Immunotherapeutic Approaches in the Treatment of NSCLC · PDF file2015;33:(suppl; Abstract...

01

Immunotherapeutic Approaches in the Treatment of NSCLC

Keith Kerr, MBChB, FRCPath.Aberdeen Royal Infirmary

02

Outline

• Review the concept and evolution of immunotherapy in the treatment of cancer

• Discuss current immunotherapeutic approaches involving checkpoint inhibitions in the treatment of NSCLC

• Discuss additional immunotherapeutic approaches being evaluated in the treatment of NSCLC

03

Development of Immunotherapy in the Treatment of Cancer

Timeline: The history of cancer immunotherapy

TAA = Tumour-associated antigen; VIN = Vulvar intraepithelial neoplasia; TLR = Toll-like receptor; BCG = Bacille Calmette-Guerin.1. Lesterhuis WJ et al. Nat Rev Drug Discov. 2011;10:591-600; 2. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm427807.htm;3. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm.

1863 1898 1957 1973 1974 1976 1983 1985 1991 1992 1995 1996 2002 2009 2010 2014 2015

Description of immune infiltrates

in tumours by Virchow

First report of allogeneic bone

marrow transplantation

Treatment of cancer with bacterial

products by Coley

Discovery of the dendritic cells by

Steinman

Discovery of MHCI-restricted CD8+ T cell

recognition by Zinkernageland Doherty

First study with adoptive cell transfer

in cancer

First study with IFNαin melanoma

(1991, 1994)Characterisation of

human TAAs by Rosenberg and Boon

Rediscovery of the regulatory T cell by

Sakaguchi

(1996-97,2000)Discovery of the immunological function of TLR

HPV vaccination in VIN

Discovery of crosspresentation

by Bevan

First study with BCG in bladder cancer

Hypothesis of cancer “immuno-

surveillance” by Burnet

First study with IL-2

First study of isolated limb perfusion with TNF in

melanoma and sarcoma

Non-myeloablativechemotherapies and adoptive T cell transfer in melanoma

FDA approved pembrolizumaband nivolumab for the treatment of melanoma

Key regulators of T-cell response are

elucidated

FDA approved nivolumab for the

treatment of squamous NSCLC

Remains an active area of research

FDA approval of sipuleucel-T in prostate cancer and ipilimumab

in melanoma

04

The Concept of Immune Surveillance and Escape

Schreiber RD et al. Science. 2011;25:331:1565-70.

05

Key Regulators of Cytotoxic T Lymphocyte Response

• Cytotoxic T cell responses are regulated by multiple costimulatory and inhibitory interactions

Pardoll DM et al. Nat Rev Cancer. 2012;12:252-64.

06

Immune Checkpoint Inhibition in the Treatment of Cancer: MOAs of Anti-CTLA-4 and Anti-PD-1/PD-L1 Agents

Ribas A. N Engl J Med. 2012;366:2517-19.

NivolumabPembrolizumab

MPDL3280AMEDI4736

Ipilimumab

• Immune checkpoints play an important role in suppressing the body’s antitumourresponse

07

PD-1/PD-L1 Inhibition in the Treatment of NSCLC

• Phase 3 data: Nivolumab in non-squamous (CheckMate 057) and squamous cell (CheckMate 017) lung cancer

• Phase 2 data: Atezolizumab in NSCLC (POPLAR trial)

• Phase 1 data: Pembrolizumab in NSCLC (KEYNOTE 001 trial)

08

CheckMate-057: Phase 3 Trial of Nivolumab vs Docetaxel in Patients With Non-Squamous NSCLC

Stage IIIb/IV non-squamous NSCLCFailed one prior platinum-based doubletPrior TKI therapy allowed for known ALK translocation or EGFR mutationPrior maintenance therapy allowedECOG PS: 0-1

Nivolumab: 3 mg/kg IV Q2Wk

Docetaxel: 75 mg/m2 IV Q3Wk

n=292

n=290

Until PD or unacceptable

toxicity

Patients stratified by prior maintenance therapy and line of therapy (2nd vs 3rd-line)

N=582Maintenance therapy included pemetrexed, bevacizumab or erlotinib (not considered a separate line of therapy)

Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; Abstract LBA109).

