REVIEW
Personalized biomarker-based treatment strategy for
patients with squamous cell carcinoma of the head
and neck: EORTC position and approach
R. Galot
1,2
, C. Le Tourneau
3,4,5
, J. Guigay
6
, L. Licitra
7,8
, I. Tinhofer
9,10
, A. Kong
11
, C. Caballero
12
,
C. Fortpied
12
, J. Bogaerts
12
, A.-S. Govaerts
12
, D. Staelens
12
, T. Raveloarivahy
12
, L. Rodegher
12
, J.-F. Laes
13
,
E. Saada-Bouzid
6
& J.-P. Machiels
1,2
*
1
Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc;
2
Institute for Clinical and Experimental Research (POLE MIRO), Universite´
Catholique de Louvain, Brussels, Belgium;
3
Department of Drug Development and Innovation, Institut Curie, Paris & Saint-Cloud, Paris;
4
INSERM U900 Research Unit,
Saint-Cloud;
5
Versailles-Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux;
6
Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France;
7
Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan;
8
Department of Oncology and Hemato-oncology,
University of Milan, Milan, Italy;
9
Charite´ – Universita¨tsmedizin Berlin, Corporate Member of Freie Universita¨t Berlin, Humboldt-Universita¨t zu Berlin, Berlin;
10
Department of Radiooncology and Radiotherapy, Berlin Institute of Health, Berlin, Germany;
11
Institute of Cancer and Genomic Sciences, University of
Birmingham, Birmingham, UK;
12
European Organization of Research and Treatment of Cancer (EORTC) Headquarters, Brussels;
13
OncoDNA, Gosselies, Belgium
*Correspondence to: Prof. Jean-Pascal Machiels, Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels,
Belgium. Tel: þ32-27645457; Fax: þ32-27645428; E-mail: jean-pascal.machiels@uclouvain.be
The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable
or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected
SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology.Trying
to select upfront the patients who will benefit from a specific treatment might be a way to improve patients’ outcome. With the
objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven
study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review
not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the
potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges
of biomarker-driven trials.
Key words:SCCHN, biomarker, personalized, umbrella, EORTC-1559-HNCG
Introduction
Squamous cell carcinoma of the head and the neck (SCCHN) is
the seventh most common malignancy [1]. The main risk factors
are smoking and alcohol consumption, which are responsible for
the majority of SCCHN occurring in the oral cavity, pharynx,
and larynx. Another risk factor for oropharyngeal cancer (OPC)
is the human papillomavirus (HPV). Tobacco and/or alcohol-
induced SCCHN and HPV-related OPC are two separate entities
with different clinical and molecular features [2–4].
Less than 60% of the patients with locally advanced SCCHN re-
main disease-free at 3 years, despite a multimodal treatment
combining surgery and/or (chemo)radiation [5]. Patients with
recurrent/metastatic disease who are not amenable to radiother-
apy or surgery have a median survival of 10–12 months.
Platinum-based chemotherapy in combination with cetuximab
improves overall survival (OS) in the first-line treatment of in-
curable disease [6]. Nivolumab increases OS of patients who pro-
gress after platinum therapy [7]. Pembrolizumab is also
approved in the same indication by the Food and Drug
Administration (FDA) [8]. No standard of care exists for patients
who progress after platinum-therapy and antiprogrammed cell
death protein 1 (PD-1) compounds.
The current treatment strategy of patients with SCCHN is still
based on tumor location and disease stage and not on tumor
V
CThe Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology 29: 2313–2327, 2018
doi:10.1093/annonc/mdy452
Published online 11 October 2018
biology [4,9,10]. Targeted therapies have shown disappointing
results [11–13]. Trying to select upfront the patients who will
benefit from a specific treatment might improve the outcome.
The European Organization for Research and Treatment of
Cancer (EORTC) is conducting the EORTC-1559-HNCG trial,
the first international biomarker-driven umbrella trial in recur-
rent SCCHN. In this article, we will review not only the different
trial designs for biomarker-driven studies with their respective
advantages and opportunities but also the potential pitfalls that
led to the design of the EORTC 1559 protocol. We will also dis-
cuss the scientific and logistic challenges of this trial.
Lessons learned from previous biomarker-
driven studies
Study designs
‘Master protocol’ terminology refers to a framework in which
several (sub)studies that investigate multiple therapies are oper-
ated in parallel under one ‘overarching’ master protocol [14].
Master protocols include two different study designs: basket and
umbrella trials. Table 1summarizes the opportunities and draw-
backs of these designs.
‘Basket trials’ are biomarker-driven clinical trials that include
patients based on pre-defined specific molecular tumor abnor-
malities, irrespective of tumor origin and histology (Table 2).
One of the advantages of this histology agnostic approach is to in-
vestigate the activity of targeted drugs across different cancer
types, even in rare cancers for which clinical trials do not exist.
They also offer the possibility to target low incidence molecular
alterations.
‘Umbrella trials’ are biomarker-driven clinical trials that are
histology-specific, investigating different therapeutic interven-
tions in a single cancer type (Table 3). A histology-specific ap-
proach is interesting to avoid the heterogeneity due to different
biology across various tumor types.
‘Strategy trials’ investigate if selecting the treatment based on
molecular alterations results in superior outcome compared with
standard therapy, independently of the drug, the disease, and the
studied biomarker(s).
‘Molecular screening programs’ have been implemented to fa-
cilitate the access to precision medicine trials. These screening
initiatives can be histology-agnostic or histology-specific.
Theranostic and molecular screening tools
Different diagnostic tests are routinely used to predict the activity
or resistance of some targeted therapies. Most of them are eval-
uated on tumor biopsies, although liquid biopsies are entering
into the clinic [e.g. epidermal growth factor receptor (EGFR)
T790M mutation in non-small-cell lung cancers (NSCLC)].
Biomarkers can be evaluated not only at the proteomic level such
as the estrogen receptor status assessed by immunohistochemis-
try (IHC) but also at the genomic level such as Human Epidermal
Receptor-2 (HER2) amplifications or EGFR activating mutations.
The tumor molecular profile has been obtained in 74%–93%
of screened patients in biomarker-driven clinical trials [16,18–
23]. Most of them use DNA sequencing on tumor biopsies.
Reproducibility and reliability of the molecular screening tools
are important. Most of the trials use certified laboratories, but the
analysis is not always centralized. In these cases, some trials car-
ried out an interlaboratory analytical validation before starting
the trial [24] or validated the assay [25].
A fresh biopsy is probably more reliable than an archival one.
Indeed, the cancer molecular profile can change during disease
evolution [26]. IMPACT [18,21] used archival formalin-fixed
paraffin-embedded (FFPE) tissue. In the LUNG-MAP trial [27]
and LUNG-MATRIX trial [23], both archival or fresh-taken tis-
sues are accepted. In the MOSCATO 01 [20], NCI-MPACT [15],
NCI-MATCH [15], BATTLE [16], and SHIVA [17] trials, a fresh
tumor biopsy has/had to be taken for the trial purpose.
