Strategies to Address Unmet Needs in Small-Cell Lung Cancer · 2016-08-09 · • Aberrant cell...
Transcript of Strategies to Address Unmet Needs in Small-Cell Lung Cancer · 2016-08-09 · • Aberrant cell...
Strategies to Address Unmet Needs in
Small-Cell Lung Cancer
Ravi Salgia MD PhD
Professor and Chair,
Department of Medical Oncology & Therapeutics Research
Associate Director of Clinical Sciences,
City of Hope Comprehensive Cancer Center
Strategies to Address Unmet Needs in
SCLC
• Novel Therapy:
- Immunotherapy
- Targeted therapy (DLL3/DLL4, EZH2, EphB4,
MET/RON)
- Stem Cells
• Biomarkers:
- Liquid Biopsy (CTC, Exosomes)
• Animal Models
Small cell lung cancer (SCLC): no treatment advances in recent years
Koinis et al. Small cell lung cancer (SCLC): no
treatment advances in recent years. Transl
Lung Cancer Res 2016; Vol. 5.
Recent developments in genomic sequencing and immunotherapy may
translate to new treatment paradigms for SCLC
Immune checkpoint inhibition is another area of great promise in the
treatment of tumors with high mutational burden, and thus it is also of
interest in SCLC. Preliminary results from the KEYNOTE- 028 trial were
recently presented. In this Phase Ib trial, 135 patients with ES-SCLC who
had progressed on platinum-based chemotherapy were screened for PD-
L1 expression, with 27% testing positive. Ultimately, 17 patients were
enrolled and received the PD-1 antibody pembrolizumab leading to 25% of
patients with a partial response and a disease control rate of 31%.
Responses were durable at more than 16 weeks, but the trial is still
ongoing. The drug-related adverse event rate was high, however, at 53%,
though only one patient reportedly had a drug-related adverse event of at
least Grade 3.Curr Opin Oncol 2016; Vol 28
Novel Therapy: Immunotherapy
Monoclonal
antibodies
SCLC
Adaptive T-cell transfer
Checkpoint
inhibitors
Therapeutic vaccines
T-cell
from patient
Virus encodes
CAR
ex vivo
Dendritic cell
from patient
INGN225 encodes
TP53
ex vivo
MHC-I
p53 peptide
B7 CD8+
CD28
TCR
MHC-I
TCR
antigen
PD1
PDL1
Anti-PD1
Anti-PDL1
antigen
toxin
Immunotherapy in SCLC
Sattler and Salgia, 2016
Immunotherapy for small-cell lung cancer
Reck et al. Future Oncol. 2016; Vol 5
Positive Control Human Placenta PD-L1-positive tumor cellsPD-L1-positive tumor-infiltrating
immune cells
IHC of PD-L1 in Resected SCLC Using Different Antibodies and Criteria
Takada et al. An Immunohistochemical Analysis of
PD-L1 Protein Expression in Surgically Resected
Small Cell Lung Cancer Using Different Antibodies
and Criteria. Anticancer Res. 2016; Vol. 36
CTLA-4 blockade may remove the inhibitory signal and stimulate antitumor
immunity
Horn et al. The Future of Immunotherapy in the
Treatment of Small Cell Lung Cancer . The
Oncologist 2016; Vol. 21
Horn et al. The Future of Immunotherapy in the
Treatment of Small Cell Lung Cancer . The
Oncologist 2016; Vol. 21
Changes in tumour burden in individual patients Kaplan-Meier curves of overall survival (A)
and progression-free survival (B)
Time (weeks)
25
-25
-75
100
75
50
0
-50
-100
60 12 24 30 36 42 48 54 60 66
Time (weeks)
-100
-75
100
75
50
25
0
-25
-50
660 6 12 18 24 30 36 42 48 54 60
Changes in Tumor Burden
Nivolumab 3
Nivolumab 1 + Ipilimumab 1
First occurrence of new lesion
% change truncated to 100%
Confirmed PR or CR
Patients still on treatment
18
Nivolumab + IpilimumabaNivolumab
Nivolumab 1 + Ipilimumab 3P
erc
en
tag
e C
han
ge
Fro
m B
ase
lin
e (
%)
aCombined data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts. Only pts with target lesion at baseline and ≥1
on-treatment tumor assessment are included (nivolumab, n = 34, nivolumab + ipilimumab, n = 40).