• Endpoints: – Primary: OS– Secondary: ORR, PFS, correlation between PD-L1 expression and efficacy

• PD-L1 expression measured using the Dako/BMS automated IHC assay– Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity,

specificity, precision, and robustness

R1:1

09

PFS in overall population

CheckMate-057: Baseline Characteristics

Nivolumabn=135

Docetaxeln=137

Median age, years (range)≥75, %

61 (37-84)7

64 (21-85)8

Male, % 52 58

Smoking status, %Current/former smokerNever smoker

7920

7821

ECOG PS, %01

2971

3367

Prior maintenance therapy, % 42 38

No. of prior systemic therapy, %12

8812

8911

EGFR-positive mutation status, % 15 13

ALK-positive translocation status, % 4 3

Baseline PD-L1 expression, quantifiable (% of evaluable patients)≥1%≥5%≥10%Not quantifiable (% of randomised patients)

53413721

55383523

78% (455/582) of randomised patients had quantifiable PD-L1 expression. Baseline expression was well balanced between nivolumab and docetaxel

Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; Abstract LBA109).

010



CheckMate-057: OS (Primary Endpoint)

100

90

80

70

60

50

40

30

20

10

00 3 6 9 12 15 18 21 24

OS

(%)

Time (months)

Nivolumabn=292

Docetaxeln=290

mOS, mo 12.2 9.4

HR = 0.73 (96% CI: 0.59, 0.89), P=0.0015

Number of patients at riskNivolumab 292 232 194 169 146 123 62 32 9 0Docetaxel 290 244 194 150 111 88 34 10 5 0

27

1-yr OS rate = 51%

1-yr OS rate = 39% Nivolumab

Docetaxel

Symbols represent censored observations. CI = confidence interval; HR = hazard ratio.Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; Abstract LBA109).

011


CheckMate-057: PFS

Symbols represent censored observations.Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; Abstract LBA109).

012


CheckMate-057: OS and PFS Hazard Ratios by Baseline PD-L1 Expression

aInteraction P-value from Cox proportional hazard model with treatment, PD-1 expression and treatment by PC-L1 expression interaction.Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; Abstract LBA109).

013

CheckMate-017: Phase 3 Trial of Nivolumab vs Docetaxel in Squamous NSCLC

• Endpoints: – Primary: OS – Secondary: ORR, PFS, correlation between PD-L1 expression and efficacy

Second-line, stage IIIb/IVsquamous NSCLC

Failed one prior platinum-based doublet

ECOG PS: 0-1

Spigel D et al. J Clin Oncol. 2015;33:(suppl; Abstract 8009).

Patients stratified by region and prior paclitaxel use

N=272

One pre-planned interim analysis for OSThe boundary for declaring superiority of OS at the pre-planned interim analysis was P<0.03

Nivolumab: 3 mg/kg IV Q2Wk

Docetaxel: 75 mg/m2 IV Q3Wk

n=135

n=137

Until PD or unacceptable

toxicityR1:1

014


CheckMate-017: Baseline Characteristics

Nivolumabn=135

Docetaxeln=137

Median age, years (range)≥75, %

62 (39-85)8

64 (42-84)13

Male, % 82 71

Disease stage, %IIIbIV

2178

1882

Performance status, %01

2079

2773

CNS metastasis, % 7 6

Prior paclitaxel, % 34 34

Current/former smoker, % 90 94

PD-L1 expression, %≥1%≥5%≥10%Not quantifiable

47312713

41292421

83% (225/272) of patients had quantifiable PD-L1 expressionSpigel D et al. J Clin Oncol. 2015;33:(suppl; Abstract 8009).

