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"Personalized biomarker-based treatment strategy for patients with squamous cell carcinoma of the head and neck: EORTC position and approach."


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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 paper, we review 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.
Personalized biomarker-based treatment strategy for
patients with squamous cell carcinoma of the head
and neck: EORTC position and approach
R. Galot
, C. Le Tourneau
, J. Guigay
, L. Licitra
, I. Tinhofer
, A. Kong
, C. Caballero
C. Fortpied
, J. Bogaerts
, A.-S. Govaerts
, D. Staelens
, T. Raveloarivahy
, L. Rodegher
, J.-F. Laes
E. Saada-Bouzid
& J.-P. Machiels
Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc;
Institute for Clinical and Experimental Research (POLE MIRO), Universite´
Catholique de Louvain, Brussels, Belgium;
Department of Drug Development and Innovation, Institut Curie, Paris & Saint-Cloud, Paris;
INSERM U900 Research Unit,
Versailles-Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux;
Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France;
Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan;
Department of Oncology and Hemato-oncology,
University of Milan, Milan, Italy;
Charite´ Universita¨tsmedizin Berlin, Corporate Member of Freie Universita¨t Berlin, Humboldt-Universita¨t zu Berlin, Berlin;
Department of Radiooncology and Radiotherapy, Berlin Institute of Health, Berlin, Germany;
Institute of Cancer and Genomic Sciences, University of
Birmingham, Birmingham, UK;
European Organization of Research and Treatment of Cancer (EORTC) Headquarters, Brussels;
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:
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
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 [24].
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
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:
Annals of Oncology 29: 2313–2327, 2018
Published online 11 October 2018
biology [4,9,10]. Targeted therapies have shown disappointing
results [1113]. 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
‘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
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
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
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
Results and impact
on outcome
All, refractory advanced
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
211/460 (45.8%)treated
with matched
therapy¼16.4% of total
Analysis on 379 with 1
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,
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
ORR: 27% in matched
therapy versus 5%
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
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
ORR: 11% versus 5%
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
All, refractory advanced
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
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-
phase II trial
Mutations by targeted NGS
(AmpliSeq cancer panel)
CNA by Affymetix IHC for es-
trogen, progesterone and
androgen receptors
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Table 2. Continued
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
Results and impact
on outcome
01 trial
All, advanced cancer Screening
New biopsy (Fresh-frozen) Screening route to phase
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
- 199 pts were treated
with a targeted therapy
¼19% of total
PFS2/PFS1 ratio >1.3 in
63/199 pts treated
with targeted therapy
(33%)¼7% of suc-
cessfully screened pts
open-label, pro-
spective clinical
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
CREATE trial
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
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
ORR No biomarker-positivity
needed for entering
the trial
Results published per
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
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
randomized trial
NGS of >380 unique action-
able variants in 20 genes
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,
Basket trial
or recent biopsy of <6 months
with no interim therapy
sequencing assay for more
than 4, 000 different variants
in 143 genes
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
Results and impact
on outcome
1 of the 30 treatment
998 pts have been
assigned to treatment,
of which 69% have
enrolled (12% of
screened population)
Advanced refractory solid
tumor harboring MA in
Hedgehog pathway
Master protocol
Phase IIa, multi-
center, non-
multiple basket
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
ORR within each
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
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
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
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Table 3. Selected histology specific biomarker-driven approaches
Study Tumor Study design Biomarker Methodology End point Identification of target
and number of treated
Results and impact on
The BATTLE trial
NSCLC Master protocol
phase II, single-
center, open-
label study
Fresh biopsy (FFPE) Testing
of 11 prespecified bio-
markers: PCR-based
sequencing for mutations
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
SAFIR01 [29] Metastatic breast
Fresh biopsy
aCGH for preselected genes
and Sanger sequencing for
mutational hotspots on
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
423 pts included, biopsy
obtained for 407 pts
Therapy could be personal-
ized in 55/423 pts (13%)
Targetable alteration in
195 (46%)
ter protocol
Advanced lung
squamous cell
Master protocol
Phase II–III um-
brella trial
Archival FFPE or fresh tumor
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
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
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
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
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
‘No actionable mutation
arm’ for patients without
specific eligibility for one
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
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
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
Results and impact on
of the targeted genomic
FOCUS4 [64] Advanced colorec-
tal cancer
Master protocol
Phase II–III um-
brella trial
FFPE block taken before com-
mencement of standard
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
Median PFS 3.48 months
with placebo and 2.96
months with AZD8931:
closed for futility
Mutations of some prese-
lected genes þsome
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.
