Welcome to the Jungle - Targeted Therapies, Immunomodulatory Approaches, and the New

Drugs in HNSCC

Ezra E. W. CohenMoores Cancer Center

University of California San Diego

“Welcome to the jungle

We've got fun 'n' games

We got everything you want...”

GNR

Incidence

• 2014, US:–~50000 new cases –~8000 deaths

• Worldwide:–500000 new cases–6th leading cause of death

• M:F = 3:1

Ten Leading Cancer Types, United States, 2012

CA Cancer J Clin 2012 Jan-Feb;62(1):10-29.

Risk Factors

• Age (majority of patients >50 years old)• Tobacco • Alcohol• Viral

– Epstein-Barr virus (NPC)– HPV (oropharynx)

• Hereditary (rare):– Family history increases risk (3.5X)– Rare genetic syndromes, e.g. Fanconi’s Anemia

HPV

Cancers with Increasing Incidence Trends in the US

• CA Cancer J Clin. 2012 Jan 4.

Three-dose HPV vaccination coverage among girls (13 to 17 years), by state, 2010.

New (HPV)–associated cancers overall, and by sex, in the United States, 2009

• JNCI 2013 Feb 6;105(3):175-201

BehaviorDiagnosis of HPV-SCCHN(case-case)

Risk of HPV-SCCH

(case-control)

Number of sexual partners + +

History of oral-genital sex + +

History of anal cancer + +

Spouse with tonsil cancer + +

Cervical CIS or cancer Assoc Assoc

Sexual Behaviors and HNC

HNC HPV

• Strong association with oropharynx, especially tonsil, cancers

• Non-smokers, non-drinkers• Younger age• M:F = 3:1• 90% of HNC cases with HPV are sub-type

16

Prognostic effect of HPV

• Langer CJ. Exploring biomarkers in head and neck cancer. Cancer. 2012 Aug 15;118(16):3882-92.13

Human Papillomavirus and Overall Survival After

Progression of Oropharyngeal Squamous Cell Carcinoma

C Fakhry et al

15

Overall survival after disease progression

Sur

viva

l (%

)

0

25

50

75

100

Years after Progression0 1 2

No. at Riskp16-positivep16-negative

10576

6127

5119

p16-positive54.6%

p16-negative 27.6%

p<0.001

DE-INTENSIFICATION…as an approach to address

HPV related disease and good prognosis

E1308 Induction followed by IMRT/Cetuximab

INDUCTION

(3 cycles)

Paclitaxel 90 mg/m2 q 7d

CDDP 75mg/m2 q21d

Cetuximab 250mg/m2

qwk

ELIGIBILITY

Stage III/IVa,b

Resectable

HPV+ Oropharynx

CONCURRENT

IMRT 69.3Gy/33fxs

Cetuximab 250mg/m2 qwk

CR*

<CR

CONCURRENT

IMRT 54Gy/30 fxs

Cetuximab 250mg/m2

qwk

Cetuximab loading dose = 400mg/m2 on Day1 of Cycle1 with Induction

* CR indicates clinical CR and in patients with near CR will undergo biopsies of primary site to confirm pathological CR

SI

MULATION

Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer (E3311)

p16+, Stage III/IV (cT1-2N1-N2b) OPSCC Credentialing of surgeon required as part of site

participation in the trial Stratify by stage and smoking status

T1-4a, N1-3HPV+ OPSCC

Amenable to TORS

BIOPSY

Nmax = 54

Cisplatin 75 mg/m2/q3wkPaclitaxel 90 mg/m2/week

BYL719 daily

TORS, SLND

Induction Chemotherapy3 cycles

9 weeks

pCR or pT1-2 N0-1

(-) margin, no ECE

Close margin, ≥pN2, or PNI/LVI

(+) margin, ECE

Observe

60 Gy IMRT

66 Gy IMRT

+ Weekly

Cisplatin

Risk-Stratified IMRT

TORS

* *

*FDG/PET-CT scan

Arm 1

Arm 2

Arm 3

Trial Schema

Treatment Overview

• Early stage (I, II): single modality – RT or surgery– 80-90% long-term survival