015



CheckMate-017: OS (Primary Endpoint)

Number of patients at riskNivolumab 135 113 86 69 52 31 15 7 0Docetaxel 137 103 68 45 30 14 7 2 0

100

90

80

70

60

50

40

30

20

10

00 3 6 9 12 15 18 21 24

Ove

rall

Surv

ival

(%)

Time (months)

Nivolumabn=135

Docetaxeln=137

Median OS mo, (95% CI)

9.2(7.3, 13.3)

6.0(5.1, 7.3)

HR = 0.59 (95% CI: 0.44, 0.79), P=0.00025)

1-yr OS: 42%

1-yr OS: 24% Docetaxel

OS

CI = confidence interval; HR = hazard ratio.Spigel D et al. J Clin Oncol. 2015;33:(suppl; Abstract 8009).

Nivolumab

016


CheckMate-017: PFS (Per Investigator Assessment)


017


CheckMate-017: OS and PFS by PD-L1 Expression

• Survival benefit with nivolumab is independent of PD-L1 expression level


018


Phase 2 Trial of Atezolizumab vs Docetaxel in 2nd/3rd-line NSCLC (POPLAR)

Archival or fresh tissue required for pre-dose testing

Spigel AI et al. J Clin Oncol. 2015;33:(suppl; Abstract 8010).

019


POPLAR: Baseline Characteristics

Characteristics of patients with NSCLCAtezolizumab

(n=144)Docetaxel

(n=143)Median age, yr 62 62

≥65 40% 39%

Male 65% 53%

Histology

Non-squamous 66% 66%

Squamous 34% 34%

ECOG score, 0/1 33%/67% 32%/68%

No. of prior chemotherapies, 1/2 65%/35% 67%/33%

History of tobacco use

Never 19% 20%

Current 17% 15%

Previous 64% 65%


020

PD-L1 Expression on TC and IC Is a Potential Predictive Biomarker for Atezolizumab in NSCLC


021


POPLAR: OS (All Patients, ITT)

aStratified HR; data cut-off Jan 30, 2015.Spigel AI et al. J Clin Oncol. 2015;33:(suppl; Abstract 8010).

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POPLAR: PD-L1 Expression and OS


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POPLAR: PD-L1 Expression and PFS


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Pembrolizumab in the Treatment of NSCLC

Garon EB et al. N Engl J Med. 2015;372:2018-28.

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Biomarker Analysis

• Anti-PD-L1 antibody clone 22C3 (Merck) and a prototype IHC assay used to determine PD-L1 status/expression in contemporaneous biopsy samples

• PD-L1 positivity was defined as membranous staining in ≥1% of cells (neoplastic and intercalated mononuclear inflammatory cells)

• Membranous PD-L1 expression ≥50% selected as the cutoff on the basis of ease of use and ROC (receiver-operating-characteristic) analysis

PS = proportion score.Garon EB et al. N Engl J Med. 2015;372:2018-28.

PS: <1% 1%-49% 50%

Low

High

026PFS in overall population

PFS in overall populationPFS in overall population

Pembrolizumab in NSCLC: PFS Per Proportional Scores (PS)


027PFS in overall population

PFS in overall populationPFS in overall population

Pembrolizumab in NSCLC:OS Per Proportional Scores (PS)


028

Current Considerations With Immunotherapeutic Approaches in the Treatment of NSCLC

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–63 –21 21 63 105 147 189 231 273 315 357

–63 –21 21 63 105 147 189 231 273 315 357 399 441 483 525

I-O = Immuno-Oncology.Figures adapted from Wolchok JD et al. Clin Cancer Res. 2009;15:7412-20; Hoos A et al. Ann of Oncol. 2012;23(suppl 8):viii47–viii52.

RECIST Criteria May Not Best Reflect Response Patterns to Immuno-Oncology Agents

Thresholds for responseor PD (RECIST)

Tum

our C

hang

e Fr

om B

asel

ine

(%) 50

25

0

–25

–50

–75

–100

–125

50

25

0

–25

–50

–75

–100

–125

50

25

0

–25

–50

–75

–100

–125

150

50

0–25–50–75

–100–125

25

100

Therapy start Therapy start

Time (days) Time (days)

Therapy start

Tum

our C

hang

e Fr

om B

asel

ine

(%)

Tum

our C

hang

e Fr

om B

asel

ine

(%)

Tum

our C

hang

e Fr

om B

asel

ine

(%)

Therapy start Total Baseline New lesions

Graphs for illustrative purposes showing responses to ipilimumab in advanced melanoma

–63 –21 21 63 105 147 189 231 273 315 357

Time (days) Time (days)–63 –21 21 63 105 147 189 231 273 315 357

Response in baseline lesions: Typically seen with chemotherapy, but also I-O therapies.