Actionable genomic alteration frequency and
enrolment rate
According to the ESMO glossary [28], ‘targetable genomic alter-
ation’ encodes an altered protein against which a drug exists or
can be synthesized and an ‘actionable genomic alteration’
Table 1. Advantages and pitfalls of ‘biomarker-driven’ clinical trial designs
Advantages Disadvantages
Master protocols
Basket trials Can include rare cancer types Assumes that molecular biology can replace histology and
that a specific genetic alteration has the same signification
across different tumor types
Histology agnostic Can target low incidence actionable/targetable molecular
alterations
Umbrella trials Targets molecular alterations in one cancer type and avoid het-
erogeneity due to multiple cancer histologies
Feasibility limited for rare cancers
Histology specific
Enables to get more conclusive results for one tumor type
Screening programs Have the potential to identify an actionable/targetable genetic
alteration
If an actionable/targetable alteration is present, the specific
drug is not always available with the risk that a low number
of patients finally benefits from this programCan facilitate the access to early development clinical trials
Strategy trials Have the potential to identify an actionable/targetable genetic
alteration
Effect of the strategy can be diluted by less effective target-
drug pairs
Review Annals of Oncology
2314 | Galot et al. Volume 29 | Issue 12 | 2018
Table 2. Selected histology agnostic biomarker-driven approaches
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
patients
Results and impact
on outcome
IMPACT [18,
21]
All, refractory advanced
cancer
Screening
program
Archival (FFPE) Screening route to phase I Clinical outcome of
pts with MA treated
with matched ther-
apy versus pts not
treated with
matched therapy
•1144/1283 pts had ad-
equate tissue for mo-
lecular analysis (89.2%)
•460/1144 analyzed pts
had 1 or more MA
(40.2%)
•211/460 (45.8%)treated
with matched
therapy¼16.4% of total
population
Analysis on 379 with 1
MA:
175 pts treated with
matched therapy ver-
sus 116 nonmatched
(88 pts excluded
from clinical out-
come analysis):
PCR-based sequencing for
selected genes (PIK3CA, BRAF,
KRAS and NRAS, EGFR, KIT,
GNAQ, TP53 and MET), Sanger
sequencing for RET analysis,
IHC for PTEN loss of expression
and FISH for ALK translocation
Assignment to phase I
clinical trial based on
the identification of
MA
•ORR: 27% in matched
therapy versus 5%
(P<0.0001)
•SD 6 months: 23%
versus 10%
•OS: 13.4 versus
9 months (P¼0.017)
Update 2017:
•1179/1436 pts had 1 or
more MA (82%)
•914/1179 had 1 or
more targetable alter-
ation (77.5%)
•390/637 (45.8%) pts
with at least 1 alteration
that were treated,
received matched
therapy¼27% of total
population
Update 2017:Update 2017: Sequencing by
NGS at MD Anderson (11, 46
or 50 genes depending on
the panel), Foundation
Medicine (182 genes), Knight
Diagnostics (48 genes) or
other CLIA-certified
laboratories
•ORR: 11% versus 5%
(P¼0.0099)
•SD6 monthsþCRþPR
: 29% versus 24%
•FFS: 3.4 versus
2.9 months (P¼0.0015)
•- OS: 8.4 versus
7.3 months (P¼0.41)! Gene panels of different sizes
were used for MP!
SHIVA trial
[17]
All, refractory advanced
cancer
Strategy trial New biopsy pts with MA in one of the
3 molecular pathways
that could be matched
with 11 different tar-
geted agents were
randomized between
the targeted therapy
and control arm
PFS •716/741 screened pts
underwent tumor
sample
•293/741 screened
patients had at least 1
MA matching one ther-
apy (40%)
•- 196/741 pts were
randomized (26%)
Negative trial: Median
PFS was 2.3 months
in the experimental
group versus 2.0
months in the con-
trol group (P¼0.41)
Multicenter, open-
label, proof-of-
concept,
randomized,
phase II trial
Mutations by targeted NGS
(AmpliSeq cancer panel)
CNA by Affymetix IHC for es-
trogen, progesterone and
androgen receptors
Continued
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2315
Table 2. Continued
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
patients
Results and impact
on outcome
MOSCATO
01 trial
[20]
All, advanced cancer Screening
program
New biopsy (Fresh-frozen) Screening route to phase
I/II
Evaluate the clinical
benefit as meas-
ured by percentage
of pts presenting
PFS on matched
therapy (PFS2) 1.3-
fold longer than the
PFS on prior ther-
apy (PFS1)
•948/1035 included pts
underwent biopsy
•MP obtained in 843/948
pts (89%)
•411/843 pts had a MA
(49%)
•- 199 pts were treated
with a targeted therapy
¼19% of total
population
PFS2/PFS1 ratio >1.3 in
63/199 pts treated
with targeted therapy
(33%)¼7% of suc-
cessfully screened pts
Single-center,
singe-arm,
open-label, pro-
spective clinical
trial
At the start of trial: targeted
sequencing (first Ion Ampliseq
Cancer Panel covering 40
genes, then the Ion Ampliseq
Cancer Hotspot Panel v2.0 in
50 genes and finally an Ion
AmpliSeq custom design cov-
ering 75 genes) aCGH analysis
and IHC for phospho-MET
RNA sequencing and whole-
exome sequencing were
added during the trial
Assignment to phase I
clinical trial based on
the identification of
MA
CREATE trial
[60–63]
Advanced tumors character-
ized by MET and/or ALK
alterations (papillary renal-
cell carcinoma type 1, al-
veolar soft part sarcoma,
clear-cell sarcoma, anaplas-
tic large-cell lymphoma, in-
flammatory myofibroblastic
tumour, and alveolar
rhabdomyosarcoma)
Multinational, mul-
titumor, pro-
spective phase
II clinical trial
Tumour containing tissue block
(FFPE) from the primary tu-
mour and/or metastatic site:
sequencing (bidirectional
Sanger sequencing method of
only 1 gene) (MET), FISH for
copy number status
Treatment with crizotinib
in the different patient
cohorts
ORR No biomarker-positivity
needed for entering
the trial
Results published per
histology
NCI-MPACT
[15]
All, advanced solid tumor Strategy trial New biopsy Pts with specific mutation
are randomized in 2 : 1
ratio to receive tar-
geted therapy versus
control (not specifically
targeting the detected
mutation/pathway of
interest)
ORR and 4-month PFS NA, 270 assessable pts are
planned for enrollment.
Over 100 patients have
been screened to
date, though no in-
terim analysis results
have been presented
to date
Double-blind,
randomized trial
NGS of >380 unique action-
able variants in 20 genes
NCI-MATCH
[15]
All, advanced solid tumors Master protocol New biopsy Pts with MA are assigned
in one of predefined
treatment cohorts
ORR •Successful laboratory
testing for 93% of pts
•18% of screened tumors
was found to have a
genetic mutation that
matched the patient to
As of July 2017, 5963
tumor samples have
been screened
Phase II, multicen-
ter, open-label,
nonrandomized
Basket trial
or recent biopsy of <6 months
with no interim therapy
sequencing assay for more
than 4, 000 different variants
in 143 genes
Continued
Review Annals of Oncology
2316 | Galot et al. Volume 29 | Issue 12 | 2018
Table 2. Continued
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
patients
Results and impact
on outcome
1 of the 30 treatment
arms.
•998 pts have been
assigned to treatment,
of which 69% have
enrolled (12% of
screened population)
Mypathway
[34]
Advanced refractory solid
tumor harboring MA in
HER2, EGFR, BRAF or
Hedgehog pathway
Master protocol
Phase IIa, multi-
center, non-
randomized,
multiple basket
study
MP was not conducted as part of
this study.
Pts are assigned to specif-
ic treatment cohorts
based on the presence
of a relevant target MA
Investigator-assessed
ORR within each
tumor-pathway
cohort
NA, pts were only
included if testing al-
ready carried out out-
side the clinical trial
Efficacy analysis popula-
tion: 230 pts
ORR: 23% within 14 dif-
ferent tumor types
SUMMIT [35] Solid tumors harboring HER2
and HER3 mutations
Master protocol
Multicohort bas-
ket study
MP was not conducted as part of
the study, locally reported
HER2/3 mutations were con-
firmed centrally
Pts with HER2-mutant
cohorts were enrolled
into disease-specific
cohorts and HER3
mutants into one
cohort
Investigator-assessed
ORR
NA Total: 125 HER2 mutant
pts and 16 HER3 mu-
tant pts
For HER2 mutant
tumors, primary end
point was met only
for breast cancer
(ORR 32%) and not
for lung, colorectal or
bladder.
No responses were
observed in the HER3
mutant cohort
aCGH, comparative genomic hybridization array; CNA, copy number alteration; DCR, disease control rate; FFPE, formalin-fixed, paraffin-embedded; FFS, failure-free survival; FISH, fluorescence in situ hybridization;
IHC, immunohistochemistry; MA, molecular alteration; MP, molecular profile; NGS, next generation sequencing, ORR: overall response rate, PFS: progression free survival, Pts: patients.
