Immunotherapeutic Approaches in the Treatment of NSCLC · Durvalumab [Rizvi ASCO 2015 Abst 8032] Phase 1, dose-escalation, cohort expansion: Any. Any ≥25% tumor cells staining at

Immunotherapeutic Approaches in the Treatment of NSCLCKeith Kerr

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

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 2010 2014 2015 2016

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 Zinkernagel and 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

Discovery of cross-presentation

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-myeloablative chemotherapies and adoptive T cell transfer in melanoma

FDA approved pembrolizumab and nivolumab for the treatment of melanoma

Key regulators of T-cell response are

elucidated

FDA approval of nivolumab and

pembrolizumab for NSCLC; nivolumab for

RCC

FDA approval of nivolumab for Hodgkin’s

lymphoma and atezolizumab for bladder

cancer

FDA approval of sipuleucel-T in prostate cancer and ipilimumab

in melanoma

Tumour Immune Responses are VERY Complex and Involve Many Factors

Modified from Slide Courtesy of Dr D Carbone, MD

CD3/CD4

S100

CD20

CD68

CD138

CD3/CD8

CD56 Treg

CD4/CD25/Fox3P

The Concept of Immune Surveillance and Escape

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

Lung cancers areamongst the MOST antigenic of solid tumours

Tumours May Alter T-Cell Activation ThroughImmune Checkpoint Signalling

• These inhibitory checkpoints probably help host (normal) tissues avoid autoimmune responses

• Tumours can dysregulate checkpoints and activating pathways, and consequently inhibit the immune response

• PD-L1 as a poor prognostic factor supports this concept

• Targeting and inhibiting checkpoints can reactivate an immune response

PD-1

CTLA-4

Inhibitory receptors

Activating receptors

TIM-3

LAG-3

T-cell activity

CD28

OX40

CD137

Adapted from Mellman I, et al. Nature 2011:480;481-9; Pardoll DM. Nat Rev Cancer 2012;12:252-64.

Adapted from Mellman I, et al. Nature 2011:480;481–9; Pardoll DM. Nat Rev Cancer 2012;12:252–64

LigandPD-L1

The Inhibitory (Checkpoint) Molecule PD-L1 Is Associated With Poor Prognosis in Patients With Resected NSCLC1-4

P < 0.05PD-L1+ (n = 58)PD-L1− (n = 51)

0.0

0.2

0.4

0.6

0.8

1.0

Ove

rall

Surv

ival

0 10 20 30 40 50Months After Surgery0

1. Chen YB et al. Tumori. 2012;98:751-5. 2. 2. Mu CY et al. Med Oncol. 2011;28:682-8.3. Wang A et al. Eur J Surg Oncol. 2015;41:450-6.

PD-L1 = programmed death-ligand 1.

4. Sorensen SF et al. Trans Oncol. 2016;9:64-9.

Less obvious signalAdvanced diseaseImmunocompetent?

P=<0.001

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;366:2517-9.

NivolumabPembrolizumab

MPDL3280AMEDI4736

Ipilimumab

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

Block PD1 or PDL1immune damage to tumour

Chen, et al. Clin Cancer Res 2012

Interferon-gamma upregulates tumour cell expressionof PD-L1

High Levels of PD-1 or PD-L1 Protein Expression (IHC) May Inhibit Immune Response

Review of Clinical Studies

Headline Studies: Outcomes and PD-L1 Expression

Agent Study Study Design Treatment Line

Histology PD-L1 Positive Definition

PD-L1 positive, %

ORR, % (n/N) Median PFS, months Median OS, monthsPositive Negative Positive Negative Positive Negative

Nivolumab CheckMate 063[Rizvi 2015]

Phase 2, single arm

≥3rd Squamous ≥5% in ≥100 cells 33 24 (6/25) 14 (7/51) NA NA NA NA

Nivolumab CheckMate 017[Brahmer NEJM

2015]

Phase 3, randomized, open-

label versus docetaxel

2nd Squamous ≥1% in ≥100 cells≥5% in ≥100 cells

≥10% in ≥100 cells

473127

17 (11/63)21 (9/42)19 (7/36)

17 (9/54)15 (11/75)16 (13/81)

3.34.83.7

3.12.22.3

9.310.011.0

8.78.58.2

Nivolumab CheckMate 057[Borghaei 2015]



2nd Non-squamous ≥1% in ≥100 cells≥5% in ≥100 cells

≥10% in ≥100 cells

534137

31 (38/123)36 (34/95)37 (32/86)

