immunotherapy for lung cancer
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Immunotherapy for Lung Cancer
Suresh S Ramalingam, MDAssociate Professor
Director, Division of Medical Oncology
Emory UniversityWinship 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
Vansteenkiste et al, ASCO 2007
DFS• Relative Benefit: 27%• HR: 0.73 (95% CI: 0.45-1.16)• P = .093 (10% one-sided )• Median FU: 28 months
chemo not indicated chemo indicated
Randomization
MAGE-A3 ASCI Placebo
Randomization
MAGE-A3 ASCI Placebo
Up to 4 cycles of chemo
Global Phase III Trial—MAGRIT*
*MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy
Completely resected IB-II-IIIA NSCLC
MAGE-A3 (+) by rt-PCR
powered for efficacypowered for efficacy
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
Butts et al, J Clin Oncol, 2005
BLP-25Median Survival•BSC = 13.3 mo•L-BPL25 = 30.6 mo – P = 0.16 – Hazard Ratio, 0.55
START (Stimulating Targeted Antigenic Responses to
NSCLC)
Gridelli C et al. The Oncologist 2009;14:909-920
N=1322 Pts
Talactoferrin, taken orally, acts on the GI epithelium to release key chemokines (e.g. CCL20)
Activated dendritic cells initiate tumoricidal response of NK-T cells (Innate immunity) and cross present tumor antigens to
CD8+ lymphocytes (Adaptive immunity)
Immature dendritic cells (iDCs) are recruited to the GALT by chemokines and undergo maturation/activation
Immune cells seek out, infiltrate and kill tumor cells
Talactoferrin is an Oral Dendritic Cell Mediated Immunotherapy (DCMI)
Postulated Role for DCs in Activating Both Innate and Adaptive Immunity
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 regimensECOG PS 0-2
RANDOMIZE
TLF 1.5 g BID12 wks on, 2 wks off
up to 5 cycles + BSC
Placebo BID12 wks on, 2 wks off
up to 5 cycles + BSC
2:1
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-cellactivation
T-cellinhibition
T-cellpotentiation
Adapted from O’Day S, et al. J Clin Oncol. 2010;28(7s): Abstract 4.
CD28
T-cell
CTLA-4
B7
TCR
MHC
APC
T-cell
TCR
MHC
APC
CTLA-4
B7
CD28 CTLA-4
T-cell
TCR
MHC
APC
B7IPILIMUMABblocksCTLA-4
Ipilimumab for NSCLC
• Primary Endpoint: Immune-related PFS (irPFS)
– P/C: 175 mg/m2 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
Chemotherapy-naïve stage
IIIB/IV NSCLC(N = 204)
RANDOMIZE
Concurrent ipilimumab + P/C (n = 70)
Phased ipilimumab + P/C (n = 68)
Placebo + P/C (n = 66)
1:1:1
Ipilimumab q 12 weeks
Ipilimumab q 12 weeks
Placebo q 12 weeks
Lynch TJ, et al. J Clin Oncol. 2010;28(15s): Abstract 7531.
Maintenance
Outcome by HistologySquamous
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)
Concurrent Schedule
SquamousHR (95% CI)
Non-SquamousHR (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, 2012Hollywood, Florida
Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD
Co-Chair and ModeratorNeil Love, MD
Faculty
Walter J Curran Jr, MDDavid Jablons, MDMark G Kris, MD
Suresh Ramalingam, MDAlan B Sandler, MD
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