Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
estimate the probability of disease recurrence (prognostic factors) and to
characterize novel biomarkers, whose targeting with specific drugs could
potentially limit the oncogenic potential and change the natural history of
this disease (predictive factors). Preliminary results of this study were
consistent with literature data: several molecular alterations might be
identified [PIK3CA, MET, FGFR3, DDR2, FRS2, CDKN2A, SMAD4, PD-L1] and
some of them might impact on the biological behavior of SqCC contributing in
the determination of patients prognosis[10]. These data will be further
presented at WCLC this year. In conclusion, as more treatment options turn
out to be available for patients, it will become essential to tailor those choices
on patient’s unique molecular characteristics and his own needs, identifying
the best sequence of treatments, especially in the era of rising healthcare
costs and longer lifespan of advanced lung cancer patients.References [1]
WHO Statistics. http://www.who.int/mediacentre/factsheets/fs297/en/
[Accessed on 21 August , 2016]. [2] Travis WD. Pathology of lung cancer. Clin
Chest Med 2011; 32: 669–92. [3] Garon EB et al. Ramucirumab plus docetaxel
versus placebo plus docetaxel for second-line treatment of stage IV
non-small-cell lung cancer after disease progression on platinum-based
therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.
Lancet 2014; 384: 665–73. [4] Brahmer J et al. Nivolumab versus docetaxel in
advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;
373(2):123-35. [5] FDA approves Keytruda for advanced non-small cell lung
cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm465444.htm [Accessed on 21 August , 2016]. [6] Soria JC et al. Afatinib
versus erlotinib as second-line treatment of patients with advanced
squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised
controlled phase 3 trial Lancet Oncol 2015; 16: 897–907. [7] LE Ang Y et al.
Profile of nivolumab in the treatment of metastatic squamous non-small-cell
lung cancer. OncoTargets and Therapy 2016:9 3187–3195. [8] Melosky B et al.
Pointed Progress in Second-Line Advanced Non–Small-Cell Lung Cancer: The
Rapidly Evolving Field of Checkpoint Inhibition. J Clin Oncol 2016;34:1676-
1688. [9] The Cancer Genome Atlas Research Network. Comprehensive
genomic characterization of squamous cell lung cancers. Nature 2012;
489(7417): 519–525. [10] S. Pilotto et al. Analyzing prognostic outliers to
unravel biologically and clinically relevant molecular and immunologic
pathways: a model from resected squamous cell lung carcinoma (R-SQCLC).
Poster presented at 58 Annual Meeting of the Italian Cancer Society helded in
Verona on 5-8 September 2016.
Keywords: lung cancer, squamous carcinoma, second line treatment
SESSION SC11: ALK, ROS1 AND RARE MUTATIONS IN NSCLC
MONDAY, DECEMBER 5, 2016 - 16:00-17:30
SC11.03 ROS1 AS A THERAPEUTIC TARGET IN ADVANCED NSCLC
Jürgen Wolf
Center for Integrated Oncology, University Hospital of Cologne, Cologne/Germany
In non-small cell lung cancer (NSCLC) chromosomal rearrangements
involving the gene encoding for the receptor tyrosine kinase ROS1 have been
first described in 2007 (1). These aberrations have been shown to trigger
constitutive kinase activity and activation of downstream pathways like
the MAPK pathway. ROS1 rearrangements can be found in about 2% of
lung adenocarcinoma and are associated with female gender and neversmoking
status (2). Different fusion partners have been described. In routine
diagnostics ROS1 fusion genes can be reliably detected by fluorescence
in situ hybridization (FISH; e.g. dual color break apart FISH), RT-PCR or
next-generation sequencing (NGS). ROS1 fusions occur mutually exclusive
of aberrations in EGFR, ALK and KRAS. However, using NGS, co-occuring
mutations, preferentially in TP53, but also in other genes involved in
oncogenic pathways, can be found in about 50% of these patients (3). ROS1
fusions also seem to be of prognostic relevance, since remarkable long survival
times have been described in patients treated with chemotherapy only (3).
The ALK/MET/ROS1 inhibitor crizotinib has been evaluated in a US-American
cohort of 50 ROS1 positive patients with advanced, mostly pretreated lung
adenocarcinoma and showed impressive activity (4). The overall response
rate (ORR) was 72% (95% CI 58 to 84) with 3 complete responses. Median
progression free survival (PFS) was 19.2 months (95% CI 14.4 to not reached).
Treatment was well tolerated and the side effect profile resembled that
observed in the treatment of ALK positive lung cancer with crizotinib. A
similiar ORR of 80% was reported in a retrospectively analyzed European
cohort (5). However, PFS was only 9.1 months in these patients. The EUCROSS
trial, a collaborative study of the German Lung Cancer Group Cologne and the
Spanish Lung Cancer Group, is a prospective European phase II trial which
recruited 34 ROS1 positive patients between June 2014 and September 2015.
