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GERBER, PAIK, AND DOWLATI
squamous carcinoma than in lung adenocarcinoma, which
suggests that there may be an increased dependence on this
pathway in squamous tumors. 16-18 This observation is underscored
by recent in vivo modeling, in which biallelic inactivation
of PTEN and LKB1 led to spontaneous squamous lung
tumor formation. 19 Alteration in one of the components of
the PI3K pathway was observed in 47% of tumors analyzed
by The Cancer Genome Atlas. 8 PIK3CA mutations, predominantly
in the catalytic and regulatory domains, occur in approximately
10% of cases, 4 with PIK3CA amplifıcation
accounting for 40% of these. 4,18 Complete PTEN loss by IHC
was found in 24% of cases, 20 and PTEN was also found to be
mutated in 7% of tumors. 4
Preclinical studies have provided a rationale for targeting
upstream PI3K pathway alterations with novel therapies. In
particular, squamous tumor cell lines and mouse models harboring
PIK3CA mutations or gene amplifıcation and PTEN
loss are sensitive to PI3K inhibitors. 21,22 There are a number
of ongoing or completed early phase trials of PI3K-alpha specifıc
inhibitors or dual PI3K-alpha/mTOR inhibitors for
patients with advanced squamous lung cancer, including studies
of GDC0032 (NCT02154490), BKM120 (NCT01297491),
and LY3023414 (NCT01655225). To date, no effıcacy data have
been presented from these trials.
Discoidin Domain Receptor 2
Discoidin domain receptor 2 (DDR2) is a receptor tyrosine
kinase that regulates cell adhesion, proliferation, and extracellular
remodeling upon binding to its endogenous ligand,
type 1 collagen. 23,24 The potential importance of DDR2 mutations
in squamous lung cancer was established by Hammerman
et al, who found an overall mutation rate of 3.8% in
this gene and demonstrated that certain mutations lead to
gain-of-function phenotypes that can be reversed with dasatinib,
a multikinase inhibitor with activity against both DDR1
and DDR2. 5 Two prior early-phase studies of dasatinib alone
or in combination with erlotinib in patients with advanced
NSCLC showed little overall effıcacy. 25,26 However, one patient
with a squamous tumor harboring a DDR2 S768R mutation
that was EGFR wild-type achieved a partial response to
dasatinib plus erlotinib. 5 A partial response to dasatinib was
also reported in a patient with synchronous chronic myelogenous
leukemia and an early-stage squamous lung tumor
bearing a DDR2 S768R mutation. 27 Given the sporadic nature
of DDR2 mutations and limited preclinical data about
their functionality, it is unclear what proportion of DDR2
mutant squamous patients might benefıt from dasatinib. A
phase II study of dasatinib in DDR2 mutant squamous lung
cancer was recently terminated as a result of poor accrual
(NCT01514864). Additional clinical data will likely rest on
the development of a DDR2-specifıc inhibitor or on case reports
of off-label use of dasatinib.
G1/S Checkpoint Inhibition
Cell division, formalized in the various phases of the cell cycle
that move the cell from a state of quiescence (G0) to DNA
synthesis (G1, S) and ultimately mitosis (G2, M), is an intricately
controlled process that depends on a series of negative
regulatory mechanisms to ensure replication fıdelity and
maintenance of homeostasis. These mechanisms can be bypassed
through the dysregulation of a handful of cell cycle
checkpoint suppressors such as retinoblastoma (RB), P53,
and p16 and activators such as the cyclin/cyclin-dependent
kinase (CDK) complexes. Cyclins D1–3, which bind to CDKs
2, 4, and 6, are important early regulators under the control of
mitogenic signaling. These complexes phosphorylate the tumor
suppressor RB, which facilitates dissociation of RB from
E2F transcription factors. In turn, E2F activation leads to a
transcriptional program that moves the cell from G1 to the S
phase. 28
G1/S checkpoint regulators are commonly altered in squamous
tumors. 4 CCND1, which encodes cyclin D1, is amplifıed
in 13% of cases, and CDK6 is amplifıed in 4%. CDKN2A,
which encodes the tumor suppressor p16 that inhibits CDK4
and 6, is mutated or homozygously deleted in 45% of tumors.
The frequency of these aberrations has made targeting the
cell cycle an attractive concept, although there are limited
published preclinical and clinical data to support this
strategy. 29-31 Palbociclib, which received U.S. Food and Drug
Administration (FDA) approval for use in combination with
letrozole for patients with advanced hormone receptor-positive
breast cancer, is also being studied in advanced squamous cell
lung cancer positive for CCND1 amplifıcation, CDK6 amplifıcation,
or CDKN2A deletion/mutation (NCT02154490).
Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) and its receptor
(VEGFR) are key mediators of angiogenesis. 32 Bevacizumab,
a monoclonal antibody against VEGF, is FDA approved for
the treatment of nonsquamous NSCLC. It is not approved for
patients with squamous NSCLC because of safety concerns
centered on hemoptysis, which is now thought to be fueled by
the common anatomic distribution of this disease (i.e., central
cavitary tumors that may abut or invade local vascular
structures) rather than any unique intrinsic biologic
characteristic. 33-35 Nevertheless, squamous cases were included
in the recently published REVEL study, which randomly
assigned patients with advanced NSCLC to receive
docetaxel with or without the anti–VEGFR-2 monoclonal
antibody ramucirumab. The addition of ramucirumab to
chemotherapy demonstrated an improvement in overall survival
(median OS 10.5 versus 9.1 months; hazard ratio [HR]
0.86, p 0.02), progression-free survival (PFS, HR 0.76, p
0.0001), and ORR (23% vs. 14%, p 0.0001) favoring addition
of ramucirumab. There was no disproportionate increase
in bleeding events for patients with squamous
tumors. 36 Ramucirumab plus docetaxel is now FDA approved
for patients with previously treated advanced
NSCLC, regardless of histologic subtype.
Epidermal Growth Factor Receptor
The epidermal growth factor receptor (EGFR) is a wellcharacterized
proto-oncogene that, when mutated, engenders
a state of oncogene addiction that has been successfully
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