NSCLC Immunotherapy Post WCLC (& ECCO/ESMO) 2015€¦ · NSCLC Immunotherapy . Post WCLC (&...

NSCLC Immunotherapy

Post WCLC (& ECCO/ESMO) 2015

Solange Peters, MD-PhD Oncology Department & Ludwig Institue CHUV Lausanne Switzerland

Hanahan & Weinberg. Cell 2011

Evading growth

suppressors Enabling

replicative immortality

Tumour- promoting

inflammation

Activating invasion & metastasis

Genome instability mutation

Resisting cell

death

Degrading cellular

energetics Sustaining

proliferative signalling

Inducing angiogenesis

PD-1

PDL-1

Avoiding immune

destruction

Therapeutic Intervention at Cancer Hallmarks

CTLA-4

To make a long story short...

CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab)

APC – T-cell Interaction

Activation (cytokine secretion, lysis,

proliferation, migration to tumor)

Tumor Microenvironment

Dendritic cell T cell Tumor cell

MHC

TCR TCR

PD-L1

PD-L2

MHC

PD-1

PD-1

B7

B7 CD28

CTLA-4

anti-CTLA-4

+++

---

+++ T cell +++

---

---

anti-PD-1

anti-PD-1

Many checkpoints representing immune synapses have been identified as potential targets

Mellman , Nature 2011

PD-1 axis immunotherapy for NSCLC

1) A new generation of expanded phase 1/2 trials for activity evaluation 2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients

• Tumour mutation load • PD-L1 expression • Tumour infiltrating lymphocytes • Tumour molecular characteristics

4) Upfront perspectives for checkpoint inhibitors

Clinical Development of Inhibitors of PD-1 Immune Checkpoint

PD-1 Nivolumab BMS-936558

Fully human IgG4 mAb Bristol-Myers Squibb Phase III

Pidilizumab CT-011

Humanized IgG1 mAb CureTech Phase II

Pembrolizumab MK-3475

Humanized IgG4 mAb Merck Phase III

AMP-224 Recombinant PD-L2-Fc fusion protein

GlaxoSmithKline Phase I

PD-L1 BMS-936559 Fully human IgG4 mAb Bristol-Myers Squibb Phase II

Durvalumab MedI-4736

Engineered human IgG1 mAb

MedImmune Phase III

Atezolizumab MPDL-3280A


Genentech Phase III

Avelumab MSB0010718C


EMD Serono Phase III

Phase I design modifications

Soria, ECCO/ESMO 2015

Pembrolizumab Phase I Study as an illustration

PN-001, Phase I study, began in 2011

Initially a 32 patient study

Actually enrolled over 1260 patients

Became basis for FDA Breakthrough designation in melanoma + lung cancer

NCT01295827

OS in Nivolumab phase 1 (3yrs FU)

• Pts were heavily pretreated; 54% had 3–5 prior therapies Gettinger, JCO 2015

Pembrolizumab phase 1 data

• Pretreated pts. Same efficacy 2mg or 10mg/kg • Lower ORR in patients with liver metastases: 13.6% vs 21.2%

Soria, ESMO 2015

Pembrolizumab phase 1 data

Hellmann, WCLC 2015

Pembrolizumab long-term phase 1 FU

Soria, ESMO 2015 FU 16 months

Pembrolizumab and brain activity

•18 patients had sufficient follow-up time for response evaluation •Brain metastasis response rate and systemic response rate were both 33% •All patients with a systemic response also had a CNS response, except for 1

Goldberg, WCLC 2015

Atezolizumab Phase 2 BIRCH trial

Besse, ESMO 2015

Besse B, et al, atezolizumab in NSCLC (BIRCH)

BIRCH: Objective Response Rate TC3 or IC3 Subgroup vs TC2/3 or IC2/3 Subgroup by Cohort

0

10

20

30

1L 2L 3L+

26% 24%

27%

19% 17% 17%

8

Enriched clinical benefit was observed in TC3 or IC3 patients ORR data were similar using RECIST V1.1 or mRECIST criteria Responses were observed in patients with EGFR or KRAS mutations, although patient numbers were small

