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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