• Advanced stage (III, IVA, IVB): multi-modality therapy – surgery/RT/chemotherapy– 50% long term survival

• Recurrent/Metastasis– 15% can be salvaged (surgery, re-RT)– Palliative systemic therapy

EGFR Directed Therapy

Stratify by Karnofsky score:

90-100 vs. 60-80 Regional Nodes:

Negative vs. Positive Tumor stage:

AJCC T1-3 vs. T4 RT fractionation:

Concomitant boostvs. Once dailyvs. Twice daily

Arm 2

Radiation therapy

Cetuximab, weekly

Cetuximab Phase III Study

RANDOI

MIZE

Arm 1

Radiation therapy

Bonner. N Engl J Med. 2006;354:567. Copyright © [2006] Massachusetts Medical Society. All rights reserved.; Posner. N Engl J Med. 2006;354:634.

Phase III: Cetuximab Plus RT for SCCHN: Results

47% vs 34% at 3 yearsP<0.01 at 3 years

55% vs 45% at 3 yearsP=0.05 at 3 years

Locoregional Control OS

EXTREME - Study design

Group ACetuximab 400 mg/m2 initial dose

then 250 mg/m2 weekly + EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)+ 5-FU (1000 mg/m2 IV, d1-4):

3-week cycles

Group B

EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)

+ 5-FU (1000 mg/m2 IV, d1-4):3-week cycles

No treatmentCetuximab

Randomized

Progressive disease or unacceptable toxicity

6 chemotherapy cycles maximum

Patients at Risk Survival Time [Months]CTX onlyCET + CTX

220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3

HR (95%CI): 0.797 (0.644, 0.986)Strat. log-rank test: 0.0362

Overall Survival

CTX onlyCET + CTX

Su

rviv

al P

rob

ab

ility

0.0

0.1

0.2

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0.4

0.5

0.6

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0.9

1.0

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10.1 mo7.4 mo

Afatinib versus methotrexate as second-line treatment for patients with R/M HNSCC who progressed after platinum-based therapy:

primary efficacy results of LUX-Head & Neck 1, a Phase III trial

J-P. H. Machiels, R. I. Haddad, J. Fayette, L. F. Licitra, M. Tahara, J. B. Vermorken, P. M. Clement, T. Gauler, D. Cupissol, J. J. Grau,

J. Guigay, F. Caponigro, G. de Castro Jr, L. de Souza Viana, U. Keilholz, J. M. del Campo, X. Cong, L. Svensson, E. Ehrnrooth,

and E. E. W. Cohen on behalf of the LUX-H&N 1 investigators

LUX-Head & Neck 1: study design

Primary endpoint: PFS

Key secondary endpoint: OSSecondary endpoints: ORR, patient-reported outcomes, safety

Randomisation (2:1)Stratified by: ECOG PS (0 vs 1) and

prior use of EGFR mAb therapy (Yes/No)

Afatinib 40 mg orally once daily

(n=316)

Methotrexate40 mg/m2 IV weekly

(n=158)

Patients with incurable R/M HNSCC progressing on/after first-line

platinum-based therapy (N=474)

Primary endpoint: PFS independent review

CI, confidence interval; MTX, methotrexate

Time (months)

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12

Est

ima

ted

PF

S p

rob

abil

ity

15 18

No. of patientsAfatinib 322 93 26 9 3 1 0MTX 161 28 6 2 0 0 0

Afatinib(n=322)

MTX(n=161)

PFS event, n (%) 275 (85.4) 135 (83.9)Median PFS (months) 2.6 1.7HR (95% CI) 0.80 (0.65–0.98)Log-rank test p-value 0.030

42.8%

30.5%

afatinib mtx0

10

20

30

40

50

60

10.2

49.1

5.6

38.5

*Odds ratio: 1.9 (0.88–4.14); p-value = 0.101†Odds ratio: 1.5 (1.03–2.26); p-value = 0.035‡Disease control rate (DCR): includes objective response and stable disease

