Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
and molecular targeted therapies are upcoming as combination partners with
radiotherapy in selected tumors. Proper patient selection criteria resulted
long term survival as high as 30-45% in multicenter prospective trials in
locally advanced NSCLC. These advantages have to be bundled into new
radiotherapeutic concepts and tested against the standard of conventional
fractionated radiotherapy up to 60 Gy and simultaneous chemotherapy in
future well designed randomized trials.
Keywords: dose painting, dose escalation, image guidence, IMRT
SESSION MTE08: IMMUNOTHERAPY IN EARLY AND
LOCALLY ADVANCED NSCLC: CHALLENGES AND PERSPEC-
TIVES (TICKETED SESSION)
MONDAY, DECEMBER 5, 2016 - 07:30-08:30
MTE08.01 IMMUNOTHERAPY IN EARLY AND LOCALLY ADVANCED
NSCLC: CHALLENGES AND PERSPECTIVES
Charles Butts 1 , Frank Griesinger 2
1 Medical Oncology, Cross Cancer Institute, Edmonton/Canada, 2 Oncology, Pius-
Hospital Oldenburg, Oldenburg/Germany
The demonstration that therapies directed at the programmed death-1
(PD-1) receptor or its ligand (PD-L1) result in durable responses and improved
survival in a number of solid tumours including non-small cell lung cancer
has awakened interest in cancer immunotherapy. The activity of PD-1/PD-L1
therapy in NSCLC implies that endogenous T-cells can recognize antigens
on tumour cells and eliminate those cancer cells. The success of checkpoint
inhibitor therapy in the metastatic setting has led to a immunotherapy
trials in early stage (adjuvant) and stage lll NSCLC. This session will provide
perspective on the current state and challenges facing immunotherapy in
these settings. Current perspectives: The concept of using immunotherapy
to prevent recurrence of NSCLC after resection of early stage NSCLC is not
new. More recently, two randomized phase lll trials of therapeutic cancer
vaccine strategies have been completed in resected, early stage NSCLC
(MAGRIT) or after chemoradiation in stage lll disease (START). The MAGRIT
trial (1) assessed the efficacy of an active, specific cancer immunotherapy
(ASCI) against the MAGE-A3 cancer testis antigen in completely resected
stage IB-IIIA NSCLC. Tumors from more than 13,000 patients were screened
for MAGE-A3 expression and 2312 patients whose tumours expressed MAGE
A3 were randomized 2:1 to MAGE-A3 (ASCI) or placebo. The MAGRIT trial failed
to meet its primary end-point of improvement in disease free survival with
MAGE-A3 ASCI. The START trial(2) assessed a MUC1 vaccine in stage III NSCLC
patients who had response or stable disease after standard chemoradiation.
The chemoradiation could have been delivered concurrently or sequentially.
The modified intention to treat population included 1239 patients. The
primary end-point was not met (adj. HRO .88, 95% CI 0.75 -103, p=0.123).
Further development of this agent has been abandoned. The failure of these
two large global phase III studies raises doubt about vaccine strategies used in
isolation in early stage NSCLC. There are a number of possible explanations for
these negative results (3). One of the primary reasons is that cancer vaccines
, when used alone, fail to address the many immunosuppressive factors
operating in the tumour microenvironment (TME). Clinical trials evaluating
anti PD-1/PD-L1 therapy in early stage or locally advanced NSCLC have not
yet reported results. The PACIFIC trial (NCT 20125461) is a randomized phase
III trial of MEDI4736 versus placebo following concurrent chemoradiation
in patients with stage III NSCLC. The primary outcome measures are OS and
PFS. This trial completed accrual in April 2016 and has randomized more than
700 patients. In addition to the important efficacy outcomes, a number of
exploratory objectives will assess tissue and blood for potential biomarkers.
The Canadian Cancer Clinical Trials Group is assessing MEDI 4736 versus
placebo in completely resected stage IB-IIIA NSCLC (NCT 02273375). This trial
will randomize 1100 patients with the primary outcome measure being DFS
in PD-L1 positive patients. PD-L1 positive is defined as > % positive tumour
cells. Immune Based Prognostic Markers: The TME consists of stromal cells
including endothelial cells and fibroblasts and a number of immune cell
types. Tumours may escape immune recognition in large part by modulating
the recruitment and function of various immune cells into the TME (4). A
comprehensive review of the prognostic value of different immune cells in
NSCLC has been reported (5). Two recent studies have separately assessed
tumour lymphocytic infiltration (TLI) (6) or stromal CD8+ T-cell density
(7) as potential prognostic markers in early stage NSCLC. Using the large,
relatively homogenous population of curative resected NSCLC patients
from the LACE-Bio collaboration, Brambilla et al examine the prognostic and
predictive value of TLI. Patients were separated into discovery and validation
sets. An intense TLI (>50% stromal lymphocytes in tumour bulk) was strongly
prognostic of favourable overall survival and disease free survival. Based
on previous work, Donner et al selected stromal CD8+ tumour infiltrating
lymphocyte as the most promising immuno-based prognostic marker.