9 (10/108)10 (14/136)11 (16/145)

4.25.05.0

2.12.12.1

17.719.419.9

10.59.89.9

Nivolumab + ipilimumab

CA209-012[Antonia SJ ASCO 2014]

Phase 1, multi-cohort

1st Any ≥5% in ≥100 cells 42 19 (3/16) 14 (3/22) 3.3 3.1 NR NR

Pembrolizumab KEYNOTE-001[Garon NEJM

2015]


≥1st Any ≥50% (strong); 1–49% (weak)

2338

45 (33/73); 17 (17/103)

11 (3/28) 6.44.1

4.0 NR10.6

10.4

Atezolizumab POPLAR study[Spira ASCO

2015]

Phase 2, randomized versus

docetaxel

2nd or 3rd Any TC staining: ≥50%; ≥5%; ≥1%

IC staining: ≥10%; ≥5%; ≥1%

TC/IC:a

16, 37, 68

TC dataa: 38; 22; 18

IC dataa: 13; 15; 18

TC/IC: 8 7.8; 4.0; 3.3 1.9 NR: 13.0; NR

9.7

Durvalumab [Rizvi ASCO 2015 Abst 8032]

Phase 1, dose-escalation, cohort

expansion

Any Any ≥25% tumor cells staining at any

intensity

48 27 (23/84) 5 (5/92) NA NA NA NA

Durvalumab +tremelimumab

[Antonia ASCO 2015]

Phase 1b dose-escalation, dose

expansion

≥2nd Any NA 29 33 (6/18) 27 (9/33) NA NA NA NA

Avelumab JAVELIN study[Gulley ASCO

2015]


expansion

≥2nd Any ≥1% tumor cells staining at any

intensity

86 16 (19/122) 10 (2/20) 2.8 1.4 8.9 4.6




PD-L1 positive, %



Phase 2, single arm



2015]




≥10% in ≥100 cells

473127

17 (11/63)21 (9/42)19 (7/36)

17 (9/54)15 (11/75)16 (13/81)

3.34.83.7

3.12.22.3

9.310.011.0

8.78.58.2





≥10% in ≥100 cells

534137

31 (38/123)36 (34/95)37 (32/86)

9 (10/108)10 (14/136)11 (16/145)

4.25.05.0

2.12.12.1

17.719.419.9

10.59.89.9






2015]



2338

45 (33/73); 17 (17/103)

11 (3/28) 6.44.1

4.0 NR10.6

10.4


2015]


docetaxel


IC staining: ≥10%; ≥5%; ≥1%

TC/IC:a

16, 37, 68

TC dataa: 38; 22; 18

IC dataa: 13; 15; 18

TC/IC: 8 7.8; 4.0; 3.3 1.9 NR: 13.0; NR

9.7



expansion


intensity

48 27 (23/84) 5 (5/92) NA NA NA NA


[Antonia ASCO 2015]


expansion



2015]


expansion


intensity

86 16 (19/122) 10 (2/20) 2.8 1.4 8.9 4.6



PD-L1 positive, %



Phase 2, single arm



2015]




≥10% in ≥100 cells

473127

17 (11/63)21 (9/42)19 (7/36)

17 (9/54)15 (11/75)16 (13/81)

3.34.83.7

3.12.22.3

9.310.011.0

8.78.58.2





≥10% in ≥100 cells

534137

31 (38/123)36 (34/95)37 (32/86)

9 (10/108)10 (14/136)11 (16/145)

4.25.05.0

2.12.12.1

17.719.419.9

10.59.89.9






2015]



2338

45 (33/73); 17 (17/103)

11 (3/28) 6.44.1

4.0 NR10.6

10.4


2015]


docetaxel


IC staining: ≥10%; ≥5%; ≥1%

TC/IC:a

16, 37, 68

TC dataa: 38; 22; 18

IC dataa: 13; 15; 18

TC/IC: 8 7.8; 4.0; 3.3 1.9 NR: 13.0; NR

9.7



expansion


intensity

48 27 (23/84) 5 (5/92) NA NA NA NA


[Antonia ASCO 2015]


expansion



2015]


expansion


intensity

86 16 (19/122) 10 (2/20) 2.8 1.4 8.9 4.6




PD-L1 positive, %



Phase 2, single arm



2015]




≥10% in ≥100 cells

473127

17 (11/63)21 (9/42)19 (7/36)