Captured by existing RECIST and WHO criteria

“SD”: Slow, steady decline in tumour volume seen with chemotherapy, targeted, and I-O therapies. Captured by existing RECIST and WHO criteria

Response after initial increase in tumour volume.Novel and specific to I-O therapy

(RECIST or WHO criteria may not be appropriate to assess)

Reduction in tumour burden after appearance of new lesions. Novel and specific to I-O therapy

(RECIST or WHO criteria may not be appropriate to assess)

030

Is Monotherapy Enough?

• ORR ranges from 15% to 24.8% for anti-PD-1/PD-L1 monotherapy in previously treated or untreated patients with NSCLC

• Depends on your expectations!

031

What Is the Right Partner for Combination?

• Chemotherapy?– Atezolizumab + platinum doublet untreated NSCLC: ORR of

67%1

– Nivolumab + platinum doublet shows similar efficacy with nivolumab monotherapy in untreated NSCLC (CheckMate-012)2

• Another checkpoint inhibitor (eg, ipilimumab)?– Nivolumab + ipi in 2nd-line NSCLC: 39% ORR3

• Targeted agent?– Nivolumab + erlotinib in erlotinib failure patients: 19% ORR4

• Tolerability (discontinuation due to treatment-related AEs)?– Nivolumab + platinum doublet: 21%2

– Nivolumab + erlotinib: 19%4

1. Liu SV et al. J Clin Oncol. 2015;33:(suppl; Abstract 8030).2. Antonia SJ et al. Multidisciplinary Symposium in Thoracic Oncology. 2014. Abstract 3.3. Patnaik A et al. J Clin Oncol. 2015;33:(suppl; Abstract 8011).4. Rivni NA et al. J Clin Oncol. 2014:32:(suppl; Abstract 8022).

032


Anti-PD-1/PD-L1 in EGFR Mutation+ NSCLC?CheckMate 057

Paz-Ares et al. ASCO 2015. Abstract LBA109.

Treatment effect on OS in predefined subgroups

033

PD-L1 as a Potential Predictive Biomarker?

034


PD-L1 as a Potential Predictive Biomarker?

Kerr K. ASCO 2015. Discussant.

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PD-L1 as a Potential Predictive Biomarker? (cont’d)

• Spira et al. ASCO 2015. Abstract 8010– POPLAR: Atezolizumab vs docetaxel in prev-Rx

NSCLC– PD-L1 as measured appears predictive of ORR, PFS

and OS


036


PD-L1 expression on TC and IC is a potential predictive biomarker for atezolizumab in NSCLC


• TC scored as percentage of tumour cells positive - any intensity• IC scored as percentage of tumour area with positive cells - any intensity• TC3 or IC3 = TC≥50% or IC≥10% PD-L1+• TC2/3 or IC2/3 = TC or IC≥5% PD-L1+• TC1/2/3 or IC1/2/3 = TC or IC≥1% PD-L1+• TC0 and IC0 = TC and IC<1% PD-L1

037


PD-L1 expression

Patients, n UnstratifiedHR(95% Cl)NIVO DOC

OS≥1% 63 56 0.69 (0.45, 1.05)<1% 54 52 0.58 (0.37, 0.92)≥5% 42 39 0.53 (0.31, 0.89)<5% 75 69 0.70 (0.47, 1.02)≥10% 36 33 0.50 (0.28, 0.89)<10% 81 75 0.70 (0.48, 1.01)Not quantifiable at baseline 18 29 0.39 (0.19, 0.82)

PFS≥1% 63 56 0.67 (0.44, 1.01)<1% 54 52 0.66 (0.43, 1.00)≥5% 42 39 0.54 (0.32, 0.90)<5% 75 69 0.75 (0.52, 1.08)≥10% 36 33 0.58 (0.33, 1.02)<10% 81 75 0.70 (0.49, 0.99)Not quantifiable at baseline 18 29 0.45 (0.23, 0.89)

OS and PFS Hazard Ratios by PD-L1 Status (CheckMate017)

0 1 2NIVO DOCSpigel D et al. J Clin Oncol. 2015;33:(suppl; Abstract 8009).

