Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
1) determine the objective response rate in: A] an unselected population
and, B] a PD-L1 positive population; 2) determine the optimal threshold
for PD-L1 expression using the 22C3 antibody-based IHC assay (Qualtek).
Exploratory correlatives profile the inflammatory microenvironment via: a)
multi-color immunofluorescence of tumor infiltrating lymphocytes (TILs) and
macrophages, b) RNA-based inflammation signatures/pathway activation, c)
characterizing underlying mutations/copy number changes. Proceeding to a
2 nd stage requires ≥3 responses in 35 patients. If an optimal threshold for PD-
L1 expression is determined, the 2 nd stage only enrolls above that threshold.
Results: 35 patients enrolled 5/15-2/16. 1 withdrew. Male 82%; median age
63 (range 26-85); PS 0/1 63%/37%; epithelial/sarcomatoid/biphasic/NOS:
69%/26%/3%/3%; pleural/peritoneal 86%/14%; 1 prior regimen: 60%. Mean
cycles: 8.5 (range 1-18). Median progression-free survival: 6.2 months (95%
CI: 3.2, 8.2). Median overall survival has not been reached. Partial response: 7
(21%), stable disease (SD): 19 (56%); progression: 6 (18%); early death: 2 (6%).
Ten patients received treatment beyond progression; 20% subsequently
achieved SD. Grade 3/4 toxicity: pneumonitis 6%, fatigue 6%, adrenal
insufficiency 6%, colitis 3%, confusion 3%, hyponatremia 3%, neutropenia
3%. Grade 1/2 immune-related toxicities: hypothyroidism 17%, rash 14%,
pruritus 11%, diarrhea 9%, uveitis 6%, arthralgia 6%, hepatitis 3%, infusion
reaction 3%, mucositis 3%. Grade 5 toxicities: autoimmune hepatitis 3%,
unknown 3%. PD-L1 expression by tumor proportion score (N=31): none (< 1%):
55%; low (1%-49%): 19%; high (≥ 50%): 26%. PD-L1 expression did not correlate
with response (ROC area 0.62; 95% CI: 0.32, 0.94). Conclusion: Pembrolizumab
has robust activity in PD-L1 unselected, previously-treated MM patients,
with a response rate of 21% and a disease control rate of 76%. An optimal
PD-L1 threshold could not be established in this small sample. The 2nd stage
is enrolling an additional 30 patients without PD-L1 pre-selection. Correlative
studies including CD8 TILs, macrophage characterization, and presence of
T-regulatory cells will be presented. Funded by a grant from the Mesothelioma
Applied Research Foundation.
Keywords: Mesothelioma, PD-1, phase 2 trial, pembrolizumab
OA13: IMMUNOTHERAPY IN MALIGNANT PLEURAL MESOTHELIOMA: CURRENT STATUS
OF TRIALS AND NEW APPROACHES
TUESDAY, DECEMBER 6, 2016 - 14:15-15:45
OA13.03 LONG-TERM OVERALL SURVIVAL FOR PATIENTS WITH
MALIGNANT PLEURAL MESOTHELIOMA ON PEMBROLIZUMAB
ENROLLED IN KEYNOTE-028
Evan Alley 1 , Juanita Lopez 2 , Armando Santoro 3 , Anne Morosky 4 , Sanatan
Saraf 4 , Bilal Piperdi 4 , Jan H.M. Schellens 5
1 University of Pennsylvania, Philadelphia/PA/United States of America, 2 Drug
Development Unit, Institute of Cancer Research, Sutton/United Kingdom, 3 Istituto
Clinico Humanitas, Milan/Italy, 4 Merck & Co., Inc., Kenilworth/NJ/United States of
America, 5 Netherlands Cancer Institute, Plesmanlaan/Netherlands
Background: Malignant pleural mesothelioma (MPM) is a highly aggressive
cancer with poor prognosis and limited treatment options after progression
on platinum-containing chemotherapy. Pembrolizumab, a humanized
anti–programmed death 1 (PD-1) antibody, has demonstrated robust
antitumor activity and a favorable safety profile in multiple tumor
types. Here, we present long-term overall survival (OS) data for patients
with malignant pleural mesothelioma enrolled in the KEYNOTE-028
(ClinicalTrials.gov, NCT02054806) study. Methods: KEYNOTE-028 is a
nonrandomized, multicohort phase 1b trial of pembrolizumab in patients
with PD-L1–positive advanced solid tumors. 25 patients with MPM were
treated with pembrolizumab in the mesothelioma cohort. Patients received
pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed
progression or intolerable toxicity, death, withdrawal of consent, or
physician decision. Response was assessed per RECIST v1.1 by investigators
every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary
end point was objective response rate (ORR; per RECIST v1.1, investigator
assessed). Secondary end points included safety, tolerability, progressionfree
survival (PFS), and OS. Results: As of June 9, 2016, median duration of
follow-up was 18.7 months (range, 1.5-24.6 months), and 4 patients (16%) are
still on treatment. ORR was 28% (n = 7); 12 (48%) patients had stable disease,
resulting in a disease control rate of 76%; median duration of response was
9.2 months (range, 2.4-20.5+ months); median PFS was 5.8 months (95% CI,
3.4-8.2 months), with 6- and 12-month PFS rates of 50% and 25%, respectively.