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2317
Table 3. Selected histology specific biomarker-driven approaches
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
patients
Results and impact on
outcome
The BATTLE trial
[16]
NSCLC Master protocol
Randomized
phase II, single-
center, open-
label study
Fresh biopsy (FFPE) Testing
of 11 prespecified bio-
markers: PCR-based
sequencing for mutations
(EGFR, KRAS, and BRAF),
CNA by FISH (EGFR,
CCND1), and protein ex-
pression levels by IHC
Multiples arms: five bio-
markers groups with differ-
ent targeted therapies
equal random assignment
for 97 first pts, and adaptive
randomization for next 158
DCR at 8 weeks 341 pts enrolled: 299 with
adequate tissue for ana-
lysis (88%) 255 pts were
randomized (75%)
Overall 8 weeks DCR: 46%
Biomarker groups less
predictive than individual
biomarkers
SAFIR01 [29] Metastatic breast
cancer
Screening
program
Fresh biopsy
aCGH for preselected genes
and Sanger sequencing for
mutational hotspots on
PIK3CA and AKT1
Screening: Based on the iden-
tified genomic alteration,
pts were treated with tar-
geted therapy if possible
(within clinical trial or not)
Proportion of pts
for whom a tar-
geted therapy
could be
offered
423 pts included, biopsy
obtained for 407 pts
Therapy could be personal-
ized in 55/423 pts (13%)
Targetable alteration in
195 (46%)
LUNG-MAP mas-
ter protocol
[27]
Advanced lung
squamous cell
carcinoma
Master protocol
Phase II–III um-
brella trial
Archival FFPE or fresh tumor
biopsies
FoundationOne NGS assay
(Foundation Medicine) for
mutations, amplifications,
rearrangements (324
genes) and some IHC
Mutiple arms: Based on the
molecular profile, each pt is
enrolled in a sub-study
with matched targeted
therapy or in nonmatch
substudy
ORR 1392 pts registered to the
screening component
523 pts registered to a
sub-study (37%)
First results for 3 biomarker
driven cohorts (S1400B,
S1400C and S1400D):
ORR 4%–7%
Cohorts closed due to futil-
ity at interim analysis
S1400A (immunotherapy):
16% ORR
Other sub-studies ongoing
The National
Lung Matrix
[23]
Advanced NSCLC Master protocol
Phase II um-
brella trial
Prescreening of tumor biop-
sies through the Stratified
Medicine Program 2 (take
place in parallel with the
patient receiving first line
treatment): adaptable 28-
gene NGS sequencing plat-
form designed by Illumina
covering the range of mo-
lecular abnormalities being
targeted
Multiples arms (8 investiga-
tional medicinal products,
within 21 distinct cohorts)
ORR or PFS As of July 2016: As of 9 June 2017, 151
patients have been regis-
tered, 125 of these
patients have received
targeted treatments
within the Lung Matrix
trial.
•1664 pts tested
•1229 passed QC step
(74%), 1098 pts with
NGS results (66%)
•731 pts with aberration
for MATRIX (44%)
•458 pts (28%) with MA
and eligible (not regis-
tered) for MATRIX
Pts are allocated to the ap-
propriate targeted ther-
apy according to the
molecular genotype of
their cancer No results available per
cohort.Bayesian adaptive design
The Osimertinib cohort has
been closed for
recruitment.
‘No actionable mutation
arm’ for patients without
specific eligibility for one
Continued
Review Annals of Oncology
2318 | Galot et al. Volume 29 | Issue 12 | 2018
includes both targetable alterations and genomic alterations that
cannot be directly targeted but that lead to dysregulation of a
pathway in which there are possible targets.
The percentage of patients that had an actionable genomic alter-
ation identified through screening programs ranged from 46% to
63% [18,20,21,29]. However, the number of patients who were fi-
nally treated with a matched targeted therapy was low: 13%, 16%,
and 19% in SAFIR01 [29], IMPACT (first published report) [21],
and MOSCATO 01 [20], respectively. This number increased to
27% in the most recent IMPACT publication [18], probably related
to the extension of the screening panels. Different reasons may ex-
plain these low enrolment rate: tumor tissue issues, decline in the
performance status or rapidly progressing disease, the absence of a
targetable event, and the access to matched clinical trials or drugs.
As IMPACT and the MOSCATO 01 were screening programs,
patients were referred to enrolling clinical trials with obvious limita-
tions in the treatment possibilities.
A way to partially solve these issues is to include the access to
drugs into the clinical trial design. The NCI-MATCH basket trial
pre-planned the access to some targeted compounds. However, only
12%ofthepatientswerefinallyenrolledinthetrial[22]. This low
enrolling rate might be due to the low incidence of the targeted var-
iants since only 18% of the screened tumors were found to have a
genomic alteration that matched one of the 30 treatment arms. In
contrast, in BATTLE and LUNG-MAP, two umbrella trials for
NSCLC, 75% and 37% of the patients were included in one of the
substudies, respectively [16,27]. The number of treated patients is
higher in these two last trials due to a preplanned access to matched
targeted therapies. In addition, for the Battle trial, the molecular pro-
file strategy was disease-specific and adapted to NSCLC, explaining
thehighprevalenceofsomeoftheinvestigatedbiomarkers.
Treatment efficacy in master protocols
Treatment selection based on DNA biomarkers has proved its ef-
ficiency: anti-HER2 therapies for HER2 amplified breast cancer
[30] and EGFR or pan-HER inhibitors for EGFR mutated
NSCLC [31]. Pembrolizumab has been approved, independently
of the tumor type, for microsatellite instability-high and mis-
match repair deficient cancers [32] as well as for the first-line
treatment of metastatic NSCLC with high PD-L1 expression [33].
Different end points are used in biomarker-driven trials. In
MOSCATO 01 [20], the primary end point was the progression-
free survival (PFS) ratio calculated for each patient, that must be
>1.3 to define clinical benefit (PFS ratio ¼PFS on the molecular-
profile selected therapy/PFS on prior therapy). The approach is
judged efficient if it modifies the natural history of the disease
and is associated with a longer PFS than the previous line of treat-
ment. Thirty-three percent of patients treated with a targeted
therapy had a PFS ratio >1.3. However, the number of patients
who benefited from the personalized approach represented only
7% of the screened patients.
In IMPACT, the clinical outcomes of patients with molecular
aberrations treated with matched therapy were compared with
those of consecutive patients who were not treated with a
matched therapy. They reported a better objective response rate
(ORR) (11% versus 5%), a longer failure-free survival (3.4 versus
2.9months),andalongerOS(8.4versus7.3months)inthe
matched group [18]. The clinical benefit rate in the matched group,
Table 3. Continued
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
patients
Results and impact on
outcome
of the targeted genomic
aberrations
FOCUS4 [64] Advanced colorec-
tal cancer
Master protocol
Phase II–III um-
brella trial
FFPE block taken before com-
mencement of standard
chemotherapy
Multiple arms PFS NA First results for 1 patient co-
hort (FOCUSD):After induction chemother-
apy, pts are enrolled in
different cohorts on the
basis of MA in the tumor,
to test different targeted
agents versus placebo or
in a no-biomarker cohort
testing standard capeci-
tabine versus placebo as
maintenance
Median PFS 3.48 months
with placebo and 2.96
months with AZD8931:
closed for futility
Mutations of some prese-
lected genes þsome
IHC, mRNA EREG
aCGH, comparative genomic hybridization array; CNA, copy number alteration; DCR, disease control rate; FFS, failure-free survival; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MA, molecu-
lar alteration; MP, molecular profile; NGS, next generation sequencing; ORR, overall response rate; PFS, progression free survival; Pts, patients; QC, quality check.
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2319
defined as the proportion of patients with either a stable disease
lasting more than 6months or a partial response or complete re-
sponse, was 29% (111/381) when compared with 24% (56/238) in
the nonmatched group. However, only 8% of the whole population
finally experienced a clinical benefit. The use of nonoptimal tar-
geted drugs or suboptimal dosages in phase I trials, and sometimes
the level of evidence concerning the investigated biomarker(s) may
explain the limited treatment efficacy observed.
