).

– Response rates of ~16%–20% with with anti‐PD‐1 in SCCHN

• ~50% of patients experienced any decrease in target lesions

– Pembrolizumab as first‐line treatment prolongs survival as monotherapy in PD‐L1‐expressing patients and with chemotherapy in all patients

– Early pembrolizumab impacts PFS2

– For patients who have not received immune‐checkpoint inhibitor in first‐line, nivolumab and pembrolizumab prolong survival relative to SoC chemotherapy or cetuximab

• Well tolerated, but potential for rare, serious AEs

• As a biomarker, PD‐L1 can enrich but NOT select patients

Thank you!

Documents

MEETING INFO FACULTY...MEETING INFO Tele ECHO Series – July 2020 FACULTY Barbara Ann Burtness, MD Professor of Medicine (Medical Oncology) Disease Aligned Research Team Leader,a