17 (9/54)15 (11/75)16 (13/81)

3.34.83.7

3.12.22.3

9.310.011.0

8.78.58.2





≥10% in ≥100 cells

534137

31 (38/123)36 (34/95)37 (32/86)

9 (10/108)10 (14/136)11 (16/145)

4.25.05.0

2.12.12.1

17.719.419.9

10.59.89.9






2015]



2338

45 (33/73); 17 (17/103)

11 (3/28) 6.44.1

4.0 NR10.6

10.4


2015]


docetaxel


IC staining: ≥10%; ≥5%; ≥1%

TC/IC:a

16, 37, 68

TC dataa: 38; 22; 18

IC dataa: 13; 15; 18

TC/IC: 8 7.8; 4.0; 3.3 1.9 NR: 13.0; NR

9.7



expansion


intensity

48 27 (23/84) 5 (5/92) NA NA NA NA


[Antonia ASCO 2015]


expansion



2015]


expansion


intensity

86 16 (19/122) 10 (2/20) 2.8 1.4 8.9 4.6


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 2/3 data:– Pembrolizumab vs docetaxel in NSCLC

(KEYNOTE 010 trial)

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

• Phase 1 and 1/2 data: – Pembrolizumab in NSCLC (KEYNOTE 001 trial)– Pembrolizumab in 1st line NSCLC (KEYNOTE 021 trial)

CheckMate 057: Nivolumab vs Docetaxel in Pretreated Non-Squamous NSCLC — 2-Year Update

Borghaei H et al. ASCO 2016; poster 9025.

Kaplan-Meier estimates of OS (2 years minimum follow-up)

PFS in overall population

CheckMate 057: PFS

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

CheckMate 017: Nivolumab vs Docetaxel in 2nd-Line SCC2-Year Update

Borghaei H et al. ASCO 2016. Poster 9025.

Kaplan-Meier estimates of OS (2 years minimum follow-up)

POPLAR: Phase 2 Trial of Atezolizumab vs Docetaxel in 2nd/3rd-Line NSCLC – Importance of Long-Term Follow-up With Anti–PD-1 Immunotherapy

aStratified HR; data cut-off Jan 30, 2015.MEMO ASCO 2016; Smith D et al. ASCO 2016. Poster 9028.

OS improvement with atezolizumab becomes apparent over time

OS (All Patients, ITT

KEYNOTE-010: Phase 2/3 of Pembrolizumab vs Docetaxel for Previously Treated PD-L1+ Advanced NSCLC; OS

Figure 2: Kaplan-Meier analysis of overall survival(A) For patients with a PD-L1 tumour proportion score of 50% or greater. (B) For all patients.

Herbst RS et al. Lancet. 2016;387:1540-50.

KEYNOTE-010: Subgroup Analysis of OS

Herbst RS et al. Lancet. 2016;387:1540-50.

JAVELIN Solid Tumour: Phase 1b of Avelumab for Advanced NSCLC

Verschraegen C et al. ASCO 2016. Poster 9036.

Avelumab vs Platinum-Based Doublet as 1st-Line Treatment for Metastatic or Recurrent PD-L1+ NSCLC: Ongoing

Current Considerations With Immunotherapeutic Approaches in the Treatment of NSCLC


–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 Oncol. 2012;23(suppl 8):viii47-52.

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)

Is Monotherapy Enough?

• ORR ranges from 15% to 24.8% for anti–PD-1/PD-L1 monotherapy (up to 45% in those with highest PD-L1 expression) in previously treated or untreated patients with NSCLC

• Depends on your expectations!

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 + ipilimumab in 2nd-line NSCLC: 47% 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. Hellmann A et al. ASCO 2016. Abstract 3001.4. Rivni NA et al. J Clin Oncol. 2014:32:(suppl; abstract 8022).

KEYNOTE 021: Phase 1/2 of Pembrolizumab as Front-Line Therapy for Advanced NSCLC ORR and Survival

Gadgeel S et al. ASCO 2016. Abstract 9016.

Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Summary of Efficacy

Presented by Matthew Hellmann at 2016 ASCO Annual Meeting

Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Efficacy Across All Tumor PD-L1 Expression Levels


Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Treatment-related Select AEs



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

Nivolumab Plus Ipilimumab in First-line NSCLC: Efficacy by Smoking and EGFR Mutation Status


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

PD-L1 as a Potential Predictive Biomarker?