In MyPathway basket trial [34], the ORR was 23% in 14 differ-
ent tumor types, a clinically significant result for advanced refrac-
tory disease. In the SUMMIT trial [35], a basket trial studying
neratinib in patients with a tumor harboring either HER2 or HER
3mutations, the primary end point was reached only for breast
cancer, and not for lung, bladder, and colorectal cancers, under-
lining the importance of the histology and the tissue of cancer
origin. In BATTLE [16], the 8-week disease control rate and ORR
were 46% and 4%, respectively. The first data of the ongoing
Lung-MAP trial reported an ORR of 4%–7% for the first three
biomarker-driven cohorts [27].
The SHIVA trial was the first randomized trial comparing a
molecularly targeted therapy based on tumor molecular profiling
versus conventional therapy for advanced cancer [17]. This study
tested the overall strategy of a biomarker-driven treatment ap-
proach versus standard therapy. The trial did not meet its pri-
mary end point (PFS). Several reasons could explain this overall
negative result. First, they used drugs that were marketed in
France at that time and not necessarily the best in class to target
the molecular alteration identified. Second, the experimental arm
was also heterogeneous with multiple drugs and various tumor
types. This could have blinded the benefit of some drugs in some
specific cancer(s). The ongoing NCI-MPACT trial [15] is also a
strategy trial. To avoid a negative trial linked with inadequate tar-
get modulation by the selected agents, all the targeted agents used
in NCI-MPACT have been validated to engage their purported
targets and have at least an established phase II dose.
Biomarker-driven studies for SCCHN
Only a few biomarker-driven trials are dedicated to SCCHN
(Table 4). Some phase II trials are selecting patients upfront based
on a rare specific genomic alteration [HRas proto-oncogene
(HRAS) mutations or fibroblast growth factor receptor (FGFR)
mutations/amplifications/translocations]. However, these trials
offer only one potential therapeutic option for the very low percent-
age of patients harboring these rare genomic events. This results in
a high rate of screening failure. There is another ongoing trial in
Korea assessing personalized therapy for recurrent/metastatic
SCCHN and esophageal cancer (NCT03292250) where patients are
allocated to different treatment arms after first line platinum-based
therapy according to molecular characterization.
Actionable or targetable genomic
alterations in SCCHN
Next generation sequencing (NGS) technologies have identified
potentially actionable/targetable genomic alterations in SCCHN
[4,9,10]. Targetable genomic alterations in HPV-negative
SCCHN include events in genes related to kinase growth factor
family receptors or their downstream molecular pathways: EGFR
(15%), FGFR1–3(14%), HER2 (5%), phosphatidylinositol-4,5-
bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (34%),
and HRAS (5%). HPV-negative SCCHN has also potentially ac-
tionable cell cycle genomic alterations: TP53 mutation (70%),
cyclin D1 (CCND1) amplification (20%–30%), and CDKN2A in-
activation (80%–90%). In HPV-positive OPC, where the onco-
protein E6 and E7 inactivate, respectively, p53 and Rb, PIK3CA
amplifications/mutations are found in 56% whereas the other
genomic alterations are rare.
The EORTC-1559-HNCG trial (UPSTREAM:
Personalized STrategy for REcurrent And/or
Metastatic SCCHN)
Our main objective was to design a biomarker-driven study dedi-
cated to SCCHN patients. Below, we describe the overall study
design as well as the different treatment cohorts.
EORTC-1559-HNCG design
The EORTC-1559-HNCG trial is a biomarker-driven umbrella
trial that enrolls patients with recurrent/metastatic SCCHN,
Table 4. Ongoing biomarker-driven trials in squamous cell carcinoma of the head and neck
Study title ClinicalTrials.gov identifier and status
Pan FGFR kinase inhibitor BGJ398 in treating patients with FGFR1–3translocated, mutated, or
amplified recurrent head and neck cancer
NCT02706691
Not yet recruiting
Phase II study of tipifarnib in squamous head and neck cancer with HRAS mutations NCT02383927
Recruiting
Copanlisib in association with cetuximab in patients with recurrent and/or metastatic head and
neck squamous cell carcinomas harboring a PI3KCA mutation/amplification and/or a PTEN
Loss
NCT02822482
Recruiting
SF1126 in recurrent or progressive SCCHN and mutations in PIK3CA gene and/or PI-3 kinase
pathway genes
NCT02644122
Terminated (slow enrollment)
Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck
(TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC)
NCT03292250
Recruiting
Review Annals of Oncology
2320 | Galot et al. Volume 29 | Issue 12 | 2018
progressing after first-line platinum-based chemotherapy. Each
patient must undergo a fresh tumor biopsy. NGS is carried out to
identify somatic mutations and copy number alterations with a
custom panel that has been designed for the trial. This panel cov-
ers 13 oncogenes and tumor suppressor genes: EGFR, HER2,
TP53, PIK3CA, CCND1, NRAS, KRAS, HRAS, PTEN, FGFR1,
FGFR2, FGFR3, and cMET. The analysis also includes p16 (p16
positive ¼Histo-score 210) and PTEN (PTEN High ¼Histo-
score >150) determined by IHC [36]. mRNA FGFR expression is
evaluated by NGS. All these analyses are carried out centrally in
an ISO 15189 certified laboratory (OncoDNA, Belgium).
Based on the molecular alterations identified, each patient is
allocated to one of the cohorts. If the patient is not eligible for
one of the biomarker-driven cohorts, he/she is included in one of
the immunotherapy cohorts. The global design of the trial as well
as the molecular rules for treatment allocation and prioritization
are depicted in Figures 1and 2.
The full protocol includes a core protocol and several addenda.
The core protocol describes the overall study design, the objec-
tives and end points, the inclusion/exclusion criteria, the study
flow chart, the statistical hypotheses, the data analysis plan, and
the biobanking processes. For each experimental treatment, there
is one separate addendum that contains the confidential informa-
tion related to the drug. The national health regulatory author-
ities, the ethical committee, and the investigators have access to
the core protocol and all the addenda. The pharmaceutical com-
panies have access to the core protocol but they can view and
comment only the addendum/addenda concerning the cohort(s)
for which they are supporting.
EORTC-1559-HNCG biomarker-driven and immuno-
therapy cohorts
Each patient cohort is designed as a phase II study with its own
statistical hypothesis (Table 5). The primary end point is either
ORR or PFS rate. Sample sizes vary from 32 to 76 patients across
cohorts. The study can be amended to add other cohorts based
on drug availabilities or other biomarker hypotheses.
Pan-human epidermal growth factor receptor (HER) inhibitor
cohorts. EGFR mutations/amplifications are described in 15% of
HPV-negative SCCHN and HER2 is altered (mutation/amplifica-
tion) in 5%.
Patients with recurrent/metastatic SCCHN, progressive after platinum-based therapy
Primary consent and screening eligibility
Biopsy with sequencing of targeted genes and IHC
Immunotherapy patient cohorts
Cohort I1
Cohort I2
Randomization 2:1:1
Monalizumab
Afatinib
Afatinib
Monalizumab
Physician’s choice
Informed consent must be taken at 2 timepoints:
1. At registration
2. After allocation to patient cohort and before
randomization, when applicable ( in the scheme)
Physician’s choice
Physician’s choice
Palbociclib
Niraparib
Niraparib
Rogaratinib
Physician’s choice
Monalizumab +
Durvalumab
Biomarker-driven patient cohorts
Cohort B1: p16 neg and EGFR
amplification/mutation or PTEN high
or HER2 amplification/mutation
Randomization 2:1
Cohort B2:
p16 neg and cutuximab naïve
Randomization 2:1
Cohort B3:
p16 neg and CCND1 amplification
Randomization 2:1
Cohort B4:
p16 neg and ‘platinum-sensitive’
Cohort B5:
p16 pos oropharyngeal cancer
Cohort B6:
FGFR1-3 mRNA overexpression
Figure 1. General design of the EORTC1559 umbrella trial.