ROS1 fusion genes were diagnosed using dual color break apart FISH and the
results were confirmed by next-generation sequencing. With an ORR of 69%
(95% CI, 49.1 to 84.3) similar efficacy has been reported (6). Based on its high
activity and favorable toxicity profile, crizotinib is now approved for the
treatment of ROS1-positive NSCLC by the FDA since March 2016 and by the
EMA since August 2016. Treatment of ROS1-positive NSCLC with crizotinib
thus has become standard first-line treatment in the leading international
guidelines. Current challenges for the further development and improvement
of targeted treatment of ROS1-positive patients are (I) implementation
of ROS1 diagnostics in routine molecular diagnostics and (II) development
of next-generation ROS1 inhibitors overcoming crizotinib resistance. The
increasing number of actionable mutations in NSCLC including ROS1 requires
implementation of molecular multiplex testing, since sequentially conducted
single gene assays are no more feasible given the usually limited biopsy tissue
specimens. However, conventional NGS technology is restricted to point
mutations and does not cover copy number variations (CNV) and gene fusions.
Thus, new NGS technologies have to be integrated in routine diagnostics like
hybrid capture-based NGS, which does not require DNA amplification by PCR
and thus allows to detect reliably CNV and gene fusions. While increasing
knowledge of the molecular mechanisms underlying TKI resistance has led
to the development of a series of highly potent next-generation inhibitors in
ALK-positive NSCLC now, resistance of ROS1-positive patients to crizotinib
is incompletely understood. In preclinical studies as well as in biopsy tissue,
somatic mutations in the ROS1 kinase domain associated with acquired
crizotinib resistance have been described (7). In functional studies these
mutations were associated with different degrees of resistance. Alternatively,
bypass activation of oncogenic signal transduction pathways has been
described as mechanism underlying resistance. For instance, a cKIT activating
mutation and EGFR pathway activation have been reported in single cases
(8). In vitro, the multikinase inhibitors cabozantinib, foretinib and lorlatinib
have been shown to overcome crizotinib reistance triggered by secondary
mutations in ROS1. Response to cabozantinib has also been described in a
ROS1-positive patient with a mutation confering resistance to crizotinib
(10) and was also observed in a phase I trial of lorlatinib in the same clinical
setting. In summary, ROS1 positivity characterizes a subgroup of patients
with a major benefit from treatment with crizotinib. Consequently, crizotinib
has become the current standard of care for these patients. ROS1 status thus
should be available before decision on first-line treatment. Acquired resitance
to crizotinib may be caused by mutations in the ROS1 kinase domain or by
activation of bypass pathways. The multikinase inhibitor cabozantinib and
the next-generation ALK/ROS1 inhibitor lorlatinib have shown promising
efficacy in early clinical evaluation. (1) Rikova K et al. Global survey of
phosphotyrosine sgnaling identifies oncogenic kinases in lung cancer. Cell
2007, 14; 131(6):1190-203. (2) Bergethon K et al. ROS1 rearrangements define
a unique molecular class of lung cancers. J Clin Oncol 2012, 30(8):863-70. (3)
Scheffler M et al. ROS1 rearrangements in lung adenocarcinoma: prgnostic
impact, therapeutic options and genetic variability. Oncotarget 2015,
6(12):10577-84. (4) Shaw A et al. Crizotinib in ROS1-rearranged non-small
cell lung cancer. NEJM 2014, 371(21): 1963-71. (5) Mazieres J et al. Crizotinib
therapy for advanced lung adenocarcinoma and a ROS1 rearrangement:
results from the EUROS1 cohort. J Clin Oncol 2015, 33(8):867-76. (6) Michels
e al. EUCROSS: a prospective European phase II trial to evaluate efficacy
and safety of crizotinib in advanced adenocarcinoma of the lung harboring
ROS1 translocations. WCLC 2016 (oral presentation). (7) Awas MM et al.
Acquired resistance to crizotinib from a mutation in CD74-ROS1. NEJM 2013,
368(25):2395-401. (8) Dzadziuszko R et al. Activating KIT mutation induces
crizotinib resistance in ROS1-positive lung cancer. J Thorac Oncol 2016,
11(8):1273-81. (9) Davies KD et al. Resistance to ROS1 inhibition mediated
by EGFR pathway activation in non-small cell lung cancer. PLoS One 2013,
13 (8):e82236. (10) Drilon et al. A novel crizotinib-resistant solvent-front
mutation responsive to cabozantinib therapy in a patient with ROS1-
rearranged lung cancer. Clin Cancer Res 2016, 22 (10):2351-8.
SC11: ALK, ROS1 AND RARE MUTATIONS IN NSCLC
MONDAY, DECEMBER 5, 2016 - 16:00-17:30
SC11.04 RARE MUTATIONS IN LUNG CANCER
Oliver Gautschi
Medical Oncology, Lucerne Cantonal Hospital, Luzern/Switzerland
“Lung adenocarcinoma” is a genetically heterogenous disease entity,
characterized by a wide spectrum of different mutations. Some of these
mutations lead to constitutive activation of receptor tyrosine kinases,
which can be inhibited by small molecules (tyrosine kinase inhibitors,
TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among
the first actionable driver mutations identified in lung adenocarcinomas.
Today, several drugs are approved for the treatment of advanced lung
adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement.
Combined, these molecular subgroups make up at least 20% of all lung
adenocarcinomas or more, depending on the poplulation. Further actionable
driver mutations include the genes BRAF, HER2, MET, and RET. These genes
are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are
clinically relevant because of the availability of targeted therapies approved
for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and
BRAF-melanoma). The discussant will summarize current knowledge about
S52 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017