KEYNOTE-001: Phase 1b Trial of Pembrolizumab in the Treatment of Advanced NSCLC — 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

Pembrolizumab in NSCLC: OS per Proportional Scores (TPS)

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

Gandhi L, et al. AACR 2014. Abstract CT105.

≥50% IHC cut off tumour cell expression

22C3 clone IHC-based assay

Expression in TILs added no predictive value


Atezolizumab and Anti–PD-L1 SP142 Clone-Based Assay: Optiview Detection and Amplification

Tumour cells: % TC positive Immune cells: % area of tumour infiltrated

Fehrenbacher L et al. Lancet. 2016;387:1837-46.

Percentage tumour areaPD-L1 expressing cells



POPLAR: PD-L1 Expression and OS

Smith D et al. ASCO 2016. Poster 9028.

Nivolumab

28-8 clone assay

Complementary orcompanion diagnostic assay?

1% threshold is‘positive’


PD-L1 expression

Patients, n Unstratified HR(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 (CheckMate 017)

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


OS and PFS Hazard Ratios by PD-L1 Status (CheckMate 057)

PD-L1 expression levelNIVO

nDOC

nUnstratified HR (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

CheckMate 057: Non-Squamous - OS by PD-L1 Expression

46

Symbols represent censored observations. mOS = median OS.

Time (months)

mOS (mo)

NIVO 10.4

DOC 10.1

mOS (mo)

NIVO 17.2

DOC 9.0

Time (months)

100

90

80

70

60

50

40

30

10

0

20

24211815129630 27

≥10% PD-L1 expression level

100

90

80

70

60

50

40

30

10

0

20

24211815129630 27

Time (months)

<10% PD-L1 expression levelmOS (mo)

NIVO 9.9

DOC 10.3

mOS (mo)

NIVO 19.4

DOC 8.0

Time (months)

100

90

80

70

60

50

40

30

10

0

20

24211815129630 27


Time (months)

100

90

80

70

60

50

40

30

10

0

20

24211815129630 27

<5% PD-L1 expression level

mOS (mo)

NIVO 18.2

DOC 8.1

mOS (mo)

NIVO 9.7

DOC 10.1

NIVODOC


OS

(%)

100

90

80

70

60

50

40

30

10

0

20

24211815129630 27

HR (95% CI) = 0.59 (0.43, 0.82)

Time (months)Time (months)

<1% PD-L1 expression level100

90

80

70

60

50

40

30

10

0

20

24211815129630 27

OS

(%)

NIVODOC

HR (95% CI) = 0.90 (0.66, 1.24)

HR (95% CI) = 0.43 (0.30, 0.63)

HR (95% CI) = 1.01 (0.77, 1.34)

HR (95% CI) = 0.40 (0.26, 0.59)

HR (95% CI) = 1.00 (0.76, 1.31)

Paz-Ares et al, ASCO 2015

CheckMate 026

Differences Between Squamous and Non-Squamous Cancers?

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

– CheckMate 057: Significant improvement in median OS but not median PFS– CheckMate 017: 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?

Kerr K. ASCO 2015. Discussant.

As Anti-PD1 and Anti–PDL-1 Immunotherapies Move Into First-Line Indications

• The ‘bar’ will be higher– Efficacy superior to first-line chemotherapy

• Attaining that efficacy will require patient selection– Trials all designed by preselecting patients according to PDL-1 IHC

expression

• Upfront, probably ‘reflex’, PD-L1 IHC will be required…

Pembrolizumab a New Standard for PD-L1 ≥50% NSCLC?

Alternative Potential Biomarkers for Response?

• Immune gene signatures

• Immune cells – Overall infiltrate– Specific cell types

• Other immune checkpoints– PD-L2, IDO, etc

• Mutational burden


CheckMate 063/017/057: Cytokines Associated With OS Identified via Stepwise Variable Selection in Cox Model Using A1Ca

Presented by Hossein Borghaei at 2016 ASCO Annual Meeting.