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2321
The ORR with cetuximab monotherapy is 13% [37]. In con-
trast to colon cancer where RAS mutations are predictive markers
of resistance, RAS alterations are found in only 4% of HPV-
negative SCCHN. Although RAS mutations might also play a role
in cetuximab resistance in SCCHN [38], other mechanisms
including activation of other HERs are involved [39,40].
Pan-HER inhibitors target all the dimers forms by HER family
and have the potential to overcome anti-EGFR therapy resistance
caused by cross-talk between EGFR and the other HERs. In unse-
lected SCCHN patients who progress after platinum therapy, afati-
nib, an irreversible pan-HER inhibitor, improves PFS compared
with methotrexate: median PFS 2.7 versus 1.6 months [41].
However, afatinib does not increase OS. Biomarkers analyses were
carried out within this trial [36]. Median PFS favored afatinib in
patients with p16-negative, EGFR-amplified (defined as 50% of
cells with 4copies,or1cellwith8 copies), HER3-low
(defined as H-score 50), and PTEN-high (defined as H-score
>150) tumors. In the MCC15780 trial where 38 SCCHN patients
were treated with cetuximab [42], PFS was also significantly
increased in PTEN-high tumors compared with PTEN-low tumors
[43]. The fact that afatinib seemed to be more active in case of
HER3-low and PTEN-high disease suggests that pan-HER inhibi-
tors could be more active when the PI3K pathway is not or lessacti-
vated. Cetuximab-naı¨ve patients with p16 negative tumor had also
a significant benefit from afatinib (ORR: 27%).
We designed two biomarker-driven cohorts in the EORTC-
1559 trial where the patients are randomized between afatinib or
investigator’s choice. The first cohort includes patients with p16
negative SCCHN harboring either an EGFR mutation/amplifica-
tion or HER2 mutation/amplification or PTEN high (H-score
>150). We did not include patients with HER3 low disease as this
IHC is not always reproducible [44]. The second cohort includes
cetuximab-naı¨ve SCCHN patients with p16-negative tumor.
SCCHN with any RAS mutations are excluded [38].
Eligible for at least
1 cohort
Biopsy adequate?
p16 status
Ye s
Ye s
No Off protocol
Allocation to patient cohort is made
according to specific eligibility criteria,
biomarker status and currently
open/closed cohorts.
Patient cohort I2
Patient cohort I1
No
Ye s
Ye s
Ye s
Ye s
Ye s
Ye s
Ye s
Positive FGFR1/2/3 mRNA pos +
RAS/PIK3CA WT +
able to swallow?
Ye s Patient cohort B6
Patient cohort B1
Patient cohort B1
Patient cohort B6
Patient cohort B4
Patient cohort B3
Patient cohort B1
Patient cohort B2
Patient cohort B5
No
Negative
EGFR activating mutation +
RAS WT?
No
No
No
No
No
No
No
HER2 activating
mutation/amplification + RAS WT?
FGFR1/2/3 mRNA pos +
RAS/PIK3CA WT +
able to swallow ?
platinum-sensitive +
able to swallow ?
CCND1 amplification
EGFR amplification or PTEN high
+ RAS WT ?
cetuximab naive +
RAS WT ?
Figure 2. Prioritization algorithm for the allocation to different patient cohorts.
Review Annals of Oncology
2322 | Galot et al. Volume 29 | Issue 12 | 2018
FGFR inhibitor cohorts. FGFRs can activate the RAS-MAPK,
PI3K, STAT, and PLCcpathways [45]. FGFR1 mutation/amplifi-
cation are found in 5%–10% of HPV-negative SCCHN, while
FGFR3 mutations are more frequent in HPV-induced OPC (1%–
12%). Genetic alterations of FGFR2 are observed in only 2%–4%.
Erdafitinib, a pan-FGFR inhibitor, induced ORR in 24%–35%
of patients with metastatic urothelial cancer harboring FGFR
alterations (including activating mutations and translocations)
[46]. Twenty-four percent of patients with urothelial cancer over-
expressing FGFR1-3 mRNA achieved ORR with Rogaratinib, an-
other pan FGFR inhibitor [47]. Partial responses were also
observed in some patients with squamous cell lung cancer,
SCCHN, and adenoid cystic carcinoma [48]. Interestingly, some
responding patients had elevated tumor FGFR3 mRNA levels
without corresponding genomic alterations. The prevalence of
FGFR1-3 mRNA positivity among 46 SCCHN patients was
56.5% [49].
We will investigate Rogaratinib in cases of high FGFR mRNA
levels assessed by NGS.
Cell cycle inhibitor cohort. The vast majority of HPV-negative
SCCHN harbors genetic alterations (TP53 mutations, CCND1
amplification, and p16 inactivation) that enable them to circum-
vent the mitotic checkpoints through aberrant cyclin-dependent
kinase (CDK) activation. Since p16 inactivates CDK4/6 whereas
cyclin D1 activates CDK4/6, there is a rationale to test CDK4/6
Table 5. Different patient cohorts of EORTC HNCG 1559 trial
Patient cohort Biomarker(s) Targeted
drug/IO
Design Sample size
(max)
Statistical
hypothesis
Biomarker-driven patient cohorts
B1
a
p16 negative and EGFR
amplification/mutation
or PTEN high or HER2
amplification/mutation
Afatinib Phase II, randomized,
open-label, multicenter
study
55 H0: PFSR at 16 weeks¼20%
H1: PFSR at 16 weeks¼40%
Simon 2 Stage design
B2
a
p16 negative and cetuxi-
mab naı¨ve
Afatinib Phase II, randomized,
open-label, multicenter
study
55 H0: PFSR at 16 weeks¼20%
H1: PFSR at 16 weeks¼40%
Simon 2 Stage design
B3 p16 negative and CCND1
amplification
Palbociclib Phase II, randomized,
open-label, multicenter
study
55 H0: PFSR at 16 weeks¼20%
H1: PFSR at 16 weeks¼40%
Simon 2 Stage design
B4 p16 negative and ‘plat-
inum-sensitive’
Niraparib Phase II, single arm, proof-
of-concept, multicenter
study
32 H0: ORR over first 16 weeks¼5%
H1: ORR over first 16 weeks¼20%
Simon 2 Stage design
B5 p16 positive OPC Niraparib Phase II, single arm, proof-
of-concept, multicenter
study
32 H0: ORR over first 16 weeks¼5%
H1: ORR over first 16 weeks¼20%
Simon 2 stage design
B6
b
FGFR1/2/3 mRNA
overexpression
Rogaratinib Phase II, single arm, proof-
of-concept, multicenter
study
20 H0: ORR over first 16 weeks¼5%
H1: ORR over first 16 weeks¼25%
Simon 2 stage design
Immunotherapy cohorts
I1 NA Monalizumab Phase II, single arm, proof-
of-concept, multicenter
study
40 H0: ORR over first 16 weeks¼3%
H1: ORR over first 16 weeks¼15%
Single stage A’Hern
design
I2 NA Monalizumab
þdurvalumab
Phase II, randomized,
open-label, multicenter
study
76 H0: ORR over first 16 weeks¼3%
H1: ORR over first 16 weeks¼15%
Simon 2 stage design
a
Patients included in the afatinib arms should not have activating mutation in RAS.
b
Patients included in the Rogaratinib arm should not have activating mutation in RAS or PIK3CA.
ORR, overall response rate; PFSR, progression-free survival rate.
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2323
inhibitors in patients with p16 negative and CCND1-amplified
SCCHN. Palbociclib in combination with cetuximab has been
investigated in recurrent SCCHN with promising preliminary
results (ORR: 35%) [50]. However, palbociclib monotherapy has
not been investigated in SCCHN.
We will investigate palbociclib in patients with p16 negative
tumors harboring CCND1 amplification.
