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Immunotherapy for Lung Cancer
Suresh S Ramalingam, MD
Associate Professor
Director, Division of Medical Oncology
Emory University
Winship Cancer Institute
Outline
• Immunotherapy background
• Novel agents under development
Immunotherapy
• Therapies that activate the immune system to
target tumors are a theoretically attractive approach
for cancer management
• Developmental hurdles
– lack of reliable biomarker
– antigenic similarity of tumor cells and normal cells
– the immunosuppressive nature of the tumor environment
MAGE-A3 Vaccine
•
•
•
•
Antigen is expressed in nearly 40% of NSCLC
Easy to detect in tumor tissues by RT-PCR
Associated with poor outcome
Rand Ph II study in NSCLC noted promising results
DFS
• Relative Benefit: 27%
• HR: 0.73 (95% CI: 0.45-1.16)
• P = .093 (10% one-sided )
• Median FU: 28 months
Vansteenkiste et al, ASCO 2007
Global Phase III Trial—MAGRIT*
Completely resected IB-II-IIIA NSCLC
MAGE-A3 (+) by rt-PCR
chemo not indicated
chemo indicated
Up to 4 cycles of chemo
Randomization
MAGE-A3 ASCI
Placebo
Randomization
MAGE-A3 ASCI
Placebo
powered for efficacy
powered for efficacy
*MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy
De Pas T, et al. Presented at International Association for the Study of Lung Cancer's 13th World
Conference on Lung Cancer (WCLC), 2 August 2009, San Francisco, California. Abstract B4.3
PD-1 Role in T Cell Activation
What is PD-1?
•
Involved in T cell regulation
•
Expressed by activated memory and regulatory T cell
•
Downregulates T cell by binding to PD-L1/L2
Tumor PD-L1 / B7-H1 Expression
• Potential way tumor cells evade immune system
(self-defense)
• Poor prognosis in multiple tumor types including
NSCLC1
• More commonly seen in Adeno vs. Squamous1
• NSCLC - membranous staining
1Mu CY
et al Med Oncol 2010, Taube J personal communication
BMS-936558 Phase I Studies
• BMS-936558
• IgG4 - no ADCC/CDCC activity
• High affinity binding and blocks PD-1 binding to PD-L1 and PD-L2
•
-
Phase I, single dose study (N=39)
Common AE rash, fatigue, lymphopenia, arthralgia/myalgia
Responses seen in melanoma, renal, colorectal
Mixed response in NSCLC
Serum t ½ = 12-20 days
Receptor occupancy lasted ~3 mos. at all dose levels
Brahmer, J et al ASCO 2010
Response in NSCLC
"As of Dec 2009, 6/16 (37.5%) evaluable pts had objective
tumor responses, including 3 at 1 mg/kg (RCC/CR, RCC/PR,
MEL/PR), 2 at 3 mg/kg (NSCLC/PR, MEL/PR) and one at 10
mg/kg (MEL/PR)."