AIC = Akaike information criterionB2M = β2 microglobulinCRP = C-reactive proteinEN-RAGE = extracellular newly identified receptor for advanced glycation endproducts-binding protein FRTN = ferritinICAM1 = intercellular adhesion molecule 1IFN = interferonIL = interleukinIL-1RA = IL-1 receptor agonistIL2RA = IL-2 receptor subunit alphaIP-10 = IFN-γ-induced protein 10

MCP2 = mitochondrial distribution and morphology protein 10-complementing protein 2MICA = MHC class I polypeptiderelatedsequence AMIG = monokine induced by gamma IFNMIP1B = macrophage inflammatory protein 1 betaMMP3 = matrix metalloproteinase-3RANTES = regulated on activation, normal T-cell–expressed and secretedTNF = tumor necrosis factorTNFR2 = TNF receptor 2VDBP = vitamin D-binding protienVWF = von Willebrand factor

CRPICAM1

IL-6IL-1RAIP-10MIG

MIP1B

FRTNIL-8IL-18MICAMMP3VDBPVWF

B2MEN-RAGEb

IL2RAMCP2

RANTESb

TNFR2

SQ NSCLC Non-SQ NSCLC

a Some key cytokines, such as IFN-γ and TNF, were not evaluable and were not considered in the cytokine selection, and cytokines measured at baseline in patients with SQ and non-SQ NSCLC were not the same (Figure 3).

b Not measured in SQ NSCLC studies.



• Other immune checkpoints– PD-L2, IDO, etc


Kerr et al. Histopathology. 1998; Johnson et al. Lung Cancer. 2000; Suzuki et al. Clin Cancer Res. 2011; Bremnes et al. J Thorac Oncol. 2011; Tao et al. Lung Cancer. 2012; Al-Shibli et al. Clin Cancer Res. 2008;14:5220-7; Al-Shibli et al. Histopathology. 2009;55:301-12; Shimizu K et al. J Thorac Oncol. 2010;5:585-90.

Surv

ival

(%)

Time (months)

0

20

40

60

80

100

0 60 180120

S100+Dendritic cells

FoxP3+ Tregs

Low expression, n = 268

0 24 48 72 96 120

144

168

192

CD8 T Cells

High expression, n = 61

P = 0.002

Time (months)

Dis

ease

-Spe

cific

Sur

viva

l 1.0

0.8

0.6

0.4

0.2

0.0

Or CD4+ or CD56+ lymphoid cells

Where is the infiltrate?


CheckMate 063/017/057: OS by SQ-Cytoscore in Patients With SQ NSCLC Treated With Nivolumab or Docetaxel

Presented by Hossein Borghaei at 2016 ASCO Annual Meeting.

Nivolumab Docetaxel Nivo vs doce

n mOS(mo)

12-mo OS(%)

18-mo OS(%) n mOS

(mo)12-mo OS

(%)18-mo OS

(%)HR

(95% CI) P

High 102 15.6 55.9 39.0 70 9.1 38.6 22.9 0.63 (0.45, 0.88) 0.0051

Low 120 5.3 29.8 21.3 48 4.9 4.3 0 0.51 (0.37, 0.71) 0.0009

High vs low SQ-cytoscoreHR (95% CI) 0.48 (0.36, 0.64) 0.39 (0.27, 0.56)P <0.0001 <0.0001

Factor HR CI P

Treatment groups(Nivo vs doce)

0.60 0.45, 0.72 <0.0001

SQ-cytoscore(High vs low) 0.44 0.35, 0.56 <0.0001

Treatment–SQ-cytoscoreinteraction

– X2 = 0.7799(df = 1) 0.3772

a Includes patients with evaluable baseline cytokine levels from CheckMate 063 and CheckMate 017 (nivolumab-treated patients) or CheckMate 017 only (docetaxel-treated patients).

Nivolumab-treated patientsa

100

80

60

40

20

00 5 15 25 30

OS

(%)

10 20

Time (Months)

Δ 10.3 mo

High SQ-cytoscore

Low SQ-cytoscore

Docetaxel-treated patientsa

100

80

60

40

20

00 5 15 25 3010 20

High SQ-cytoscore

Low SQ-cytoscore

Δ 4.2 mo

OS

(%)

Time (Months)



• Other immune regulators– PD-L2, IDO, LAG3,– Interferon gamma


Anti-PD-L1 therapy – Durvalumab

PD-L1 protein AND Interferon-gamma mRNA expression

Higher RR (46%) in combined expression versus

Interferon-gamma (33%) or PL-L1 (27%) alone

Higgs et al, 15LBA, ECCO 2015

Anti-PD-1 therapy – Pembrolizumab

PD-L1 and PD-L2 IHC better than either alone

Crowley et al. LBA, ECCO 2015


Rizvi NA et al. Science. 2015;348:124-8.