All hazard ratios

Favour Nivolumabover Docetaxel

Regardless of PD-L1 status

in squamous cell carcinoma

038


OS and PFS Hazard Ratios by PD-L1 Status (CheckMate057)

PD-L1 expression levelNIVO

nDOC

nUnstratifiedHR (95% Cl) P-valuea

OS≥1% 123 123 0.59 (0.43, 0.82) 0.0646<1% 108 101 0.90 (0.66, 1.24)≥5% 95 86 0.43 (0.30, 0.63)

0.0004<5% 136 138 1.01 (0.77, 1.34)≥10% 86 79 0.40 (0.26, 0.59)

0.0002<10% 145 145 1.00 (0.76, 1.31)Not quantifiable at baseline 61 66 0.91 (0.61, 1.35)

PFS≥1% 123 123 0.70 (0.53, 0.94)

0.0227<1% 108 101 1.19 (0.88, 1.61)≥5% 95 86 0.54 (0.39, 0.76)

<0.0001<5% 136 138 1.31 (1.01, 1.71)≥10% 86 79 0.52 (0.37, 0.75)

0.0002<10% 145 145 1.24 (0.96, 1.61)Not quantifiable at baseline 61 66 1.06 (0.73, 1.56)

aInteraction P-value from Cox proportional hazard model with treatment, PD-L1 status and treatment by PD-L1 status interaction.Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; Abstract LBA109).

HRs

Favour Nivolumab

over Docetaxel

inPD-L1

‘positive’

Non-squamous

cell carcinoma

NIVO DOC0 1 2

039

Differences Between Squamous and Non-Squamous Cancers?

• Biomarker not predictive in Squamous (017) but predictive in non-squamous (057)

– CheckMate057: Significant improvement in median OS but not median PFS– CheckMate017: Significant improvement in median OS and PFS

• Same drug, same biomarker

• Current/former smokers– CheckMate 017: 92%– CheckMate 057: 79.5%; EGFR/ALK in 17.5%

• Greater mutational load in 017 squamous cell cancers?• Immune system and squamous vs glandular epithelia?

• Does the immune status or immune microenvironment differ between these patients?

• Immune infiltrates in and around tumours differ

• Does the mutation burden make a difference? Are immunomodulatory mechanisms different?

• Are the cut offs correct? Are 1, 5 & 10% too low?


040


• Data are variable

• Rule in/Rule out– Biomarker to predict patient will benefit (and to what

degree)– Biomarker to predict patient will not benefit– 10% is easier than 5% is easier than 1%

• Assessment of immune cells– Relevance of immune cells present?– Cytology samples lack architecture

• Is a biomarker required?


041


• Is it the correct marker?

• Does the oncology community trust immunohistochemistry?

• Are our expectations of a biomarker in this setting reasonable?– PD-L1 is not ‘present’ or ‘absent’– Expression is biological continuum– Cut offs; definitions of positive are ‘artificial’


042


• Is it the correct marker?

• Does the oncology community trust immunohistochemistry?

• Are our expectations of a biomarker in this setting reasonable?– PD-L1 is not ‘present’ or ‘absent’– Expression is biological continuum– Cut offs; definitions of positive are ‘artificial’– Immune Checkpoint inhibition is NOT like inhibiting an

addictive oncogene driver

• Four drugs, four different ‘biomarker tests’, all for ‘PD-L1’


043

Other Potential Biomarkers for Response?

