Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Cancer Center, Houston/TX/United States of America, 2 Bionformatics and
Computational Biology, The University of Texas MD Anderson Cancer Center,
Houston/TX/United States of America, 3 The University of Texas MD Anderson
Cancer Center, Houston/United States of America, 4 Translational Molecular
Pathology, M.D. Anderson Cancer Center, Houston/TX/United States of America
Background: Activating mutations in the KRAS proto-oncogene define
a prevalent and clinically heterogeneous molecular subset of lung
adenocarcinoma (LUAC). We previously identified three major subgroups of
KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP),
STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors
exhibit a “cold” tumor immune microenvironment, with reduced expression
of several immune checkpoint effector/mediator molecules, including PD-L1
(CD274). Here, we extend these findings and examine the clinical outcome of
co-mutation defined KRAS subgroups to therapy with immune checkpoint
inhibitors. Methods: We conducted a single-institution analysis of clinical
and molecular data (PCR-based next generation sequencing of panels of 50,
134 or 409 genes) prospectively collected from patients enrolled into the MD
Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were
separated into KP, KL and K (wild-type for TP53 and STK11) groups. The logrank
test and Fisher’s exact test were used for comparison of progression-free
survival (PFS) and objective response rate (ORR) respectively between the
groups. In addition, automated IF-based enumeration of lymphocyte subsets
was performed in 40 surgically resected LUAC (PROSPECT cohort) with
available whole exome sequencing data. Results: Among 229 patients with
KRAS-mutant LUAC who consented to the protocol we identified 35 patients
with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy
with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1)
and durvalumab/tremelimumab (N=2) and had robust clinical outcome
data. There was no impact of different KRAS alleles (G12C/G12V/G12D)
on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors
(P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation
defined KRAS subgroups exhibited significantly different median PFS to
immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank
test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%)
K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3
contingency table). In the PROSPECT cohort of surgically resected LUACs
with available whole exome sequencing data, somatic mutation in STK11 was
associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+
(P=0.0125) and CD4+ (P=0.0036) lymphocytes. Conclusion: Mutations in
STK11/LKB1 are associated with an inert tumor immune microenvironment
and poor clinical response of KRAS-mutant LUAC to immune checkpoint
blockade. The mechanism that underlies this phenotype and strategies to
overcome it are under investigation. The impact of additional co-mutations on
the immune profile and response of KRAS-mutant LUAC to immunotherapy is
also being explored.
Keywords: KRAS, Immunotherapy, STK11, Co-Mutations
MA04: HER2, P53, KRAS AND OTHER TARGETS IN ADVANCED NSCLC
MONDAY, DECEMBER 5, 2016 - 16:00-17:30
MA04.09 RICTOR AMPLIFICATION IN NON-SMALL CELL LUNG
CANCER: AN EMERGING THERAPY TARGET
Jeffrey Ross 1 , Haiying Cheng 2 , Roman Perez-Soler 3 , James Suh 1 , Dean Pavlick 1 ,
Siraj Ali 1 , Alexa Schrock 1 , Julia Elvin 1 , Jo-Anne Vergilio 1 , Shakti Ramkissoon 1 ,
David Fabrizio 1 , Vincent Miller 1 , Philip Stephens 1 , Laurie Gay 1
1 Foundation Medicine, Cambridge/MA/United States of America, 2 Montefiore
Medical Center, Bronx/NY/United States of America, 3 Oncology, Montefiore
Medical Center, Bronx/NY/United States of America
Background: Comprehensive genomic profiling (CGP) can discover novel
therapy targets in NSCLC. Amplification of RICTOR, encoding a component of
the MTORC2 complex, has recently been identified as a targetable alteration
leading to clinical benefit. Methods: CGP was performed on hybridizationcaptured,
adaptor ligation-based libraries for up to 315 cancer-related genes
plus select introns from 28 genes frequently rearranged in cancer on 14,698
consecutive cases of NSCLC, comprising lung adenocarcinoma, squamous cell
carcinoma (SCC) or NSCLC not otherwise specified (NOS). Tumor mutational
burden (TMB) was determined on 1.1 Mb of sequenced DNA. All classes of
genomic alterations (GA) were assessed simultaneously, including base
substitutions, indels, rearrangements/fusions, and copy number changes.