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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%), FGFR13(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 identifier and status
Pan FGFR kinase inhibitor BGJ398 in treating patients with FGFR13translocated, mutated, or
amplified recurrent head and neck cancer
Not yet recruiting
Phase II study of tipifarnib in squamous head and neck cancer with HRAS mutations NCT02383927
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
SF1126 in recurrent or progressive SCCHN and mutations in PIK3CA gene and/or PI-3 kinase
pathway genes
Terminated (slow enrollment)
Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck
(TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC)
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,
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
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
Physician’s choice
Monalizumab +
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
Ye s
Ye s
Ye s
Ye s
Ye s
Ye s
Ye s
Positive FGFR1/2/3 mRNA pos +
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
EGFR activating mutation +
HER2 activating
mutation/amplification + RAS WT?
FGFR1/2/3 mRNA pos +
able to swallow ?
platinum-sensitive +
able to swallow ?
CCND1 amplification
EGFR amplification or PTEN high
+ RAS WT ?
cetuximab naive +
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
Design Sample size
Biomarker-driven patient cohorts
p16 negative and EGFR
or PTEN high or HER2
Afatinib Phase II, randomized,
open-label, multicenter
55 H0: PFSR at 16 weeks¼20%
H1: PFSR at 16 weeks¼40%
Simon 2 Stage design
p16 negative and cetuxi-
mab naı¨ve
Afatinib Phase II, randomized,
open-label, multicenter
55 H0: PFSR at 16 weeks¼20%
H1: PFSR at 16 weeks¼40%
Simon 2 Stage design
B3 p16 negative and CCND1
Palbociclib Phase II, randomized,
open-label, multicenter
55 H0: PFSR at 16 weeks¼20%
H1: PFSR at 16 weeks¼40%
Simon 2 Stage design
B4 p16 negative and ‘plat-
Niraparib Phase II, single arm, proof-
of-concept, multicenter
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
32 H0: ORR over first 16 weeks¼5%
H1: ORR over first 16 weeks¼20%
Simon 2 stage design
FGFR1/2/3 mRNA
Rogaratinib Phase II, single arm, proof-
of-concept, multicenter
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
40 H0: ORR over first 16 weeks¼3%
H1: ORR over first 16 weeks¼15%
Single stage A’Hern
I2 NA Monalizumab
Phase II, randomized,
open-label, multicenter
76 H0: ORR over first 16 weeks¼3%
H1: ORR over first 16 weeks¼15%
Simon 2 stage design
Patients included in the afatinib arms should not have activating mutation in RAS.
Patients included in the Rogaratinib arm should not have activating mutation in RAS or PIK3CA.
ORR, overall response rate; PFSR, progression-free survival rate.
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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
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.
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
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
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.
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.
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).
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.
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Volume 29 | Issue 12 | 2018 doi:10.1093/annonc/mdy452 | 2327
... For this reason, new biomarker-driven trials have been designed to explore the efficacy of genotypedrug matching. The EORTC 1559 study (NCT03088059), the first international biomarkerdriven study including HNSCCs, will compare the activity of targeted agents (including afatinib, palbociclib, niraparib, and entrectinib) with immunotherapy [68]. NGS technology will be used to analyse copy number variations and somatic mutations of 13 tumour suppressor genes and oncogenes; PTEN and p16 expression will be evaluated through immunohistochemistry. Patients will be divided into the different treatment arms based on genomic results and a pre-defined algorithm [68]. ...