Afatinib

Methotrexate50

40

30

20

10

0ORR DCR‡

*

†

Per

cen

tag

e o

f p

atie

nts

Overall tumour response

60

Overall survival

Time (months)

Est

ima

ted

OS

pro

bab

ilit

y

No. of patientsAfatinib 322 255 172 89 53 28 14 6 1 0MTX 161 115 76 48 29 16 9 7 3 0

Afatinib(n=322)

MTX(n=161)

OS event, n (%) 237 (73.6) 121 (75.2)Median OS (months) 6.8 6.0HR (95% CI) 0.96 (0.77–1.19)Log-rank test p-value 0.700

0

0.2

0.4

0.6

0.8

1.0

0 3 9 15 21 24 2718126

Time to deterioration of pre-specified patient-reported outcomes*

*Assessed using European Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ-C30 and Head and Neck cancer-specific module (QLQ-H&N35) for pain (composite of items 31–34) and swallowing (composite of items 35–38).†Based on log-rank test.

Global health status

Est

imat

ed p

rob

abili

ty

Time (months)

0

0.2

0.4

0.6

0.8

1.0

0 151413121110987654321

Afatinib

Methotrexate

Pain Swallowing

Est

imat

ed p

rob

abili

ty

Time (months)

0

0.2

0.4

0.6

0.8

1.0

0 16 17 18151413121110987654321

Est

imat

ed p

rob

abili

ty

Time (months)

0

0.2

0.4

0.6

0.8

1.0

0 16 17 18 19 20 21151413121110987654321

HR (95% CI); p-value† 0.74 (0.56–0.97); 0.027

HR (95% CI); p-value† 0.67 (0.50–0.89); 0.004

HR (95% CI); p-value† 0.73 (0.55–0.96); 0.022

Molecular Phenotyping

COMPREHENSIVE GENOMIC CHARACTERIZATION OF SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Neil Hayes, MD, MPHUNC Chapel HillLineberger Comprehensive Cancer Center

ASCO6/3/2013

40

Significantly mutated genes in HNSCC by whole exome sequencing

Analysis – Juok Cho, Peter Hammerman, Carrie Sougnez

CDKN2A 17%FAT1 naTP53 44%CASP8 naJUB naPIK3CA 6%NOTCH1 14%MLL2 7%NSD1 6%HLA-A naTGFBR2 naHRAS 8%EPHA2 naRB1 naNFE2L2 5%KEAP1 naB2M naRAC1 na

COSMIC

MS Lawrence et al. Nature 517, 576-582 (2015) doi:10.1038/nature14129

Deregulation of signalling pathways and transcription factors.

Cancer Immunotherapy

Surgery

Removal of the tumor

Radiotherapy

Energy delivery to specific anatomical site

ImmunotherapyHarnessing the body’s own immune system to

fight cancer

Chemotherapy

Drugs designed to exploit cancer mutations

Pursuing Immunotherapy in Head and Neck Cancer

KEYNOTE-012 – Study Design• Multi-center, non-randomized Phase Ib HNSCC expansion

cohort• Multi-cohort trial* HNSCC cohort

*Additional cohorts included: Bladder Cancer, Triple Negative Breast Cancer, Gastric Cancer

• Presented by: Tanguy Seiwert

Efficacy: Waterfall Plot*

• Presented by: Tanguy Seiwert

51% (26/51) of patients had decreased tumor burden

HPV (+)HPV (-)

Subjects–100

–80

–60

–40

–20

0

20

40

60

80

100

Ch

ang

e F

rom

Bas

elin

e, %

Best percent change from baseline in target lesions (site assessment) delineated by HPV status

*as of May 23, 2014; Includes only patients with RECIST measurable lesions at baseline and at least 1 follow-up scan (n=51)

Best Overall Response*

• Presented by: Tanguy Seiwert

56 pts evaluable for

Response

Total Head/neck

N=56†HPV (+)

N=20

HPV (-)