Mutation Burden

Molecular Smoking Signature

Other Factors Related to Genomic Instability

–Smoking–Smoking signatures in mutations

–Polymerase E (POLE) mutations–Mismatch repair genes (MMR)–Microsatellite instability (MSI)

Biomarkers for Immunotherapy?

PDL-1 IHCSurrogates of immune responseImmune cellsGene signature

Mutational burden or surrogate

Rizvi NA et al. Science. 2015;348:124–128.



• 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?

Kerr K. ASCO 2015. Discussant.

Your tumour is ‘negative’Addictive oncogenic mutation or fusion gene is

ABSENTYou will not benefit from therapy

Biomarker ‘Positivity’: Present or Absent?

Your tumour is ‘positive’Addictive oncogenic mutation or fusion gene is

PRESENTYou will benefit from therapy



Biomarker ‘Positivity’: Present, Absent, or Graduated?



Biological continuum of biomarker expression

Biomarker is ABSENT or at low level

You are unlikely to benefit from therapy

Biomarker is PRESENT at intermediate level

You maybenefit from therapy

Biomarker is PRESENT at a high level

You are likely to benefit from therapy



Biomarker ‘Positivity’: Present, Absent, or Graduated? (cont’d)










How do we define ‘positive’? Where do we set the cut-off value?

1% 80%50%25%

Clinical Efficacy vs PD-L1 Positivity…








1% 80%50%25%

How muchless responsivewill this patient be… Compared with this one?

Differential effects depend upon the dose-response relationship

Lower chance of response

Higher chance of response

Heterogeneity and PD-L1

• Expression is dynamic

• Expression is heterogeneous

• Sampling ‘error’ must occur

• Greater impact at lower thresholds

• Part of the reason why the biomarker appears worse than it is

• Trials ‘control’ for heterogeneity to some extent

PD-L1 Immunohistochemistry as a Biomarker

• Is the drug target a ‘singular’ factor in the target system?

• Is the biomarker present or absent?

• Is the biomarker stable and functionally unique?

• Is the biomarker easily measured?

• Is the biomarker 100% predictive?

• But it is all we currently have, and what chance is there anything else is better?

It Depends on How You Look at This. What ‘Odds’ of Success Are You Willing to Accept?

PD-L1 as a Predictive Immune Biomarker: Assays, Sample Collection, and Analysis in NSCLC Studies

PD-L

1As

say

Sam

ple

Sour

ce

and

Col

lect

ion

Def

initi

on o

f Po

sitiv

ity†

PembrolizumabMerck

• Prototype or clinical trial IHC assay (22C3 Ab)

• Surface expression of PD-L1 on tumour specimen

• Ph I: Fresh or archival tissue

IHC Staining:• Strong vs weak

expression• PD-L1 expression

required for NSCLC for enrollment• Note that one arm

of KEYNOTE 001 trial requires PD-L1- tumours

Tumour PD-L1 expression:• ≥50% PD-L1+ cut-off:

32% (41/129)• 1–49% PD-L1+ cut-off:

36% (46/129)

NivolumabBristol-Myers Squibb

• Dako automated IHC assay

• (28-8 Ab)

• Surface expression ofPD-L1 on tumour cells

• Archival or fresh tissue

IHC Staining:• Strong vs weak

expression• Patients not restricted

by PD-L1 status in 2nd- & 3rd-line

• Ph III 1st-line trial in PD-L1+

Tumour PD-L1expression:

• 1% PD-L1+ cut off• 5% PD-L1+ cut-off: 59%

(10/17)• 5% PD-L1+ cut-off: 49%

(33/68• 10% PD-L1+ cut off

AtezolizumabRoche/Genentech

• Central laboratory IHC assay

• Ventana PD-L1 (SP142)

• Surface expression of PD-L1 on TILs or tumour cells

• Archival or fresh tissue

IHC Staining Intensity (TC: 0, 1, 2, 3):• IHC 3 (≥50% PD-L1+)• IHC 2,3 (≥5% PD-L1+)• IHC 1,2,3 (≥1% PD-

L1+)• IHC 0,1,2,3 (all

patients with evaluable status)6,7

• PD-L1 expressionrequired for NSCLC for enrolment in Ph II trials

• x

IC: TIL PD-L1 expression:• IHC 3 (≥10% PD-L1+):

11% (6/53) • PD-L1 low (IHC 1, 0):

62% (33/53)