Poly-ADP ribose polymerase inhibitor cohorts. DNA repair defi-
ciency increases sensitivity to platinum-based chemotherapy and
poly-ADP ribose polymerase (PARP) inhibitors [51]. A compre-
hensive analysis for homologous recombination deficiency
(HRD) was carried out, and HRD was associated with ovarian,
lung, SCCHN, and bladder cancer. Preclinical studies have shown
that HPV-positive SCCHN have DNA double strand repair
defects responsible for increased sensitivity to the PARP inhibitor
veliparib [52]. These data support the two patient cohorts that
will investigate niraparib, another PARP-inhibitor, in p16-
positive OPC and in platinum-sensitive p16 negative SCCHN.
Immunotherapy cohorts. PD-1/PD-L1 blockers have activity in
SCCHN but the 2-year’s OS rate is still low: 16.9% [53].
Therefore, other immunotherapy approaches have to be
investigated.
HLA-E is a nonclassical major histocompatibility complex
molecule that constitutes a way for cancer cells to escape immune
surveillance. HLA-E is highly expressed in 70% of SCCHN [54].
HLA-E binds to NKG2A receptor on NK cells and T-lymphocytes
to inhibit the cytotoxic functions of CD8þT lymphocytes and
NK cells. Monalizumab is a human IgG4 antibody targeting the
NKG2A receptor. In the first immunotherapy cohort, patients
will receive monalizumab monotherapy. In the second immuno-
therapy cohort, patients will be randomized to receive the com-
bination of durvalumab and monalizumab versus monalizumab
monotherapy versus physician’s choice.
EORTC1559 feasibility
The trial is open for inclusion since December 2017. On 19 July
2018, 19 sites are open in 3 countries. Sixty-four patients have
been screened, 24 included in one of the biomarkers cohorts, and
23 in one of the immunotherapy cohorts. The turnaround time
between the biopsy and the molecular diagnosis provided by the
central laboratory is 10 calendar days.
Discussion
The EORTC-1559-HNCG trial is the first European international
umbrella trial assessing a personalized treatment strategy for
patients with recurrent/metastatic SCCHN. We hypothesize that
this approach can improve patients’ outcome.
The trial design has different strong points: one single protocol
with pre-planned access to matched targeted therapies, one fresh
tumor biopsy to deal with tumor evolution over time, an ISO-
certified central laboratory, well-defined biomarker hypotheses,
and the possibility to have a never-ending protocol with the op-
portunity of adding new cohorts.
Besides the inherent complexity of such trials, numerous logis-
tic and scientific challenges were encountered when designing
this protocol.
Although the pharmaceutical companies accepted the concept
of having only one protocol including the different compounds,
complex negotiations were crucial to successfully achieve that all
stakeholders agreed (i) to standardize the processes, (ii) to accept
the predefined protocol structure, (iii) to use the central bio-
marker laboratory, (iv) to match the company interests with the
academic wishes, and (v) to align all the companies on the same
protocol wording in particular for the inclusion/exclusion crite-
ria. The protocol was submitted in four different countries
(Belgium, France, Italy, and UK) and will be submitted in
Germany to both competent authorities (CA) and applicable eth-
ics committees (EC). Overall, the study was well received by the
CA and EC without major comments on the study design. The
main question received from EC was concerning the criteria to al-
locate patients to the different cohorts. Regarding the regulatory
strategy, having all those cohorts in only one study simplifies the
submission process, as it requires only one initial clinical trial ap-
plication to each CA and one initial request of opinion to each
EC. Also, each amendment can group modifications concerning
more than one cohort at the same time. If we had considered each
cohort as one trial, different submissions would have been neces-
sary, increasing the regulatory workload and probably time for
activation. As separate trials, the advantage would have been that
the current cohorts could be opened/closed independently across
the countries without the need of a main protocol amendment.
In addition, the liaison with the stakeholders would be easier, as
the number of stakeholders per trial would be significantly
reduced.
The new European clinical trials regulation [55] fully in appli-
cation next year might bring a novel perspective for studies with a
complex design. Multiple member states will participate on the
coordinated assessment of some sections of the dossier, ensuring
that consolidated communication reaches the applicant. This
may reduce the volume of correspondence and facilitate the man-
agement of any protocol modifications if they are required.
Several challenges remain. Optimal management of country-
specific documents adaptation and effective communication
with the stakeholders might be the key to ensure fulfillment of ad-
equate deadlines and quick activation of new cohorts to follow
the fast advancing head and neck cancer research field.
At the scientific level, the study is still missing some treatment
arms that target important genetic aberrations. PIK3CA altera-
tions occur in 16%–34% of HPV-negative patients and in up to
56% of HPV-positive patients. Patient-derived SCCHN tumor
xenografts with PIK3CA activating mutations are sensitive to
mTOR/PI3K inhibitors [56] and, in the BERIL-1 trial, buparlisib
improved OS when added to paclitaxel [57]. Among other inter-
esting targets, there is a scientific rationale to test Farnesyl trans-
ferase inhibitors in the 5% of SCCHN harboring HRAS
mutations or WEE1 inhibitors in TP53 mutated tumors.
In the current design, immunotherapy cohorts are not linked
to biomarker(s). Among others, HPV-positivity, PD-L1 overex-
pression, in-frame, or frameshift alterations of specific tumor
suppressor genes, and mutational burden are potential bio-
markers that have been associated with a higher efficacy of im-
munotherapy in SCCHN [7,8,58]. However, these predictive
Review Annals of Oncology
2324 | Galot et al. Volume 29 | Issue 12 | 2018
markers are far to be optimal. Umbrella trials represent an ideal
platform to further investigate the predictive value of immune
biomarkers.
We cannot deny that tumor heterogeneity that can cause treat-
ment resistance is not addressed by the use of targeted com-
pounds in monotherapy. Therefore, we also collect whole blood,
plasma as well as tumor biopsies for translational research.
Analyzing these biologic samples will give us more insight on the
genetic landscape of recurrent/metastatic SCCHN, which may
lead to the discovery of new therapeutic targets, and may help to
investigate more precisely the utility of liquid biopsy.
Translational research will also provide information regarding
drug resistance mechanisms and will help us to develop new com-
bination treatments that are able to tackle them.
A finding of biomarker-driven studies is the low number of
patients who benefit from this approach. This suggests that for
heterogeneous cancers with multiple potential oncogenic drivers,
biomarkers assessed only at the DNA level may not predict drug
responses reliably. The signification of some genomic alterations
can vary from one cancer histology to another. Therefore, for fur-
ther developments, we will have to take into account several
others parameters such as the phenotype (e.g. gene expression/
proteomic profiles) and the tissue of cancer origin [59].
In conclusion, precision medicine remains a major challenge
for the medical community. Large efforts are needed to optimize
the study designs, the theranostic tools, and the trial logistics.
Designing biomarker-driven studies requires close collaboration
with country CA, EC, and pharmaceutical companies to reduce
the administrative burden and facilitate the processes linked with
the design and conduct of such clinical trials.
Acknowledgements
This study concept was developed in 2015 at the Flims-
workshop (ECCO-AACR-EORTC-ESMO, Methods in Clinical
Cancer Research workshop). We are grateful to the following
Flims faculty members: Dr Edward Kim, Dr Ignacio Wistuba,
and Dr Charles R. Thomas.
Funding
RG is a research fellow supported by a grant from the Belgian
National Research Fund (Te´le´vie/FNRS N7650918F). This
study is also supported in part by a grant from The ‘Fondation
Louvain’ (Universite´ catholique de Louvain, Belgium).
Disclosure
J-PM is a member of the advisory board of MSD (uncompen-
sated) and INNATE; CLT has been part of advisory boards of
MSD, BMS, Merck Serono, Roche, Amgen, Novartis,
Nonobiotix; JG has been part of advisory boards for
AstraZeneca, Bristol-Myers Squibb, Innate Pharma, and Merck
KGaA and has received grants for research from GSK, Bristol-
Myers Squibb, Chugai, and Merck KGaA; LL has served as con-
sultant/adviser and/or give lectures for Astrazeneca, Bayer,
BMS, Boehringer Ingelheim, Debiopharm, Eisai, Merk-Serono,
MSD, Novartis, Roche and Sobi. She has received research
funds from AstraZeneca, Boehringer Ingelheim, Eisai, Merck-
Serono, MSD, Novartis and Roche. She received travel cover-
age for medical meetings from Bayer, BMS, Debiopharm,
Merck-Serono, MSD and Sobi; JFL is an employee of
OncoDNA; ES-B is a member of advisory board of BMS; AK
has served as an adviser for PUMA Biotechnology and
Avvinity/Centuari Therapeutics Limited. He has received
research grants from AstraZeneca and PUMA Biotechnology
and has also received honoraria from Merck, BMS and MSD
as an invited speaker.
