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Immunotherapy for Lung Cancer Suresh S Ramalingam, MD Associate Professor Director, Division of Medical Oncology Emory University Winship Cancer Institute 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 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 indicatedchemo indicated Randomization MAGE-A3 ASCIPlacebo Randomization MAGE-A3 ASCIPlacebo 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 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 NSCLC 1 More commonly seen in Adeno vs. Squamous 1 NSCLC - membranous staining 1 Mu 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-25 Median 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 regimens ECOG PS 0-2 742 patients enrolled Stage IIIB/IV NSCLC who have failed two or more prior regimens ECOG PS 0-2 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE TLF 1.5 g BID 12 wks on, 2 wks off up to 5 cycles + BSC TLF 1.5 g BID 12 wks on, 2 wks off up to 5 cycles + BSC Placebo BID 12 wks on, 2 wks off up to 5 cycles + BSC Placebo BID 12 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-cell activation T-cell inhibition T-cell potentiation Adapted from O’Day S, et al. J Clin Oncol. 2010;28(7s): Abstract 4.
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