J, Powderly, Carolina BioOncology Institute
BLP-25
• Peptide vaccine strategy to target MUC1
• MUC1 is aberrantly glycosylated and expressed in
several cancers
• MUC1 contributes to tumorigenicity, evasion of
apoptosis and metastasis
• BLP-25 is a liposome formulation of 25 amino acid
sequence
BLP-25
Median Survival
• BSC = 13.3 mo
• L-BPL25 = 30.6 mo
– P = 0.16
– Hazard Ratio, 0.55
Butts et al, J Clin Oncol, 2005
START
(Stimulating Targeted Antigenic Responses to NSCLC)
N=1322 Pts
Gridelli C et al. The Oncologist 2009;14:909-920
Talactoferrin is an Oral Dendritic Cell Mediated
Immunotherapy (DCMI)
Postulated Role for DCs in Activating Both Innate and Adaptive Immunity
Talactoferrin, taken orally, acts on the GI epithelium to release key
chemokines (e.g. CCL20)
Immature dendritic cells (iDCs) are recruited to the GALT by chemokines
and undergo maturation/activation
Activated dendritic cells initiate tumoricidal response of NK-T cells (Innate
immunity) and cross present tumor antigens to CD8+ lymphocytes
(Adaptive immunity)
Immune cells seek out, infiltrate and kill tumor cells
FORTIS-M (LF-0207): A Randomized, Double-blind, Placebo-controlled
Study of Oral TLF in Addition to Best Supportive Care in Patients with
NSCLC Who Have Failed Two or More Prior Regimens
742 patients
enrolled
Stage IIIB/IV
NSCLC who have
failed two or
more prior
regimens
ECOG PS 0-2
R
A
N
D
O
M
I
Z
E
TLF 1.5 g BID
12 wks on, 2 wks off
up to 5 cycles
+ BSC
2:1
Placebo BID
12 wks on, 2 wks off
up to 5 cycles
+ BSC
Primary Endpoint: Overall Survival
Secondary Endpoints: 6-month & 1-year Survival Rate, PFS, ORR, Disease Stabilization Rate
(PR+CR+SD), TLF Safety and Tolerability
Stratifications: Prior regimens (2 vs ≥3), ECOG PS, geographical region
U.S. National Institutes of Health. Clinicaltrials.gov. Accessed 05/25/11 at: http://www.clinicaltrials.gov.
Ipilimumab: Mechanism of Action
T-cell
activation
T-cell
inhibition
T-cell
potentiation
CTLA-4
T-cell
CD28
CD28
TCR
TCR
MHC
MHC
APC
T-cell
T-cell
B7
APC
CTLA-4
CTLA-4
TCR
MHC
B7
APC
Adapted from O’Day S, et al. J Clin Oncol. 2010;28(7s): Abstract 4.
B7
IPILIMUMAB
blocks
CTLA-4
Ipilimumab for NSCLC
Maintenance
Chemotherapy
-naïve stage
IIIB/IV NSCLC
(N = 204)
R
A
N
D
O
M
I
Z
E
Concurrent ipilimumab
+ P/C (n = 70)
Ipilimumab q 12 weeks
Phased ipilimumab
+ P/C (n = 68)
Ipilimumab q 12 weeks
Placebo + P/C (n = 66)
Placebo q 12 weeks
1:1:1
– P/C: 175
paclitaxel + AUC = 6 carboplatin q 3 weeks x 6 doses
– Concurrent ipilimumab: 10 mg/kg q 3 weeks x 4 doses
– Phased ipilimumab: placebo q 3 weeks x 2 doses followed by IPI q 3 weeks x 4 doses
mg/m2
• Primary Endpoint: Immune-related PFS (irPFS)
Lynch TJ, et al. J Clin Oncol. 2010;28(15s): Abstract 7531.
Outcome by Histology
Concurrent Schedule
Squamous
HR (95% CI)
Non-Squamous
HR (95% CI)
PFS
0.87
(0.42 – 1.81)
0.88
(0.57 – 1.35)
OS
1.02
(0.50 – 2.08)
0.96
(0.60 – 1.53)
Squamous
HR (95% CI)
Non-Squamous
HR (95% CI)
PFS
0.40
(0.18 – 0.87)
0.81
(0.53 – 1.26)
OS
0.48
(0.22 – 1.03)
1.17
(0.74 – 1.86)
Phased Schedule
Lynch TJ, et al. J Thorac Oncol. 2011;6: Abstract MO21.06.
Conclusions
• Several immunotherapy strategies have
shown promise in lung cancer
• Definitive clinical trials will read out in the
near future
• Patient selection based on biomarkers is the
key
Sunday, February 12, 2012
Hollywood, Florida
Co-Chairs
Rogerio C Lilenbaum, MD
Mark A Socinski, MD
Co-Chair and Moderator
Neil Love, MD
Faculty
Walter J Curran Jr, MD
David Jablons, MD
Mark G Kris, MD
Suresh Ramalingam, MD
Alan B Sandler, MD