... The EORTC 1559 study (NCT03088059), the first international biomarkerdriven study including HNSCCs, will compare the activity of targeted agents (including afatinib, palbociclib, niraparib, and entrectinib) with immunotherapy [68]. NGS technology will be used to analyse copy number variations and somatic mutations of 13 tumour suppressor genes and oncogenes; PTEN and p16 expression will be evaluated through immunohistochemistry. Patients will be divided into the different treatment arms based on genomic results and a pre-defined algorithm [68]. However, biomarker-driven clinical trials still have some limitations, such as narrow gene panels and restrictive matching algorithms, which entail a low matching rate [69]. ...
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Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.
... The patients with recurrent and/or metastatic HNSCC are the focus of this overarching biomarker-driven investigation. It is the first multicentre study that proposes a strategy centered on biomarkers for recurrent/metastatic HNSCC patients, where Palbociclib® is recommended for patients with cyclin D1 amplification and p16 negativity (Galot et al., 2018). ...
Regulated cell division is one of the fundamental phenomena which is the basis of all life on earth. Even a single base pair mutation in DNA leads to the production of the dysregulated protein that can have catastrophic consequences. Cell division is tightly controlled and orchestrated by proteins called cyclins and cyclin-dependent kinase (CDKs), which serve as licensing factors during different phases of cell division. Dysregulated cell division is one of the most important hallmarks of cancer and is commonly associated with a mutation in cyclins and CDKs along with tumor suppressor proteins. Therefore, targeting the component of the cell cycle which leads to these characteristics would be an effective strategy for treating cancers. Specifically, Cyclin-dependent kinases (CDKs) involved in cell cycle regulation have been identified to be overexpressed in many cancers. Many studies indicate that oncogenesis occurs in cancerous cells by the overactivity of different CDKs, which impact cell cycle progression and checkpoint dysregulation which is responsible for development of tumor. The development of CDK inhibitors has emerged as a promising and novel approach for cancer treatment in both solid and hematological malignancies. Some of the novel CDK inhibitors have shown remarkable results in clinical trials, such as—Ribociclib®, Palbociclib® and Abemaciclib®, which are CDK4/6 inhibitors and have received FDA approval for the treatment of breast cancer. In this chapter, we discuss the molecular mechanism through which cyclins and CDKs regulate cell cycle progression and the emergence of cyclins and CDKs as rational targets in cancer. We also discuss recent advances in developing CDK inhibitors, which have emerged as a novel class of inhibitors, and their associated toxicities in recent years.
... Due to differences in patient-specific tumor characteristics, these treatments show varying efficiency and new therapeutic concepts to improve the patients' outcomes are urgently needed. Thus, the socalled personalized therapy including molecular targeting is drawing more and more attention of clinicians and cancer researchers [9][10][11]. As a fundamental procedure of obtaining basic characterization of tumorigenesis and testing the efficiency of designed personalized treatment, primary tumor cell cultures provide preclinical models mimicking the patient-specific genetic and molecular features [12,13]. ...
