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Immunotherapy for Lung Cancer

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Immunotherapy for Lung Cancer

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  1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. Immunotherapy for Lung Cancer Suresh S Ramalingam, MD Associate Professor Director, Division of Medical Oncology Emory University Winship Cancer Institute

  3. Outline • Immunotherapy background • Novel agents under development

  4. 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

  5. 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

  6. 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 Randomization MAGE-A3 ASCI Placebo MAGE-A3 ASCI Placebo powered for efficacy powered for efficacy *MAGE-A3 as Adjuvant Non-Small Cell LunG CanceRImmunoTherapy 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. START (Stimulating Targeted Antigenic Responses to NSCLC) N=1322 Pts Gridelli C et al. The Oncologist 2009;14:909-920

  14. 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

  15. 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 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 742 patients enrolled Stage IIIB/IV NSCLC who have failed two or more prior regimens ECOG PS 0-2 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.

  16. CTLA-4 T-cell T-cell T-cell CD28 CD28 CTLA-4 CTLA-4 TCR TCR TCR IPILIMUMABblocksCTLA-4 MHC MHC B7 MHC B7 B7 APC APC APC 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.

  17. Ipilimumab for NSCLC Maintenance Chemotherapy-naïve stage IIIB/IV NSCLC(N = 204) Concurrent ipilimumab + P/C (n = 70) R A N D O M I Z E • Primary Endpoint: Immune-related PFS (irPFS) Ipilimumab q 12 weeks Phased ipilimumab + P/C (n = 68) Ipilimumab q 12 weeks Placebo q 12 weeks Placebo + P/C (n = 66) 1:1:1 – 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 Lynch TJ, et al. J Clin Oncol. 2010;28(15s): Abstract 7531.

  18. Outcome by Histology Concurrent Schedule Phased Schedule Lynch TJ, et al. J Thorac Oncol. 2011;6: Abstract MO21.06.

  19. 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

  20. Sunday, February 12, 2012Hollywood, 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

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