• Other immune checkpoints

• Immune cells – Overall infiltrate– Specific cell types

• Immune gene signatures

• Mutational burden– Global burden– Mismatch repair genes (MMR)– Microsatellite instability (MSI)– Polymerase E (POLE) mutations– Smoking

044

Immune Checkpoint Inhibition Is an Active Area of Clinical Development in the Treatment of NSCLC

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Phase 3 Trials With Immunotherapeutic Agents in NSCLC

Agent Patients Regimen 1° Endpoint StatusIpilimumab(NCT02279732)

Stage IV or recurrent SCC

Ipilimumab + CP vs

Placebo + CP

OS Currently recruiting

Ipilimumab(NCT02477826)

Chemo-naive or recurrent stage IV or recurrent

NSCLC

Nivolumab vs nivolumab + Ipi vsplatinum doublet*

OSPFS

Not yet recruiting

Nivolumab(NCT02066636)

Stage IIIB-IVNSCLC; failed at

least one prior systemic regimen

Nivolumab3 mg/kg IV until progression vs

Nivolumab3 mg/kg IV 1 year

Grade 3-4 and 5 treatment-related

AEs

Currently recruiting


Chemo-naive or recurrent stage

IV NSCLC

Nivolumab vs platinum doublet

PFS Currently recruiting


Chemo-naive or recurrent stage

IV NSCLC

Nivo vs nivo + ipivs platinum-

doublet

OSPFS

Not yet recruiting

*Squamous: gemcitabine + cisplatin or carboplatin; non-squamous: pemetrexed + cisplatin or carboplatin.CP = carboplatin + paclitaxel.Available at: www.clinicaltrials.gov. Accessed July 15, 2015.

046



Agent Patients Regimen 1° Endpoint StatusPembrolizumab(NCT02142738)

Untreated stage IV strong

PD-L1-expressing

NSCLC

Pembro vs PC vs Pem + C vs

Pem + Cis vs Gem + Cis vs

Gem + C


Pembrolizumab(NCT02220894)

Chemo-naivePD-L1+ NSCLC

Pembro vsStandard of care platinum doublet

OS Currently recruiting

MEDI4736(NCT02453282)

Chemo-naive advanced or

metastatic NSCLC

MEDI vs MEDI + Treme vs platinum

doublet

PFS Not yet recruiting

MEDI4736(NCT02352948)

Stage IIIb/IV NSCLC failed ≥2 prior therapies

PD-L1+:MEDI vs SOC

PD-L1-:MEDI vs SOC vsMEDI + Treme vs

SOC


SOC = standard-of-care; C = carboplatin.Available at: www.clinicaltrials.gov. Accessed July 15, 2015.

047



Agent Patients Regimen 1° Endpoint StatusMEDI4736(NCT02273375)

Completely resected NSCLC

MEDI vs placebo DFS Currently recruiting

MEDI4736(NCT02454933)

T790M+NSCLC failed prior EGFR TKI

MEDI + AZD9291 vs AZD9291

PFS Not yet recruiting

MEDI4736(NCT02125461)

Stage III NSCLC not progressed

following definitive platinum-based

concurrent chemoradiation

MEDI vs placebo OSPFS

Currently recruiting

Available at: www.clinicaltrials.gov. Accessed July 15, 2015.

048



Agent Patients Regimen 1° Endpoint StatusAtezolizumab(NCT02409355)

Chemo-naive, stage IV squamous

NSCLC

MPDL vs Gem + Cis vs

Gem + C


Atezolizumab(NCT02409342)

Chemo-naive or recurrent stage IV

or recurrent NSCLC

MPDL vs C or cis + pem



Chemo-naive or recurrent stage IV

or recurrent NSCLC

MPDL + nab-CP vsnab-CP



Chemo-naive stage IV SCC

MPDL + CP or MPDL + nab-CP vs

nab-CP



Chemo-naive stage IV NSCLC

MPDL + CP vs MPDL + CP + bev vs

CP + bev



Completely resected stage IB-

IIIA NSCLC

MPDL vs BSC DFS Currently recruiting

CP = carboplatin + paclitaxel; nab-CP = carboplatin + nab-paclitaxel; C = carboplatin.Available at: www.clinicaltrials.gov. Accessed July 15, 2015.