DurvalumabAstraZeneca

• Ventana automated IHC (BenchMark ULTRA using Ventana PD-L1 (SP263) clone)

• Surface expression of PD-L1 on tumour cells

• Unknown

IHC Staining Intensity:• Not presented to

date

Tumour PD-L1expression:• PD-L1+ cut off 25%

• PD-L1+: 34% (20/58)• PD-L1–: 50% (29/58)

AvelumabPfizer/Merck Serono

• Dako assay• Clone not known

• Surface expression of PD-L1 on tumour cells

• Unknown

IHC Staining Intensity:• Not presented to

date

Tumour PD-L1expression (all doses):

• PD-L1+ cut off 1%

• PD-L1+: 34% (20/58)• PD-L1-: 50% (29/58)

How Will We Deal With Four- or Five-Drug Assay Combinations?

• Is it likely that labs will provide multiple tests?– No– How many platforms are available?– How different are the assays?

• Laboratory-developed tests (LDTs)– ‘Modification’ of the companion/complementary assay– LDT built around a ‘trial’ clone– LDT built around another clone

The outcome of an IHC test is a function of the primary antibody AND the detection system used…and functional validation

PD-L1 IHC: What Chance One Test?

• Is all anti–PD-L1 IHC the same?

• Are all the companion diagnostics the same?

• Can we use any IHC for any drug?– No evidence to support this practice– One IHC – multiple scoring definitions– Implications for how PD-L1 IHC would be reported by pathologists % cells positive Indicate different thresholds? Mention actual drugs in report?

• 28-8, 22C3 & SP263 very similar

• German ring study – Good concordance after training– Test performance similar

• BluePrint Study– IASLC and 6 commercial partners (AACR & ASCO)– Comparing the four trial-validated assays

Test ‘Harmonization’?Technical Equivalence?

Equivalent CLINICAL Predictive Value?

Ratcliffe MJ et al. AACR 2016, LB094.

BluePrint Project

• Four pharma partners

• Two diagnostic companies

• IASLC

• 40 cases, four assays, stained and read by diagnostic company laboratories

• TECHNICAL PERFORMANCE compared

The BluePrint Project: IASLC and Partners

% Im

mun

e C

ell S

tain

ing

Tumour cell staining % Immune cell staining %

28-8-, 22C3-, and SP263-based assays are quite similar SP142 assay is different

Reading Cases According to Different Assays and Assay-Associated Scoring Rules

30/38 cases

(78.9%)

26/38 cases (60.5%)

26/38 cases (60.5%)

20/38 cases (52.6%)

Number of cases (%) with PD-L1 expression above the assay specific selected cut-off

Reading Assay-Staining Slides According to Different Scoring Algorithms – Cut-offs

Assays and LDTs: Mix and Match? ‘Ski Off Piste’??

Drug Anti–PD-L1 Assay Definition of Positivity

Outcome Risk to Patient?

By choice Assay validated for drug in trial

Definition validated in trial for drug

Predictable based upon trial data

Known

By choice Any trial-validated assay

Definition validated in trial for drug of choice

Uncertain Not known

By choice Any trial-validated assay

Definition validated with the assay

Very uncertain Not known

By choice LDT using any clone Unknown Very, very uncertain Not known

By how much is it safe to deviate from trial-validated practice?Are there any medico-legal implications?

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

Looking Beyond PD-1/PD-L1: TIM-3 or Other Backbones?

Dual checkpoint inhibition CTLA-4PD-1/PD-L1LAG-3TIM-3

Checkpoint inhibitor + costimulatory agonists

CD137/41BBOX40GITRCD27

Checkpoint inhibitor + innate immune modulators

IDOCSF-1KIR (NKG2)

Checkpoint inhibitors + other immune activators

ChemoIL-2VaccinesGM-CSF

Mellman et al. Nature. 2011.

Vaccines in the Treatment of NSCLC

MOA of Cancer Vaccines

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

Tumour cells

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

endpoint

1. 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, 2016.

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/

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 under way 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/.

BI 1361849: Current Clinical Development

• 1st-line EGFR m+ combo with afatinib

• Monotherapy in locally advanced disease after chemoradiation

Summary/Conclusions

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

• Anti–PD-L1 mAb 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

Documents

Immunotherapeutic Approaches in the Treatment of NSCLC · Durvalumab [Rizvi ASCO 2015 Abst 8032] Phase 1, dose-escalation, cohort expansion: Any. Any ≥25% tumor cells staining at