Median OS was 18.0 months (95% CI, 9.4 months-not reached) with 6- and
12-month OS rates of 83.5% and 62.6%, respectively. No new safety signals
have been identified. Sixteen (64%) patients experienced a drug-related
adverse event (DRAE), and 5 (20%) experienced grade 3/4 DRAEs. Three
patients required dose interruption because of immune-related adverse
events (1 each, ALT increased, iridocyclitis, and pyrexia/arthralgia]). There was
no treatment-related mortality or discontinuation due to DRAE. Conclusion:
Single-agent pembrolizumab has significant clinical activity in patients with
PD-L1–positive MPM. Responses from pembrolizumab in patients with MPM
are durable; the 62.6% 12-month OS rate in this mostly pretreated patient
population warrants further investigation. Long-term administration of
pembrolizumab is feasible in patients with MPM, and no new safety signals
were identified.
Keywords: Mesothelioma, pembrolizumab, Immunotherapy, anti–PD-1
OA13: IMMUNOTHERAPY IN MALIGNANT PLEURAL MESOTHELIOMA: CURRENT STATUS
OF TRIALS AND NEW APPROACHES
TUESDAY, DECEMBER 6, 2016 - 14:15-15:45
OA13.05 SOMATIC GENETIC ALTERATIONS AND IMMUNE
MICROENVIRONMENT IN MALIGNANT PLEURAL MESOTHELIOMA
Wickii Vigneswaran 1 , Hiroyuki Inoue 2 , Jae-Hyun Park 2 , Sope Olugbile 3 , Yusuke
Nakamura 4
1 Thoracic and Cardiovascular Surgery, Loyola University Health System, Maywood/
IL/United States of America, 2 University of Chicago, Chicago/IL/United States of
America, 3 Medicine, University of Chicago, Chicago/IL/United States of America,
4 Medicine, University of Chicago, Chicago/United States of America
Background: The genomic landscape of malignant pleural mesothelioma
(MPM) is not well understood. Advanced high-throughput sequencing
technologies allow comprehensive characterization of genetic alterations.
Knowledge of the somatic mutations and the immune microenvironment
in patients with MPM will help to develop effective targeted therapies.
Methods: We examined biopsy specimens from 12 MPM patients (8 epithelioid
and 4 biphasic) that were removed during maximal cyto-reductive surgery.
Specimens from 3 different sites (anterior, posterior and diaphragm, a total
of 36 tissue samples) were studied through whole exome sequencing, T
cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells (TILs),
and expression levels of immune-related genes. We also performed in silico
prediction of potent neoantigens derived from non-synonymous somatic
mutations in each specimen. For the comparison of tumor tissues from 3
different sites, we performed hierarchical clustering to assess the tumor
heterogeneity and differences in immune environment. Results: High
mutation/neoantigen load was significantly correlated with higher clonal
expansion of TILs (R=0.46) and high expression levels of immune-associated
cytolytic factors, granzyme A (R=0.25) and perforin 1 (R=0.48), in tumor
tissues. In the clustering analysis, heterogeneous MPM cases revealed unique
neoantigens and clonotypes of TILs that were restricted to each of tumor
site, suggesting infiltration of the neoantigen-specific T cells. Further subanalysis
according to histologic types showed that biphasic tumors had higher
mutation/neoantigen load and stronger oligo-clonal T cell expansion (p=0.01)
than epithelioid tumors. Conclusion: Our analysis demonstrated a significant
correlation between somatic mutation/neoantigen load, clonality of TILs, and
the immune-related tumor microenvironment in MPM. Our findings suggest
that high mutation/neoantigen load in tumor cells might promote effective
expansion and infiltration of functional (tumorocidal) T cells into the tumor
bed. These findings provide a rationale for selecting MPM patients who
can benefit from treatment with immune checkpoint blockades. This may
accelerate development of the neoantigen targeting TCR-engineered T cell
therapy for MPM.
Keywords: T cell receptor, Somatic mutation, malignant pleural
mesothelioma, sequencing
OA13: IMMUNOTHERAPY IN MALIGNANT PLEURAL MESOTHELIOMA: CURRENT STATUS
OF TRIALS AND NEW APPROACHES
TUESDAY, DECEMBER 6, 2016 - 14:15-15:45
OA13.06 AUTOLOGOUS DENDRITIC CELLS LOADED WITH
ALLOGENEIC TUMOR CELL LYSATE (PHERALYS®) IN PATIENTS WITH
MESOTHELIOMA: FINAL RESULTS OF A PHASE I STUDY
Joachim Aerts 1 , Robin Cornelissen 1 , Cor Van Der Leest 1 , Joost Hegmans 1 ,
Koen Bezemer 1 , Margaretha Kaijen-Lambers 1 , Ferry Eskens 2 , Eric Braakman 3 ,
Bronno Van Der Holt 4 , Rudi Hendriks 1 , Henk Hoogsteden 1
1 Pulmonary Diseases, Erasmus MC Cancer Centre, Rotterdam/Netherlands,
2 Medical Oncology, Erasmus MC Cancer Centre, Rotterdam/Netherlands,
3 Hematology, Erasmus MC Cancer Centre, Rotterdam/Netherlands, 4 Clinical Trial
Centre, Erasmus MC Cancer Centre, Rotterdam/Netherlands
Background: Mesothelioma is an aggressive malignancy without curative
treatment options. We have previously shown promising activity of dendritic
cell (DC) immunotherapy loaded with autologous tumor cell lysate (Hegmans
2013, Cornelissen 2016). Because of quality and quantity issues (availability,
standardization etc) with the autologous lysate, we have developed an
off-the-shelf allogenic tumor cell lysate from human mesothelioma cell lines
(Pheralys. ® ). Methods: Patients (pts) with advanced mesothelioma, either
treatment naive, or non-progressing after chemotherapy, were included.
Leucapheresis was performed to obtain an enriched monocyte fraction from
which immature DC were generated which were loaded with the allogenic
lysate. The DC were matured, frozen and stored. In subsequent cohorts of
S150 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017