Using four separate cohorts of curatively resected stage I-III patients, they
established training and validation sets. Tissue microarrays were scored for
stromal CD8 TLI’s; stromal CD8 TIL density was found to be an independent
prognostic factor and retained significant prognostic impact within each
stage. The value of PD-L1 as a biomarker in NSCLC has been investigated
primarily in advanced disease and focused on prediction of response and/
or survival. Studies investigating the value of PD-L1 as a prognostic marker
in early stage NSCLC have many limitations. These studies are small, include
heterogenous populations, assess PD-L1 using different antibodies and
scoring systems and included PD-L1 on tumour cells only or tumour cells
and TLI’s. It is not surprising that these studies show conflicting results.
Based on the available evidence, the prognostic value of PD-L1 expression in
early stage NSCLC remains uncertain. The adjuvant trials of anti-PD1/PD-L1
therapy currently being conducted may clarify the value of PD-L1 as both
prognostic and predictive biomarkers in this setting. Challenges One of the
fundamental challenges to developing effective cancer immunotherapies is
our limited understanding of the human immune system in steady state and
its response to stress. Animal models do not necessarily translate to humans.
The Human Vaccines Project (8) is a global initiative that has as one of its
primary objectives the decoding of the human immune system and providing
a map of the human “immunome”. This private-public partnership uses stateof-the-art
machine learning and technologies to elucidate the principles of
immunogenicity to accelerate the development of new immunotherapies
against infectious diseases and cancer. A second challenge is how best to
target micrometastases in the adjuvant and locally advanced setting. While
the primary tumor and metastatic lesions have many mutations in common,
metastatic tumors possess mutations that are distinct from the primary.
Do adjuvant therapies need to target the metastatic cascade and if so,
which steps are the most susceptible to intervention? (9) The complex of the
TME would predict that focusing on TIL’s or PD-L1 is likely to result in only
modest improvements in outcome. Blank et al (10) argue that it will take a
combination of biomarkers, the “cancer immunogram” , to determine the best
approach in individual patients.References:
Lancet Oncol 2016. 17;(8): 22-35
Lancet Oncol 2014; 15 : 59-68
Ann Oncol 2015; 26: 2213-2220
Nat Rev Immunology, 2015; 15: 73-86
Clin Cancer Res 2011; 17(16): 5247-56
J Clin Oncol 2016; 34:1223-30
Clin Cancer Res 2015; 21(11): 2635-43
Science Translational Medicine 2016; 8(334): 334-339
Nature Reviews Cancer 2015; 16: 201-218
Science 2016; 352(6286):658-660
Keywords: non-small cell lung, early stage, adjuvant, immunotherapy
SESSION MTE09: BIOMARKERS FOR TARGETED THERAPIES
AND IMMUNE CHECKPOINT INHIBITORS IN ADVANCED
NSCLC (TICKETED SESSION)
MONDAY, DECEMBER 5, 2016 - 07:30-08:30
MTE09.01 BIOMARKERS FOR TARGETED THERAPIES AND IMMUNE
CHECKPOINT INHIBITORS IN ADVANCED NSCLC
Jie Wang
Thoracic Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences,
Beijing/China
The targeted therapy based on genotyping has become an important
treatment approach for advanced non-small cell lung cancer (NSCLC),
especially adenocarcinoma. It is reported that nearly fifty to sixty percent
of Asian patients with lung adenocarcinoma could have survival benefit
from the first generation epidermal growth factor receptor-tyrosine kinase
inhibitors (EGFR-TKI) and Anaplastic Lymphoma kinase (ALK)-TKI. However,
the targeted therapy has apparently reached a plateau due to the drug
resistance. The spatial and temporal heterogeneity of tumors are regarded
as the foundation of both primary and acquired resistance. Multiple studies
show that the mechanism of acquired resistance to first generation EGFR-
TKI is complicated, including T790M mutation, PI3KCA mutation, c-MET
amplification, and histologic transformation from NSCLC to SCLC et al, some
of which could co-exist in the same patient. Although the third generation
EGFT-TKI targeted at T790M mutation has been proved with dramatic
efficacy, most patients become resistant after 10 months of therapy, the
S80 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017