Novel Therapy:
Targeted therapy: Targeted
therapy (DLL3/DLL4, EZH2,
EphB4, MET/RON)
Mamdani et al. Novel therapies in small cell lung cancer.
Transl Lung Cancer Res. Vol 5, No 1 :2016
Signaling pathways recurrently affected in SCLC
George J et al., Nature, 2015.
Karachaliou et al. Cellular and molecular biology of small cell lung
cancer: an overview. Transl Lung Cancer Res. Vol 5, No 1 :2016
Pharmacologic inhibition of EZH2 in SCLC inhibits growth in vitro and in
vivo
EZH2 expression is high in SCLC and correlates with progression of SCLC.
These results suggested new therapeutic strategies for targeting EZH2 and
ASCL1 in SCLC therapy.
Murai et al. Cell Discovery 2015
Human Receptor Tyrosine Kinases (MET/RON)
Cell proliferation,
Motility, Scattering,
Angiogenesis, EMT,
Invasion and Metastasis
MET and RON Synergism
The protein tyrosine kinase activity profile on PamChip microarrays
and their network analyses using MetaCore (GeneGo).
Ichiro Kawada et al. Cancer Res 2014
EphB4 in SCLC
Figure 2. EPHB4 mutations are mutually exclusive of other frequently aberrant cancer genes. A multiplex analysis of genes related to cancer using the SNaPshot platform was conducted on 23 SCLC patient samples.
Figure 3. EPHB4 protein expression in SCLC patient tissues. (A) Representative images of EPHB4 staining by IHC. (B) Summary of automated IHC scoring for EPHB4 expression between normal and tumor tissues (n=13). (C) Patient demographics and staging.
Figure 1. EphB4 protein structure and mutations identified in patient samples. Domains: LB, ligand binding;
CRD, cysteine-rich; FNIII, fibronectin III repeats; TM, transmembrane; TK, tyrosine kinase; SAM, sterile alpha motif.
Four novel nonsynonymous mutations were detected in SCLC patients samples: W534*, E536K, G723S, and P881S.
Novel Therapy:
Stem Cells
Codony-Servat et al. Cancer stem cells in small cell lung
cancer. Transl Lung Cancer Res. Vol 5, No 1 :2016
CSC characteristics:
Capacity of self-renewal;
asymmetric cell division;
slow division kinetic;
multipotency;
persistence;
infrequent;
tumorigenicity;
drug resistance;
metastasis and relapse
CSCs are associated with aggressive cancer behavior
Delta-like Protein 3 (DLL3): a novel target in neuroendocrine tumors
• An atypical inhibitory Notch ligand
• Induced by the key neuroendocrine transcription
factor, ASCL1
• Aberrant cell surface expression in >80% of small
cell lung and large cell neuroendocrine cancers
• On both cancer stem and tumor cells but not normal adult
tissues
• Not prognostic, and does not predict response to
chemotherapy
p53-/-
Precancerous
Lung
Stem Cell
Mature
Neuroendocrine
Tumor Cell
p53-/- RB1-/-
ASCL1
NotchDLL3
Cancer
Stem Cell
Tumor
Progenitor
Cell
Tu
mo
r-In
itia
tin
g C
ell
s
Saunders et al., Sci Transl Med 2015Rudin ASCO 2016
RECIST Confirmed Responses per Investigator
18%
39%
68%
89%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
60 26 60 26
≥50%
Number Evaluable
AllDLL3
Objective Response Rate
(ORR = PR+CR)
Clinical Benefit Rate
(CBR = SD+PR+CR)
Rate
≥50%All
Response-Evaluable Subjects
Active Doses (0.2-0.4 mg/kg)
Rudin ASCO 2016
Best Responses per Investigator by DLL3
-100
-80
-60
-40
-20
0
20
40
60
80
100
% C
hange f
rom
Baselin
e
+20%
-30%
Active Doses (0.2-0.4 mg/kg)
+20%
Rudin ASCO 2016
Comparison of the chemosensitivities of SCLC CTCs and tumor cell lines to cisplatin and etoposide
GLC14 and GLC16 stem cells from the same patient
before and after first cycles of chemotherapy.