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Background New concepts for a more effective anti-cancer therapy are urgently needed. Experimental flaws represent a major counter player of this development and lead to inaccurate and unreproducible data as well as unsuccessful translation of research approaches into clinics. In a previous study we have created epithelial cell cultures from head and neck squamous cell carcinoma (HNSCC) tissue. Methods We characterize primary cell populations isolated from human papillomavirus positive HNSCC tissue for their marker expression by RT-qPCR, flow cytometry, and immunofluorescence staining. Their sensitivity to MDM2-inhibition was measured using cell viability assays. Results Primary HNSCC cell cultures showed the delayed formation of spheroids at higher passages. These spheroids mimicked the morphology and growth characteristics of other established HNSCC spheroid models. However, expression of epithelial and mesenchymal markers could not be detected in these cells despite the presence of the HNSCC stem cell marker aldehyde dehydrogenase 1 family member A1. Instead, strong expression of B- and T-lymphocytes markers was observed. Flow cytometry analysis revealed a heterogeneous mixture of CD3 + /CD25 + T-lymphocytes and CD19 + B-lymphocytes at a ratio of 4:1 at passage 5 and transformed lymphocytes at late passages (≥ passage 12) with CD45 + CD19 + CD20 + , of which around 10 to 20% were CD3 + CD25 + CD56 + . Interestingly, the whole population was FOXP3-positive indicative of regulatory B-cells (Bregs). Expression of transcripts specific for the Epstein-Barr-virus (EBV) was detected to increase in these spheroid cells along late passages, and this population was vulnerable to MDM2 inhibition. HPV + HNSCC cells but not EBV + lymphocytes were detected to engraft into immunodeficient mice. Conclusions In this study we present a primary cell culture of EBV-infected tumor-infiltrating B-lymphocytes, which could be used to study the role of these cells in tumor biology in future research projects. Moreover, by describing the detailed characteristics of these cells, we aim to caution other researchers in the HNSCC field to test for EBV-infected lymphocyte contaminations in primary cell cultures ahead of further experiments. Especially researchers who are interested in TIL-based adopted immunotherapy should exclude these cells in their primary tumor models, e.g. by MDM2-inhibitor treatment. BI-12-derived xenograft tumors represent a suitable model for in vivo targeting studies.
... HNSCC is a histologically and genetically heterogeneous disease that originates from a variety of anatomical parts, including the oral cavity, tongue, salivary glands, nasopharynx, and larynx (2). Smoking, drinking, and human papillomavirus infection are the main causes of HNSCC (3). Patients with HNSCC often experience cervical lymph node metastasis, local recurrence, and resistance to radiotherapy and chemotherapy (4). ...
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Purpose This study aimed to construct a prognostic signature consisting of immune-related RNA-binding proteins (RBPs) to predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) effectively. Methods The transcriptome and clinical data of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, we ascertained the immunological differences in HNSCC, through single-sample gene set enrichment analysis, stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE), and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) deconvolution algorithm. Then we used univariate proportional hazards (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to screen immune-related RBPs and acquire the risk score of each sample. Subsequently, we further investigated the difference in prognosis, immune status, and tumor mutation burden in high- and low-risk groups. Finally, the efficacy of immunotherapy was measured by the tumor immune dysfunction and exclusion (TIDE) score. Results We derived 15 immune-related RBPs, including FRMD4A, ASNS, RAB11FIP1, FAM120C, CFLAR, CTTN, PLEKHO1, SELENBP1, CHCHD2, NPM3, ATP2A3, CFDP1, IGF2BP2, NQO1, and DENND2D. There were significant differences in the prognoses of patients in the high- and low-risk groups in the training set ( p < 0.001) and the validation set ( p < 0.01). Furthermore, there were statistical differences between the high-risk group and low-risk group in immune cell infiltration and pathway and tumor mutation load ( p < 0.001). In the end, we found that patients in the low-risk group were more sensitive to immunotherapy ( p < 0.001), and then we screened 14 small-molecule chemotherapeutics with higher sensitivity to the high-risk group ( p < 0.001). Conclusion The study constructed a prognostic signature of HNSCC, which might guide clinical immunotherapy in the future.
... Four patients with alterations J o u r n a l P r e -p r o o f in PIK3CA or PTEN were treated with PI3K inhibitors, one patient with a MAPK1 mutation with an ERK inhibitor, one patient with a HRAS mutation with a farnesyltransferase inhibitor, and one patient with a SMARCB1 deletion with an EZH2 histone methyltransferase inhibitor (42). More recently, the European Organization for Research and Treatment of Cancer (EORTC) has launched the first international umbrella clinical trial (EORTC 1559 HNCG: UPSTREAM study; NCT03088059) in which patients with R/M SCCHN were allocated to receive standard of care, targeted therapy, or immunotherapy according to a comprehensive sequencing-based molecular tumor characterization (43). Other recent studies have shown that mutations in the HRAS proto-oncogene, found in 4-5% of patients with R/M SCCHN, make tumors more vulnerable for treatment with tipifarnib, a potent and highly selective inhibitor of farnesyltransferase (44,45). ...
Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options. The lack of significant improvement in SCCHN patient survival over the last decades stresses the need for reliable predictive biomarkers and new therapeutic strategies for personalized clinical management of SCCHN patients. Targeting the SCCHN-associated microenvironment or the interaction of the latter with cancer cells may represent such paradigm shift in the development of new strategies to treat SCCHN patients, as exemplified by the recent implementation of immune checkpoint inhibitors to improve clinical outcomes by increasing anti-tumor immune responses in SCCHN patients. Several clinical trials are in progress in SCCHN patients to evaluate the activity of monoclonal antibodies and small-molecule inhibitors targeting the tumor microenvironment (TME) at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy. This review describes the current knowledge about the influence of the TME on intratumoral heterogeneity and clinical relapse in human SCCHN patients. More precisely, the role of hypoxia as well as the presence of non-cancer cells (e.g. cancer-associated fibroblasts and immune cells) on therapy response of SCCHN cells is highlighted. We also discuss relevant (pre)clinical models that may help integrate the microenvironment-tumor cell interplay in translational research studies for SCCHN. Finally, this review explores potential therapeutic strategies that may exploit the crosstalk between TME and SCCHN cells in order to implement fundamental changes in the tumor treatment paradigm of patients with locally advanced or R/M SCCHN.
Technological advancement in human genome analysis and ICT (information & communication technologies) brought ‘precision medicine’ into our clinical practice. Precision medicine is a novel medical approach that provides personalized treatments tailored to each individual by precisely segmenting patient populations, based on robust data including a person’s genetic information, disease information, lifestyle information, etc. Precision medicine has a potential to be applied to treating a range of tumors, in addition to non-small cell lung cancer, in which precision oncology has been actively practiced. In this article, we are reviewing precision medicine in head and neck cancer (HNC) with focus on tumor agnostic biomarkers and treatments such as NTRK , MSI-H/dMMR, TMB-H and BRAF V600E, all of which were recently approved by U.S. Food and Drug Administration (FDA).
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All patients with the same TNM stage are treated according to the current algorithms for the clinical treatment of patients with head and neck squamous cell carcinoma (HNSCC). Patient outcomes can be considerably improved by choosing a therapy based on a patient's unique distinctions in the genetic and biological properties of the tumour. Rapid technology advancements that enable thorough molecular characterisation of malignancies quickly and affordably have improved our understanding of the molecular pathways involved in tumour transformation and HNSCC disease development. Mining genetic data to enhance tumour staging, prognosis, and personalised therapy choices for HNSCC patients has not yet become standard practice despite noteworthy accomplishments in other tumour forms. We analyse and summarise both old and new data on predictive biomarkers for HNSCC in this review, intending to potentially enhance clinical patient care shortly.
Full-text available
All patients with the same TNM stage are treated according to the current algorithms for the clinical treatment of patients with head and neck squamous cell carcinoma (HNSCC). Patient outcomes can be considerably improved by choosing a therapy based on a patient's unique distinctions in the genetic and biological properties of the tumour. Rapid technology advancements that enable thorough molecular characterisation of malignancies quickly and affordably have improved our understanding of the molecular pathways involved in tumour transformation and HNSCC disease development. Mining genetic data to enhance tumour staging, prognosis, and personalised therapy choices for HNSCC patients has not yet become standard practice despite noteworthy accomplishments in other tumour forms. We analyse and summarise both old and new data on predictive biomarkers for HNSCC in this review, intending to potentially enhance clinical patient care shortly.
