welcome to the jungle - targeted therapies, immunomodulatory approaches, and the new drugs in hnscc...
TRANSCRIPT
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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
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“Welcome to the jungle
We've got fun 'n' games
We got everything you want...”
GNR
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Incidence
• 2014, US:–~50000 new cases –~8000 deaths
• Worldwide:–500000 new cases–6th leading cause of death
• M:F = 3:1
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Ten Leading Cancer Types, United States, 2012
CA Cancer J Clin 2012 Jan-Feb;62(1):10-29.
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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
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HPV
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Cancers with Increasing Incidence Trends in the US
• CA Cancer J Clin. 2012 Jan 4.
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Three-dose HPV vaccination coverage among girls (13 to 17 years), by state, 2010.
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New (HPV)–associated cancers overall, and by sex, in the United States, 2009
• JNCI 2013 Feb 6;105(3):175-201
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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
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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
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Prognostic effect of HPV
• Langer CJ. Exploring biomarkers in head and neck cancer. Cancer. 2012 Aug 15;118(16):3882-92.13
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Human Papillomavirus and Overall Survival After
Progression of Oropharyngeal Squamous Cell Carcinoma
C Fakhry et al
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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
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DE-INTENSIFICATION…as an approach to address
HPV related disease and good prognosis
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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
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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
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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
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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
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EGFR Directed Therapy
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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
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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
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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
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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
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
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|| | |
10.1 mo7.4 mo
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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
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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)
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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%
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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
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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
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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
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Molecular Phenotyping
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COMPREHENSIVE GENOMIC CHARACTERIZATION OF SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
Neil Hayes, MD, MPHUNC Chapel HillLineberger Comprehensive Cancer Center
ASCO6/3/2013
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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
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MS Lawrence et al. Nature 517, 576-582 (2015) doi:10.1038/nature14129
Deregulation of signalling pathways and transcription factors.
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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
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Pursuing Immunotherapy in Head and Neck Cancer
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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
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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)
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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
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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
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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
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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
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Study Schema
175 patients with locally advanced or metastatic head/neck cancerPrimary endpoint: progression-free survival
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Mutation frequency among cancers of different histotypes
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Mutational screen of 305 HNSCC exome sequences deposited in TCGA
HNSCC tumors express missense mutations
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Mutational screen of 305 HNSCC exome sequences deposited in TCGA
HNSCC tumors express missense mutations
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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”
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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
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