N=36§

Response Evaluation n (%) 95% CI† n (%) 95% CI† n (%) 95% CI†

Complete Response 1 (1.8) (0.0, 9.6) 1 (5.0) (0.1, 24.9) 0 (0.0) (0.0, 9.7)

Partial Response 10 (17.9) (8.9, 30.4) 3 (15.0) (3.2, 37.9) 7 (19.4) (8.2, 36.0)

Best Overall Response (Complete + Partial)‡

11 (19.6)

(10.2, 32.4)

4 (20.0) (5.7, 43.7)

7 (19.4) (8.2, 36.0)

Stable Disease 16 (28.6) (17.3, 42.2) 8 (40.0) (19.1, 63.9) 8 (22.2) (10.1, 39.2)

Progressive Disease 25 (44.6) (31.3, 58.5) 7 (35.0) (15.4, 59.2) 18 (50.0) (32.9, 67.1)

No Assessment 4 (7.1) (2.0, 17.3) 1 (5.0) (0.1, 24.9) 3 (8.3) (1.8, 22.5)Based on RECIST 1.1 Per site assessment; includes confirmed and unconfirmed responses†61 patients eligible for treatment; 60 patients dosed; 56 patients eligible for pre-defined full analysis set. ‡A single patient with PD followed by PR on treatment was classified as PR.§Includes 2 patients for whom HPV data unavailable.† Based on binomial exact confidence interval method.

• PD-L1 expression correlates with Response• Using a Youden-Index derived, preliminary PD-L1 cut point:

Above cutpoint: 45.5% (5/11) RR Below cutpoint: 11.4% (5/44) RR

*as of May 23, 2014

Time on treatment and disposition*

• Presented by: Tanguy Seiwert

Swimmer plot of all patients who experienced CR or PR. 8 additional patients had SD >6 months, of which 7/8 remain on treatment.

0 4 8 12 16 20 24 28 32 36 40 44 48Treatment Exposure, weeks

Su

bje

cts

Complete ResponsePartial ResponseTreatment Ongoing

*as of May 23, 2014

Toll-like Receptor 8 (TLR8) Pathway is Important in Human Immune Responses

• Activation induces potent Th1 immune response • Expressed on myeloid dendritic cells (CD11c+), monocytes

(CD14+), and natural killer cells (CD56+) in humans• Induces significant IL-12 production in humans• Can be activated by small molecule agonists

• 58

A Randomized, Double-Blind, Placebo-Controlled Study of Chemotherapy Plus Cetuximab in

Combination with VTX-2337 in Patients with Recurrent or Metastatic Squamous Cell Carcinoma

of the Head and Neck

Active8

Study Schema

175 patients with locally advanced or metastatic head/neck cancerPrimary endpoint: progression-free survival

Mutation frequency among cancers of different histotypes

Mutational screen of 305 HNSCC exome sequences deposited in TCGA

HNSCC tumors express missense mutations

Mutational screen of 305 HNSCC exome sequences deposited in TCGA

HNSCC tumors express missense mutations

HNSCC pt

Project: Exome-guided neoantigen discovery in HNSCC

In office/clinic1) Tumor: FNA, core, or excision biopsy2) <1 ml PBL

Bioinformatics:Reassembly, alignment, QC

mutation calling

Confirm SNVs in expressed genes (RNAseq)

gDNA & mRNA

Whole Exome Sequencingsalvage surgery

expand TIL with ‘antigenic mutanome’ peptides

Establish PDX model & perform ACT with ‘improved” TIL

Test peptides for recognition by autologous T cells w ELISPOT

(use prediction algorithm as needed)

Immune monitoring of checkpoint blockade trials

“antigenic mutanome”

CONCLUSIONS• EGFR inhibitors still the only proven

“targeted therapy” in HNSCC• HPV is a recognized prognostic marker

– Other stratification factors needed• Immunotherapy extremely promising

– Phase 3 trials underway in R/M disease likely to complete accrual this year

– PDL1 being explored as predictive biomarker