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ECONOMOPOULOU, BOURHIS, AND PSYRRI
RECURRENT/METASTATIC HEAD AND NECK
SQUAMOUS CELL CARCINOMA
Afatinib versus Methotrexate as Second-Line Therapy
in Recurrent/Metastatic HNSCC after Platinum
Therapy: LUX Head and Neck 1
For patients with R/M HNSCC, the recommended fırst-line
treatment is combination platinum/fluorouracil with or without
cetuximab for fıt patients. 1 Limited options are available for
second-line therapy, and, unfortunately, a small proportion of
patients are fıt enough to be suitable candidates for second-line
therapy. The epidermal growth factor receptor (EGFR), a transmembrane
tyrosine kinase receptor belonging to the HER/ErbB
family, is a longstanding, challenging target in HNSCC, which is
overexpressed in up to 90% of cases; overexpression of EGFR
also correlates with poor clinical outcomes. 28,29 Cetuximab, a
chimeric immunoglobulin G1 human monoclonal antibody
against the extracellular domain of EGFR, has emerged as a
powerful tool in the treatment of R/M head and neck cancer,
and it is the only targeted agent currently approved for HNSCC.
In the EXTREME (erbitux in fırst-line treatment of recurrent or
metastatic head and neck cancer) study, the addition of cetixumab
to platinum-based chemotherapy with fluorouracil was
shown to improve OS, PFS, and response rates. 30 However, cetuximab
has demonstrated modest response rates when used as
monotherapy. 31 Afatinib, an oral irreversible ErbB family
blocker that inhibits all kinase-active members (EGFR, HER2,
and HER4), and which is currently approved for the treatment
of EGFR-mutated non–small cell lung cancer, 32 has shown similar
clinical activity to cetuximab in R/M HNSCC in a recent
phase II trial. 33 On the basis of these results, the phase III LUX
Head and Neck 1 clinical trial presented at the 2014 European
Society of Medical Oncology Congress assessed the effıcacy of
afatinib as monotherapy compared with single-agent methotrexate
as second-line treatment in HNSCC. 5 Patients were
stratifıed according to performance status (PS) and prior use of
cetuximab. The study met its primary endpoint, showing an increase
in PFS of 0.9 months with afatinib compared with methotrexate
(2.6 vs. 1.7 months; HR, 0.8; p 0.03). In addition, it
showed improvement in tumor shrinkage and response rate in
favor of afatinib, whereas no improvement in OS with afatinib
versus methotrexate was noted. Grades 3 and 4 treatmentrelated
adverse events were skin rash (9.7%) and diarrhea (9.4%)
with afatinib and stomatitis (8.1%) and neutropenia (6.9%) with
methotrexate. A signifıcant delay in the deterioration of global
health status, pain, and swallowing was noted with afatinib. In
practical terms, the difference in PFS of 0.9 months is of unclear
signifıcance and is unlikely to lead to drug approval. 5 However,
this study is important, because it is the second study since the
EXTREME trial that showed a benefıt of a novel agent in HN-
SCC and the fırst study to demonstrate an active oral, targeted
agent in HNSCC. Of note, subgroup analysis showed a benefıt
primarily seen in cetuximab-naive patients, which suggested a
degree of cross-resistance that was not seen in phase II studies.
Ongoing studies evaluating adjuvant afatinib in locally advanced
HNSCC after chemoradiotherapy (LUX Head and Neck
2) hopefully will clarify the role of afatinib in HNSCC; until then,
an active search for predictive biomarkers might lead to the
identifıcation of specifıc groups of patients who derive benefıt
from afatinib.
Molecular Screening for Cancer Treatment
Optimization in Head and Neck Cancer: MOSCATO 01
In the era of personalized medicine, there is a push toward utilizing
next-generation sequencing to identify driver mutations
in individual tumors. The identifıcation of driver molecular alterations
in individual tumors may allow personalization of cancer
therapy. Targeted agents matched with tumor molecular
alterations were associated with improved outcomes compared
with nonmatched therapy in patients who had advanced cancers,
in some studies. 34 Recently, four whole-exome sequencing
studies conducted in 190 HNSCC specimens shed light onto the
molecular pathogenesis of HNSCC, identifying key mutations
of several tumor suppression genes, such as TP53 (60%),
CDKN2A (9% to 74%), PI3KCA (8% to 20%), Notch (9% to 19%)
and PTEN (13.6%). 35-38 These studies revealed, for the fırst time,
the presence of novel inactivating mutations in tumor suppressor
genes that regulate cellular squamous differentiation within
the normal stratifıed squamous epithelium, such as NOTCH1,
TP63, and FBXW7, as driver genetic events of neoplastic transformation
in the head and neck area. Elucidation of the mutational
spectrum of HNSCC is anticipated to have a great impact
on the treatment of the various subtypes of the disease according
to the constellation of targetable driver genetic events. In a prospective
study that included 78 heavily pretreated patients with
HNSCC, biopsy specimens obtained from the primary or metastatic
tumor sites were subjected to comparative genomic hybridization
and next-generation sequencing for up to 74 target
genes (10% tumor cells required). 8 A weekly molecular tumor
board reviewed the results of the molecular analysis to identify
actionable molecular alterations for which the most relevant targeted
therapy may be available through early clinical trials or
approved drugs. In 30 of 78 heavily pretreated patients included
in the MOSCATO 01 trial, actionable molecular aberrations
were encountered and were defıned as aberrations with signifıcant
prognostic and therapeutic implications for specifıc drugs
currently used in other cancers. One-third of those patients were
treated with a targeted therapy according to the molecular profıle.
Among patients treated on the basis of the genomic profıle,
three attained partial response, three had stable disease, one developed
disease progression, and two were not evaluable. In
this study, actionable molecular aberrations were observed
in the following pathways: fıbroblast growth factors
(FGFs) and their receptors (FGFRs; 35%), phosphoinositide
3-kinase (PI3K)/AKT/mammalian target of rapamycin
(mTOR) (26%), MYC (24%), CDKs/Cyclins (13%), EGFR
(9%), HER2 (7%), Notch (4%), and KIT (2%). 8 This study
shows early results of a personalized medicine strategy in
R/M HNSCC, and further results will be awaited with great
interest. It is important to emphasize, however, that implementing
a personalized cancer medicine program requires
adequate tumor tissue available for molecular characterization;
a standardized, high-quality laboratory for molecular
profıling to ensure the accuracy, reliability, and timeliness of
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2015 ASCO EDUCATIONAL BOOK | asco.org/edbook