DMS153 was cultured from a liver metastases and NCI-
H526 from bone metastases.
NCI-H417 was established from a primary lung SCLC
before treatment.
Comparison of the chemosensitivities of SCLC CTCs and tumor cell lines to epirubicin and topotecan
Hamilton et al. Second-line therapy for small cell lung
cancer: exploring the potential role of circulating tumor cells.
Transl Lung Cancer Res. Vol 5, No 1 :2016
Biomarkers:
Liquid Biopsy-(CTC, Exosomes)
Comparison of patient CTCs and CDXs
Hodgkinson et al. Nat Med. 2014
EXOSOMES IN LUNG CANCER PATIENTS
Exosome
s
Taverna et al. Oncotarget 2016
Animal Models SCLC:Genetically Engineered Models
(GEMMs)
Orthotopic Models
PDX Models
Gazdar et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of
the lung. J Thorac Oncol. 2015; Vol. 10
New orthotopic model for SCLC metastasis
Sakamoto et al. New metastatic model of
human small-cell lung cancer by
orthotopic transplantation in mice.
Cancer Sci 2015; Vol. 106
• Patient-Derived Xenograft (PDX) Mouse Models
Tentler et al., 2012
• PDX models are established by directly implanting patient tumor tissue into immune-deficient mice
• Passaging of the tumor is done by removal from one mouse and re-implanting a piece of the tumor in the new mouse
• There is no “in vitro” culturing of the tumor cells
Fig. 4. Demonstration of in vivo efficacy with
SC16LD6.5 (A to F) Mice bearing SCLC LU64
(A and D), SCLC LU86 (B and E), or LCNEC
LU37 (C and F) PDX tumors were treated with
IgG1LD6.5 or SC16LD6.5 (1 mg/kg) (A to C) on
a Q4D×3 regimen, or vehicle (saline) or SOC
chemotherapy (D to F). (G) DLL3 surface
expression quantified by IHC (H-score)
correlated with dTTP in 10 SCLC and 1 LCNEC
PDX model. (H and I) Mice bearing SCLC LU64
PDX tumors were treated with C/E and, upon
tumor recurrence (35 days after initial C/E
treatment), were randomized and treated again
either with (H) IgG1LD6.5 or SC16LD6.5 (1
mg/kg) on a Q4D×3 regimen or with (I) vehicle
or C/E.
Saunders et al. Sci Transl Med. 2016
The availability of a large high-grade pulmonary neuroendocrine PDX tumor repository facilitated the
discovery and validation of DLL3 as a therapeutic target.
Ideogram summarising variants predicted to result in mutations commonly seen in SCLC and Small Cell Lung Cancer Patient-
Derived Xenografts Generated from Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Specimens
PDX models have recently emerged as a way of more accurately modelling therapeutic responses outcome and as source of high quality material for next-generation sequencing.
Genes are ranked by % according to their prevalence in the COSMIC database. Mutations detected in both
the primary sample and the xenograft are shown. doi:10.1371/journal.pone.0106862.g004
Leong et al. 2014
Conclusions
• Novel Therapies need to be tested more rapidly
• The role of immunotherapy is beginning to be
defined
• Genomics and other ‘omics’ platforms will be crucial
for us to identify newer targets
• Animal modeling has become more sophisticated
and needs to be utilized pre-clinically and hopefully
also clinically