Preclinical data support investigation of selective CDK4/6 inhibition as a therapeutic strategy for human papillomavirus (HPV)–unrelated head and neck squamous cell carcinoma (HNSCC). Phase 1 clinical trials established the feasibility of combining palbociclib with cetuximab in patients with recurrent or metastatic HNSCC. Nonrandomized phase II trials showed that palbociclib plus cetuximab resulted in efficacy outcomes better than cetuximab in biomarker-unselected, platinum-resistant or cetuximab-resistant, HPV-unrelated HNSCC. A double-blind, randomized phase II trial (PALATINUS) evaluated the efficacy of palbociclib or placebo and cetuximab in patients with biomarker-unselected, platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC. Palbociclib and cetuximab did not significantly prolong overall survival compared with placebo and cetuximab. However, correlative biomarker analyses identified that trends for better overall survival with palbociclib and cetuximab were observed in certain prespecified subsets; the largest reduction in risk of death with palbociclib versus placebo and cetuximab occurred in the subset with CDKN2A mutations. Several phase II–III trials are underway investigating palbociclib in biomarker-selected patients with HPV-unrelated locally advanced or recurrent or metastatic HNSCC.
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Background: The outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field. Aim: To evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials. Methods: We searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials. Results: Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy. Conclusion: Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.
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Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.
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Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, ‘basket’ trial using the pan-HER kinase inhibitor neratinib (SUMMIT; identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
Purpose Genomic profiling is increasingly used in the management of cancer. We have previously reported preliminary results of our precision medicine program. Here, we present response and survival outcomes for 637 additional patients who were referred for phase I trials and were treated with matched targeted therapy (MTT) when available. Patients and Methods Patients with advanced cancer who underwent tumor genomic analyses were treated with MTT when available. Results Overall, 1,179 (82.1%) of 1,436 patients had one or more alterations (median age, 59.7 years; men, 41.2%); 637 had one or more actionable aberrations and were treated with MTT (n = 390) or non-MTT (n = 247). Patients who were treated with MTT had higher rates of complete and partial response (11% v 5%; P = .0099), longer failure-free survival (FFS; 3.4 v 2.9 months; P = .0015), and longer overall survival (OS; 8.4 v 7.3 months; P = .041) than did unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders versus nonresponders was 7.6 versus 4.3 months ( P < .001) and OS was 23.4 versus 8.5 months ( P < .001), whereas for non-MTT patients (responders v nonresponders), FFS was 6.6 versus 4.1 months ( P = .001) and OS was 15.2 versus 7.5 months ( P = .43). Patients with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathway alterations matched to PI3K/Akt/mammalian target of rapamycin axis inhibitors alone demonstrated outcomes comparable to unmatched patients. Conclusion Our results support the use of genomic matching. Subset analyses indicate that matching patients who harbor a PI3K and mitogen-activated protein kinase pathway alteration to only a PI3K pathway inhibitor does not improve outcome. We have initiated IMPACT2, a randomized trial to compare treatment with and without genomic selection.
e17520 Background: No biomarker of C resistance has been identified in HNSCC. PTEN loss is present in approximately 30% of HNSCC. Biomarker analysis of the E5397 study suggested that addition of C to cisplatin in R/M HNSCC improves PFS in PTEN high/PIK3CA wild type patients but not those with PTEN loss or PIK3CA mutation. We hypothesized that PTEN testing may aid patient (pt.) selection for C therapy in HNSCC. Methods: MCC15780 was a phase II randomized trial of C plus sorafenib or C plus placebo in R/M HNSCC. 52/56 pts. in this study received C. PTEN analysis using AQUA as previously described was performed on tumor from 38 pts. Automated image capture was performed with HistoRx PM-2000 using the AQUAsition software. AQUA PTEN cut off determined as 1177 based on the first tertile.Fisher’s exact test used to compare low and high expression group. Event-time distributions estimated by Kaplan-Meier and compared using log-rank. Stratified Cox proportional hazards models used to estimate hazard ratios (HR) and test for significance for OS and PFS. All p-values are two-sided. A level of p < 0.05 is considered statistically significant. Results: 12/37 (32%) tumors were PTEN low. There was statistically significant improvement in PFS in PTEN high tumors compared to PTEN low tumors (HR (high/low) =0.33, 95% CI= (0.14, 0.75), p=0.008); and this remains significant after adjusting for age, sex, race, and ethnicity (HR (high/low) =0.27, 95% CI= (0.11, 0.67), p=0.004). Conclusions: PFS is significantly longer in PTEN high tumors compared to PTEN low tumors (HR=0.33, 95% CI= (0.14-0.75), p=0.008) in patients with R/M HNSCC treated with C. This finding remains significant after adjusting for age, sex, race, and ethnicity (HR=0.27, 95% CI= (0.11-0.67), p=0.004).This warrants PTEN analysis of specimens from larger cetuximab-based RCT. [Table: see text]
Background Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. Patients and methods Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. Results Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1–19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49–235), median OS: 277 days (232–442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6–73.0), 26.9% (9.8–43.9), 7.7% (1.3–21.7) and 7.7% (1.3–21.7), respectively. Among two assessable MET− patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. Conclusions The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. Clinical trial number EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.