All remaining authors have declared no conflicts of interest.
References
1. Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortal-
ity worldwide: sources, methods and major patterns in GLOBOCAN
2012. Int J Cancer 2015; 136(5): E359–E386.
2. Gillison ML, D’Souza G, Westra W et al. Distinct risk factor profiles for
human papillomavirus type 16-positive and human papillomavirus type
16-negative head and neck cancers. J Natl Cancer Inst 2008; 100(6):
407–420.
3. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in
head and neck cancers. J Clin Oncol 2006; 24(17): 2606–2611.
4. Cancer Genome Atlas Network. Comprehensive genomic characteriza-
tion of head and neck squamous cell carcinomas. Nature 2015; 517:
576–582.
5. Fakhry C, Westra WH, Li S et al. Improved survival of patients with
human papillomavirus-positive head and neck squamous cell carcinoma
in a prospective clinical trial. J Natl Cancer Inst 2008; 100(4): 261–269.
6. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy
plus cetuximab in head and neck cancer. N Engl J Med 2008; 359(11):
1116–1127.
7. Ferris RL, Blumenschein G Jr, Fayette J et al. Nivolumab for Recurrent
Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016;
375(19): 1856–1867.
8. Seiwert TY, Burtness B, Mehra R et al. Safety and clinical activity of pem-
brolizumab for treatment of recurrent or metastatic squamous cell car-
cinoma of the head and neck (KEYNOTE-012): an open-label,
multicentre, phase 1b trial. Lancet Oncol 2016; 17(7): 956–965.
9. Stransky N, Egloff AM, Tward AD et al. The mutational landscape of
head and neck squamous cell carcinoma. Science 2011; 333(6046):
1157–1160.
10. Agrawal N, Frederick MJ, Pickering CR et al. Exome sequencing of head
and neck squamous cell carcinoma reveals inactivating mutations in
NOTCH1. Science 2011; 333(6046): 1154–1157.
11. Vokes EE, Worden FP, Adkins D et al. A randomized phase II trial of the
MET inhibitor tivantinib þcetuximab versus cetuximab alone in patients
with recurrent/metastatic head and neck cancer. J Clin Oncol 2015; 33(15):
6060.
12. Schmitz S, Kaminsky-Forrett MC, Henry S et al. Phase II study of figitu-
mumab in patients with recurrent and/or metastatic squamous cell car-
cinoma of the head and neck: clinical activity and molecular response
(GORTEC 2008-02). Ann Oncol 2012; 23(8): 2153–2161.
13. Machiels JP, Henry S, Zanetta S et al. Phase II study of sunitinib in recur-
rent or metastatic squamous cell carcinoma of the head and neck:
gORTEC 2006-01. J Clin Oncol 2010; 28(1): 21–28.
14. Renfro LA, Sargent DJ. Statistical controversies in clinical research: bas-
ket trials, umbrella trials, and other master protocols: a review and exam-
ples. Ann Oncol 2017; 28: 34–43.
15. Coyne GO, Takebe N, Chen AP. Defining precision: the precision medi-
cine initiative trials NCI-MPACT and NCI-MATCH. Curr Probl Cancer
2017; 41(3): 182–193.
16. Kim ES, Herbst RS, Wistuba II et al. The BATTLE trial: personalizing
therapy for lung cancer. Cancer Discov 2011; 1(1): 44–53.
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2325
17. Le Tourneau C, Delord JP, Goncalves A et al. Molecularly targeted ther-
apy based on tumour molecular profiling versus conventional therapy
for advanced cancer (SHIVA): a multicentre, open-label, proof-of-con-
cept, randomised, controlled phase 2 trial. Lancet Oncol 2015; 16(13):
1324–1334.
18. Tsimberidou AM, Hong DS, Ye Y et al. Initiative for molecular profiling
and advanced cancer therapy (IMPACT): an MD Anderson Precision
Medicine Study. JCO Precis Oncol 2017 2017; (1): 1.
19. Von Hoff DD, Stephenson JJ Jr, Rosen P et al. Pilot study using molecu-
lar profiling of patients’ tumors to find potential targets and select treat-
ments for their refractory cancers. J Clin Oncol 2010; 28(33): 4877–4883.
20. Massard C, Michiels S, Ferte C et al. High-throughput genomics and
clinical outcome in hard-to-treat advanced cancers: results of the
MOSCATO 01 trial. Cancer Discov 2017; 7(6): 586–595.
21. Tsimberidou AM, Iskander NG, Hong DS et al. Personalized medicine in
a phase I clinical trials program: the MD Anderson Cancer Center initia-
tive. Clin Cancer Res 2012; 18(22): 6373–6383.
22. Lyndsay Harris AC, O’Dwyer P, Flaherty K et al. Abstract B080: update
on the NCI-molecular analysis for therapy choice (NCI-MATCH/
EAY131) precision medicine trial. Proceedings of the AACR-NCI-
EORTC international conference: molecular targets and cancer therapeu-
tics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR. Mol
Cancer Ther 2018; 17(Suppl 1): Abstr nr B080.
23. Middleton G, Crack LR, Popat S et al. The National Lung Matrix Trial:
translating the biology of stratification in advanced non-small-cell lung
cancer. Ann Oncol 2015; 26(12): 2464–2469.
24. Richman SD, Adams R, Quirke P et al. Pre-trial inter-laboratory analytic-
al validation of the FOCUS4 personalised therapy trial. J Clin Pathol
2016; 69(1): 35–41.
25. Lih CJ, Harrington RD, Sims DJ et al. Analytical validation of the next-
generation sequencing assay for a nationwide signal-finding clinical trial:
molecular analysis for therapy choice clinical trial. J Mol Diagn 2017;
19(2): 313–327.
26. Hedberg ML, Goh G, Chiosea SI et al. Genetic landscape of metastatic
and recurrent head and neck squamous cell carcinoma. J Clin Invest
2016; 126(4): 1606.
27. Lam VK, Papadimitrakopoulou V. Master protocols in lung cancer:
experience from Lung Master Protocol. Curr Opin Oncol 2018; 30(2):
92–97.
28. Yates LR, Seoane J, Le Tourneau C et al. The European Society for Medical
Oncology (ESMO) Precision Medicine Glossary. Ann Oncol 2018; 29(1):
30–35.
29. Andre F, Bachelot T, Commo F et al. Comparative genomic hybridisa-
tion array and DNA sequencing to direct treatment of metastatic breast
cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet
Oncol 2014; 15(3): 267–274.
30. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a
monoclonal antibody against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med 2001; 344(11): 783–792.
31. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel
in pulmonary adenocarcinoma. N Engl J Med 2009; 361(10): 947–957.
32. U.S. Food and Drug Administration: FDA grants accelerated approval to
pembrolizumab for first tissue/site agnostic indication. http://www.fda.
gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm (25
October 2018, date last accessed).
33. Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus
chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J
Med 2016; 375(19): 1823–1833.
34. Hainsworth JD, Meric-Bernstam F, Swanton C et al. Targeted therapy
for advanced solid tumors on the basis of molecular profiles: results from
MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol
2018; 36(6): 536–542.
35. Hyman DM, Piha-Paul SA, Won H et al. HER kinase inhibition in
patients with HER2- and HER3-mutant cancers. Nature 2018;
554(7691): 189–194.
