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Immunotherapy for lung cancer

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.


Immunotherapy for lung cancer

Immunotherapy for Lung Cancer

Suresh S Ramalingam, MD

Associate Professor

Director, Division of Medical Oncology

Emory University

Winship Cancer Institute


Outline

Outline

  • Immunotherapy background

  • Novel agents under development


Immunotherapy

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

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


Immunotherapy for lung cancer

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


Pd 1 role in t cell activation

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

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 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

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

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


Immunotherapy for lung cancer

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


Immunotherapy for lung cancer

START

(Stimulating Targeted Antigenic Responses to NSCLC)

N=1322 Pts

Gridelli C et al. The Oncologist 2009;14:909-920


Immunotherapy for lung cancer

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


Immunotherapy for lung cancer

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.


Ipilimumab mechanism of action

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.


Ipilimumab for nsclc

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.


Outcome by histology

Outcome by Histology

Concurrent Schedule

Phased Schedule

Lynch TJ, et al. J Thorac Oncol. 2011;6: Abstract MO21.06.


Conclusions

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

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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