Results: 747 (5.0%) NSCLC featured RICTOR amplification (amp). There were
380 (51%) male and 367 (49%) female patients with a mean age of 64.1 years
(range 18-88 years). The primary tumor was analyzed in 333 (45%) cases and a
metastasis biopsy in 414 (55%) cases. Genes most frequently co-altered with
RICTOR amp included TP53 (79.5%) and FGF10 (64.6%), which is located close
to RICTOR on chromosome 5 and is frequently co-amplified. Several known
oncogenes in NSCLC were mutated at significantly higher rates in tumors
with RICTOR amp, including EGFR (22%), MET (8.4%), ERBB2 (7%), as well as
FGFR1 (5%), FGFR3 (1.4%), and FGFR4 (1.6%). 42.2% of tumors with RICTOR
amp did not harbor additional alterations in KRAS or genes indicated in the
NCCN guidelines. KRAS GA were identified in 19.6% of RICTOR amp tumors,
compared with 29.8% of all NSCLC, but this difference was not statistically
significant. Mean TMB in RICTOR amp tumors was intermediate (14.9 mut/
Mb), and is higher than the overall average for NSCLC (9.2 mut/Mb). The
number of RICTOR-amplified tumors with high TMB (>20 mut/Mb) was
23%, higher than the rate for non-RICTOR amp NSCLC (12.9%). Examples of
patients with RICTOR amplification within late stage NSCLC responding to
MTOR inhibitors will be presented. Conclusion: RICTOR amplification, when
compared to other non-EGFR known drivers of NSCLC, is a relatively frequent
clinically relevant GA that has been shown to respond to MTOR inhibitors. The
co-occurrence of RICTOR amplification with mutation of known oncogenic
drivers suggests a possible mechanism of acquired resistance to therapy that
should be explored further. Tumors with RICTOR amp more often have higher
levels of TMB than other NSCLC. Further study of RICTOR amp as a therapy
target NSCLC in a clinical trial setting appears warranted.
Keywords: NSCLC, Rictor, comprehensive genomic profiling, tumor
mutational burden
MA04: HER2, P53, KRAS AND OTHER TARGETS IN ADVANCED NSCLC
MONDAY, DECEMBER 5, 2016 - 16:00-17:30
MA04.10 LUNG CANCER GROWTH IS SUPPRESSED BY CD26/
DPP4-INHIBITION VIA ENHANCED NK CELL AND MACROPHAGE
RECRUITMENT
Jae-Hwi Jang, Florian Janker, Stephan Arni, Yoshito Yamada, Walter Weder,
Wolfgang Jungraithmayr
Thoracic Surgery, University Hospital Zürich, Zürich/Switzerland
Background: Lung cancer is the leading cause of death among cancers.
There is broad evidence that immune cells are involved in the growth and
development of these malignancies. CD26/DPP4 (dipeptidyl peptidase
4) is a transmembrane glycoprotein, that is constitutively expressed on
hematopoetic cells, but also found on lung epithelial and endothelial cells.
We found previously that the activity of CD26/DPP4 of lung cancer patients
at early stages is four times higher than in normal tissue. Here, we tested
if CD26/DPP4-inhibition is able to modulate lung cancer growth in mice.
Methods: An orthotopic lung tumor model was employed by sc. injections
of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung
adenocarcinoma cell line (H460). These were developed in mice C57BL6
(n=18) and CD1-nude mice (n=20) respectively. The CD26/DPP4-inhibitor
Vildagliptin was given in drinking water of 50mg/kg daily dose. Tumor
growth was evaluated by wet weight of tumor mass at 2 weeks. Histological
assessments included TUNEL, immunohistochemistry (IHC) of CD3, B220,
F4/80 and NKp46. IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and
Perforin 1 were analyzed by RT-PCR. In vitro analysis of surfactant protein
(SP) expression in LLC and H460 were performed by western blotting. For
a proof of concept, macrophage ablation was performed by clodronateliposome
during Vildagliptin treatment. Results: Vildagliptin treatment
significantly reduced the tumor growth of both, LLC and H460 in mice. IHC
showed macrophages (F4/80+) and NK cells (NKp46+) to be significantly
increased by Vildagliptin within tumors, while TUNEL stain and IHC of T-
and B cell infiltration did not show any difference. Gene expression levels
of anti-inflammatory markers (IL-10, and Arginase) were unchanged, while
the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell
markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were significantly
upregulated within the tumor by Vildagliptin, indicating that inhibition of
CD26/DPP4 recruits NK cells into the tumor. Furthermore, we found enhanced
SP expressions in lung cancer cell lines by Vildagliptin treatment in vitro.
Macrophage ablation with clodronate-liposome in Vildagliptin treated
mice reversed the tumor size significantly. Conclusion: The Inhibition of
CD26/DPP4 decreased lung cancer growth in primary models of mouse and
human lung cancer and increased inflammatory macrophages and NK cell
cytotoxicity within those tumors. Furthermore, an increased expression of
SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant
production in lung cancer activates macrophages to fight against lung cancer
via the recruitment of macrophages and NK cells.
Keywords: Lung; Cancer; CD26/DPP4; Immunity
MA04: HER2, P53, KRAS AND OTHER TARGETS IN ADVANCED NSCLC
MONDAY, DECEMBER 5, 2016 - 16:00-17:30
MA04.11 MECHANISTIC INSIGHTS INTO CAR T-CELL EFFICACY IN
THE TREATMENT OF HETEROGENOUS ANTIGEN EXPRESSING LUNG
ADENOCARCINOMA
Aurore Morello 1 , Masha Zeltsman 2 , Adam Bograd 2 , David Jones 2 , Prasad
Adusumilli 1
S184 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017