36. Cohen EEW, Licitra LF, Burtness B et al. Biomarkers predict enhanced
clinical outcomes with afatinib versus methotrexate in patients with
second-line recurrent and/or metastatic head and neck cancer. Ann
Oncol 2017; 28(10): 2526–2532.
37. Vermorken JB, Trigo J, Hitt R et al. Open-label, uncontrolled, multicen-
ter phase II study to evaluate the efficacy and toxicity of cetuximab as a
single agent in patients with recurrent and/or metastatic squamous cell
carcinoma of the head and neck who failed to respond to platinum-
based therapy. J Clin Oncol 2007; 25(16): 2171–2177.
38. Braig F, Voigtlaender M, Schieferdecker A et al. Liquid biopsy monitor-
ing uncovers acquired RAS-mediated resistance to cetuximab in a sub-
stantial proportion of patients with head and neck squamous cell
carcinoma. Oncotarget 2016; 7(28): 42988–42995.
39. Wheeler DL, Huang S, Kruser TJ et al. Mechanisms of acquired resistance
to cetuximab: role of HER (ErbB) family members. Oncogene 2008;
27(28): 3944–3956.
40. Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to
the EGFR monoclonal antibody cetuximab. Cancer Biol Ther 2011;
11(9): 777–792.
41. Machiels JP, Haddad RI, Fayette J et al. Afatinib versus methotrexate as
second-line treatment in patients with recurrent or metastatic
squamous-cell carcinoma of the head and neck progressing on or after
platinum-based therapy (LUX-Head & Neck 1): an open-label, rando-
mised phase 3 trial. Lancet Oncol 2015; 16(5): 583–594.
42. Gilbert J, Schell MJ, Zhao X et al. A randomized phase II efficacy and cor-
relative studies of cetuximab with or without sorafenib in recurrent and/
or metastatic head and neck squamous cell carcinoma. Oral Oncol 2015;
51(4): 376–382.
43. Eze N, Chung CH, Neumeister V et al. PTEN loss as a predictive bio-
marker in head and neck squamous cell cancer (HNSCC) patients treated
with cetuximab (C). J Clin Oncol 2017; 35(Suppl 15): e17520.
44. Luhtala SSS, Barok M, Tanner M, Isola J. Comparison of antibodies for
immunohistochemistry-based detection of HER3 in breast cancer. Appl
Immunohistochem Mol Morphol 2018; 26(3): 212–219.
45. Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcino-
genesis. Biochim Biophys Acta 2012; 1823(4): 850–860.
46. Yohann Loriot AN, SH, Park J, Garcı´a-Donas RA et al. Erdafitinib
(ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR)
inhibitor, in patients (pts) with metastatic or unresectable urothelial car-
cinoma (mUC) and FGFR alterations (FGFRa): phase 2 continuous ver-
sus intermittent dosing. Presented at the 2018 American Society of
Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium,
February 8-10, 2018, San Francisco, CA, 2018.
47. Markus Joerger PC, N, Penel R, Cathomas H et al. Rogaratinib in
patients with advanced urothelial carcinomas pre-screened for tumor
FGFR mRNA expression and effects of mutations in the FGFR signaling
pathway. Poster Presented at the 2018 American Society of Clinical
Oncology Annual Meeting, June 1-5, 2018, Chicago, IL, 2018.
48. Peter Ellinghaus MOS, Bender C, Kneip S et al. Use of tumor mRNA ex-
pression for patient selection in a Phase I study of the pan-fibroblast
growth factor receptor inhibitor BAY 1163877. Poster Presented at the
AACR Annual Meeting 2017, 1–5 April 2017, Washington, DC, USA.
49. Goke F, Franzen A, Hinz TK et al. FGFR1 expression levels predict
BGJ398 sensitivity of FGFR1-dependent head and neck squamous cell
cancers. Clin Cancer Res 2015; 21(19): 4356–4364.
50. Michel L, Ley J, Wildes TM et al. Phase I trial of palbociclib, a selective
cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in
patients with recurrent/metastatic head and neck squamous cell carcin-
oma. Oral Oncol 2016; 58: 41–48.
51. Marquard AM, Eklund AC, Joshi T et al. Pan-cancer analysis of genomic
scar signatures associated with homologous recombination deficiency
suggests novel indications for existing cancer drugs. Biomark Res 2015;
3: 9.
52. Weaver AN, Cooper TS, Rodriguez M et al. DNA double strand break re-
pair defect and sensitivity to poly ADP-ribose polymerase (PARP) inhib-
ition in human papillomavirus 16-positive head and neck squamous cell
carcinoma. Oncotarget 2015; 6: 26995–27007.
53. Ferris, RL Blumenschein, G.R. Fayette, J Guigay, J et al. Two-year update
from CheckMate 141: outcomes with nivolumab (Nivo) vs investigator’s
Review Annals of Oncology
2326 | Galot et al. Volume 29 | Issue 12 | 2018
choice (IC) in recurrent or metastatic (R/M) squamous cell carcinoma of
the head and neck (SCCHN) in the overall population and PD-L1 sub-
groups. Cancer Res 2018; 78(Suppl 13): CT116.
54. Silva TG, Crispim JC, Miranda FA et al. Expression of the nonclassical
HLA-G and HLA-E molecules in laryngeal lesions as biomarkers of
tumor invasiveness. Histol Histopathol 2011; 26(12): 1487–1497.
55. Regulation (EU) No 536/2014 of the European Parliament and of the
Council of 16 April 2014 on clinical trials on medicinal products for
human use, and repealing Directive 2001/20/EC. https://ec.europa.eu/
health/human-use/clinical-trials/regulation_en (25 October 2018, date
last accessed).
56. Liu N, Rowley BR, Bull CO et al. BAY 80-6946 is a highly selective intra-
venous PI3K inhibitor with potent p110alpha and p110delta activities in
tumor cell lines and xenograft models. Mol Cancer Ther 2013; 12(11):
2319–2330.
57. Soulieres D, Faivre S, Mesia R et al. Buparlisib and paclitaxel in patients
with platinum-pretreated recurrent or metastatic squamous cell carcin-
oma of the head and neck (BERIL-1): a randomised, double-blind, pla-
cebo-controlled phase 2 trial. Lancet Oncol 2017; 18(3): 323–335.
58. Hanna GJ, Lizotte P, Cavanaugh M et al. Frameshift events predict anti-
PD-1/L1 response in head and neck cancer. JCI Insight 2018; 3(4):
e98811.
59. Voest EE, Bernards R. DNA-guided precision medicine for cancer: a case
of irrational exuberance? Cancer Discov 2016; 6(2): 130–132.
60. Schoffski P, Wozniak A, Kasper B et al. Activity and safety of crizotinib
in patients with alveolar soft part sarcoma with rearrangement of TFE3:
European Organization for Research and Treatment of Cancer (EORTC)
phase II trial 90101 ‘CREATE’. Ann Oncol 2018; 29(3): 758–765.
61. Schoffski P, Wozniak A, Leahy MG et al. The tyrosine kinase
inhibitor crizotinib does not have clinically meaningful activity in heavily
pre-treated patients with advanced alveolar rhabdomyosarcoma with
FOXO rearrangement: European Organisation for Research and Treatment
of Cancer phase 2 trial 90101 ‘CREATE’. Eur J Cancer 2018; 94: 156–167.
62. Schoffski P, Wozniak A, Stacchiotti S et al. Activity and safety of crizoti-
nib in patients with advanced clear-cell sarcoma with MET alterations:
european Organization for Research and Treatment of Cancer phase II
trial 90101 ‘CREATE’. Ann Oncol 2017; 28(12): 3000–3008.
63. Schoffski P, Wozniak A, Escudier B et al. Crizotinib achieves long-lasting
disease control in advanced papillary renal-cell carcinoma type 1 patients
with MET mutations or amplification. EORTC 90101 CREATE trial. Eur
J Cancer 2017; 87: 147–163.
64. Schmoll HJ. FOCUS4: a new trial design for evaluation of targeted
drugs in colorectal cancer? Lancet Gastroenterol Hepatol 2018; 3(3):
143–145.
Annals of Oncology Review
Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2327