411 Background: Although immune checkpoint inhibitors (ICI) have improved outcomes in some pts with platinum-resistant mUC, many pts (eg, pts with TCGA luminal 1 tumors, many of whom are FGFRa) may not benefit. ERDA, a pan-FGFR (1-4) inhibitor, demonstrated promising phase 1 activity: 11 partial responses among 24 FGFRa mUC pts. We report efficacy and safety of ERDA in the ongoing global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with specific FGFR2/ FGFR3 mutations or translocations per central lab Janssen assay, ECOG 0-2, and were chemorefractory (progressed during/following ≥ 1 line of prior systemic chemo or ≤ 12 mos of [neo]adjuvant chemo). Cisplatin-ineligible, chemo-naïve pts, and prior ICI treatment were allowed. Pts were randomized 1:1 to 28-d cycles of oral 6 mg/d continuous dosing (6 C) or 10 mg/d intermittent 7 d on/7 d off dosing (10 I) ERDA; the dose was further uptitrated if no significant treatment-related adverse events (TRAEs) were observed. The primary end point was ORR. Results: 78 pts received 6 C and 33 pts received 10 I (10 I cohort stopped early) ERDA. 31 pts in 6 C arm were further uptitrated. Across arms, 50% had ≥ 2 prior lines of therapy; 93% were chemorefractory. Confirmed ORRs (RECIST 1.1) were 35% and 24%, and disease control rates (CR+PR+SD) were 74% and 73% in the 6 C and 10 I arms, respectively. Adverse events (AEs) were manageable, and there were no treatment-related deaths (Table). Treatment is ongoing in 10 pts. Conclusions: ERDA (6 C or 10 I) has promising efficacy and tolerability in pts with FGFRa mUC. Based on these results and ERDA pharmacometric modeling, dosing was optimized at 8 mg/d (continuous), and this cohort is ongoing. Phase 3 study is planned. Clinical trial information: NCT02365597. [Table: see text]
Purpose of review: Contemporary advances in the understanding of the molecular and immunologic basis of metastatic lung cancer have firmly changed its treatment paradigm to a personalized, biomarker-driven approach. However, the majority of lung-cancer patients [especially lung squamous cell carcinoma (LUSC)] still do not have effective targeted therapeutic options. Master protocols, such as Lung-MAP, represent an innovative clinical trial approach designed to accelerate evaluation of novel biomarker-driven therapies. Recent findings: Lung-MAP is an umbrella trial for advanced LUSC and has been active since 2014. Cumulative experience from this overarching, multi-institution master protocol has demonstrated that centralized, real-time biomarker screening is feasible and substudy modularity is essential for protocol adaptability in a rapidly changing treatment landscape. In addition, screening and efficacy results from Lung-MAP affirm that LUSC has several putative drivers but remains difficult to effectively treat with targeted therapy. Summary: Master protocols are a feasible and efficient approach for evaluating biomarker-driven therapies in lung cancer. As we begin to target less common genomic and immunotherapy subtypes, centrally coordinated clinical trial designs such as Lung-MAP are necessary to rapidly deliver effective therapies to patients, whereas also maximizing the quality of research data obtained.