TC2/3 or IC2/3 TC3 or IC3

OR

R, %

N=115 N=253 N=267 N=139 N=65 N=122


Progression-free Survival by IRF per RECIST v1.1

Line of Therapy PD-L1 Status

Median PFS (95% CI), mo

6-month PFS Rate

3L+ TC3 or IC3 4.2 (2.8, 5.6) 39%

3L+ TC2/3 or IC2/3 2.8 (2.7, 3.7) 31%

2L TC3 or IC3 4.1 (1.8, 5.5) 34%

2L TC2/3 or IC2/3 2.8 (1.5, 3.5) 29%

1L TC3 or IC3 5.5 (2.7, 8.3) 48%

1L TC2/3 or IC2/3 5.5 (3.0, 6.9) 46%

12 Data cut-off May 28, 2015.


BIRCH: Overall Survival by Cohort TC2/3 or IC2/3 Subgroup

Data cut-off May 28, 2015.

Subgroup Median OS, mo (95% CI)

6-mo OS, %

Cohort 1 (1L) 14.0 (14.0, NE) 82%

Cohort 2 (2L) NE (11.2, NE) 76%

Cohort 3 (3L+) NE (8.4, NE) 71%

19


BIRCH: Overall Survival by Cohort TC3 or IC3 Subgroup

20 Data cut-off May 28, 2015. 11

Subgroup Median OS, mo (95% CI)

6-mo OS, %

Cohort 1 (1L) NE (10.4, NE) 79%

Cohort 2 (2L) NE (10.6, NE) 80%

Cohort 3 (3L+) NE (NE, NE) 75%

Activity in pretreated patients Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab

N 129 475 175 228 184

RR Squamous

Non Sq.

17% 18%

23.5% 19%

27% 21%

21% 13%

14%

Drug rel AE

All grades Grade 3/4

41% 4.7%

71% 9.5%

66% 11%

50% 8%

77% 12%

RR PDL-1 + PDL-1 -

16% 13%

42% (>50%) 10% (<1%)

34% IC2/3 or TC 2/3 (half

if 3 used)

Gettinger S, J Clin Oncol 2015; 33: 2004-2012; Herbst R, Nature 2014; 515: 563-7; Soria JC, ESMO 2013; Garon E, NEJM 2015; 372: 2018-28; Rizvi N, ASCO 2015; Guley LJ, ASCO 2015

Proportion of high expressors?

Agent Atezolizumab1 Pembrolizumab Nivolumab3,4

Highest PD-L1+ cut-off TC3 or IC3 TC ≥50% TC ≥10%

Trial/ Analysis

MDACC and UCCC tumor specimens1

POPLAR2 KEYNOTE-0013 CheckMate 0574

CheckMate 0175

Total samples 698 287 91 582 272

Positive based on cut-off

26% 16% 29.7% 12.4% 25.4%

MDACC=MD Anderson Cancer Center; UCCC=University of Colorado Cancer Center. 1. Gettinger SN, et al. Presented at: ASCO; May 29-June 2, 2015, Abstract 3015. 2. Spira A, et al. Presented at: ASCO; May 29-June 2, 2015, Abstract 8010. 3. Rizvi N et al. Presented at ASCO; May 29-June 2, 2015, Abstract 8026. 4. Paz-Ares L,, et al. Presented at: ASCO; May 30-June 3, 2014; Chicago, Illinois. Abstract LBA 109. 5. Brahmer J, et al. N Engl J Med. 2015 May 31. [Epub ahead of print].

A consistant and significant tail of the curve across trials

Soria, ESMO 2015 FU 16 months

Anti-PD1/PDL1 mAB: key-lessons for phase 1/2 trials

• Inability to identify a maximum tolerated dose (outside

CTLA4) – favorable toxicity profile in general • Lack of Dose –Response relationship • Huge variety of doses and schedules evaluated upfront (flat

doses) • Benefit possibly better translated in OS data than RR or PFS • Optimal duration of therapy not defined

• Like “vaccines”, a limited nb of boost sufficient to trigger a durable immune response?