049

Vaccines in the Treatment of NSCLC

050

MOA of Cancer Vaccines

Adapted from Drakes CG et al. Nat Rev Clin Oncol. 2014;11:24-37.

Tumour cells

051

MAGE-A3 and Adjuvant Therapy

• MAGE-A3 is an antigen that is expressed almost exclusively on the surface of tumour cells, including NSCLC1

– 17-50% of NSCLC expresses MAGE-A3– Expression is associated with poor prognosis

• Phase 2 trial in stage IB-II completely resected NSCLC: MAGE-A3 vaccine vs SOC2

– DFS: HR 0.76 (95% CI: 0.48-1.21)– OS: HR 0.81 (95% CI: 0.47-1.40)

• MAGRIT trial: Phase 3 trial of MAGE-A3 cancer vaccines vs placebo in stage IB-IIIA completed resected NSCLC (N=2278)3

– 2:1 randomisation– Primary endpoint: DFS– Study was discontinued by GSK due to failure to meet its

primary endpoint1. Massarelli E et al. Transl Lung Cancer Res. 2014;3:53-63; 2. Vansteenkiste J et al. J Clin Oncol. 2013;31:2396-403; 3. GSK website. http://us.gsk.com/en-us/media/press-releases/2014/update-on-phase-iii-clinical-trial-of-investigational-mage-a3-antigen-specific-cancer-immunotherapeutic-in-non-small-cell-lung-cancer/. Accessed August 4, 2015.

http://us.gsk.com/en-us/media/press-releases/2014/update-on-phase-iii-clinical-trial-of-investigational-mage-a3-antigen-specific-cancer-immunotherapeutic-in-non-small-cell-lung-cancer/

052


Agent Patients Regimen 1° Endpoint Status

EGF cancer vaccine (NCT02187367)

Untreated EGFR WT

NSCLC

EGF cancer vaccine vs BSC OS Currently recruiting

Tergenpumatucel-L(NCT01774578)

Progressive or relapsed NSCLC

Tergenp vs docetaxel OS Currently recruiting

GV1001(NCT01579188)

Inoperablestage III post-

chemoradiationtherapy

GV1001 vs BSC OS Not yet recruiting

Racotumomab(NCT01460472)

Previously treated stage

IIIA-B, IV NSCLC

Racotumomab vs BSC OS Currently recruiting

TG4010(NCT01383148)

Untreatedstage IV NSCLC

TG4010 + chemo vs

placebo + chemo

PFS (Phase 2)OS (Phase 3) Currently recruiting

BSC = best supportive care.Available at: www.clinicaltrials.gov. Accessed July 15, 2015.

Select Ongoing Phase 3 Trials With Vaccine in NSCLC

053

BI 1361849*: Therapeutic mRNA-based Vaccine

• A novel investigational therapeutic mRNA-based vaccine developed in collaboration with CureVac

• Mobilises the patient’s own immune system to fight the tumour with a specific immune response

• Clinical investigation is underway in lung cancer settings

*This is an investigational compound and has not yet been approved. Its safety and efficacy have not yet been fully established.mRNA = messenger ribonucleic acid.

Source: Boehringer Ingelheim (data on file).

Source: http://www.curevac.com/rna-technology/rnactiver/

054

BI 1361849: Current Clinical Development

• 1st-line EGFR m+ combo with afatinib

• Monotherapy in locally advanced disease after chemoradiation

055

Summary/Conclusion

• Recent advances in molecular biology have “revived” and validated immunotherapeutic approaches for the treatment of cancer

• Anti-PD-L1mAb has significantly improved survival in patients with advanced or metastatic NSCLC

• However, there are still a number of issues associated with anti-PD-1/PD-L1 therapy, and it continues to be an active area of research and development

• Additional therapeutic approaches under clinical development include cancer vaccination

Immunotherapeutic Approaches in the Treatment of NSCLC · PDF file2015;33:(suppl; Abstract...

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Transcript of Immunotherapeutic Approaches in the Treatment of NSCLC · PDF file2015;33:(suppl; Abstract...