• Selection based on PD-L1 expression as a enrichment for better outcome data. A matter of discussion


1) A new generation of expanded phase 1/2 trials for activity evaluation

2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients



Second line single agent chemotherapy improves survival

The database for a survival advantage of 2nd line chemotherapy is small and based on only one study of docetaxel vs BSC

Shepherd, J Clin Oncol 2000

Poplar: atezolizumab vs docetaxel Randomized phase 2

Vansteenkiste, ESMO 2015

Both PD-L1 expression on TC and IC are independent predictors of overall survival

Vansteenkiste & Schmid ESMO 2015

Primary Objective • Overall survival (OS) Secondary Objectives • ORR • PFS • ORR and OS by PD-L1 status • Duration of OR • Time to OR • Proportion of patients exhibiting disease-

related symptom progression (Lung Cancer Symptom Scale)

Docetaxel

Nivolumab

Docetaxel

Nivolumab

CA209-017 NCT01642004

(Phase 3; N = 264)

Patients with stage IIIb/IV squamous

cell NSCLC

CA209-057 NCT01673867

(Phase 3; N = 574)

Patients with stage IIIb/IV

non-squamous cell NSCLC

Nivolumab phase III trial

Squamous & non-squamous 2nd line vs docetaxel

16th World Conference on Lung Cancer, September 6-9, 2015 ̶ Denver, CO, USA

Overall Survival Nivolum

ab n=135

Docetaxel n=137

mOS mo (95% CI)

9.2 (7.33, 12.62)

6.0 (5.29, 7.39)

# events 103 122

HR=0.62 (0.48, 0.81); P=0.0004

Minimum follow-up for survival: 18 months • Survival was monitored until death or withdrawal of consent

Docetaxel 18-month OS rate=13%

OS

(%)

Time (months)

0 6 14 25 37 51 57 69 86 113 135 0 Nivolumab Number of Patients at Risk

0 4 7 11 17 22 33 46 69 104 137 Docetaxel 1

Nivolumab 18-month OS rate=28%

100

90

80

70

60

50

40

30

10

0

20

33 27 24 21 18 15 12 9 6 3 0 30

RR: 20% vs 9%

Reckhamp, WCLC 2015

16th World Conference on Lung Cancer, September 6-9, 2015 ̶ Denver, CO, USA

Efficacy by PD-L1 Expression

Based on December 2014 DBL

18th ECCO ̶ 40th ESMO European Cancer Congress, September 25-29, 2015, Vienna, Austria Note: this draft is currently undergoing editorial review and QC

DRAFT: Highly Confidential

12-mo OSa 18-mo OSb

Nivo (n = 292) Doc (n = 290) Nivo (n = 292) Doc (n= 290)

mOS, mos 12.2 9.4 12.2 9.4

1-year OS rate, % 51 39 51 39

18-mo OS rate, % – – 39 23

No. of events, n/N 190/292 223/290 206/292 236/290

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

HR (95% CI) = 0.72 (0.60, 0.88) Post-hoc P = 0.0009c

Overall Survival

• Minimum follow-up for 12-mo OS rate, 13.2 mos; for 18-mo OS rate, 17.1 mos

100

90

80

70

60

50

40

30

10

0

20

27 18 15 9 6 21 12 3 0 24 30

Nivolumab Docetaxel

Number of patients at risk (18-mo OS)b 292 233 195 171 148 128 107 55 4 27 290 244 194 150 111 89 61 23 4

0 0 6

Nivolumab Docetaxel

Nivolumab Docetaxel

Number of patients at risk (12-mo OS)a 292 232 194 169 146 123 62 32 0 9 290 244 194 150 111 88 34 10 0 5

18-mo OS rate = 23%

18-mo OS rate = 39%

1-yr OS rate = 39%

1-yr OS rate = 51%

Time (Months)

OS

(%)

RR: 12% vs 9%

Horn, ESMO 2015

18th ECCO ̶ 40th ESMO European Cancer Congress, September 25-29, 2015, Vienna, Austria Note: this draft is currently undergoing editorial review and QC

DRAFT: Highly Confidential

OS by Baseline PD-L1 Expression PD-L1 expression level

Nivo n

Doc n

Unstratified HR (95% Cl)

Interaction 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 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 61 66 1.06 (0.73, 1.56)

Based on a March 18, 2015 DBL aInteraction p-value from Cox proportional hazard model with treatment, PD-L1 expression and treatment by PD-L1 expression interaction

PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable

1.0 0.5 2.0 0.25 Nivo Doc

Horn, ESMO 2015

Lets discuss toxicty…

Toxicité Nivolumab squamous %

Docetaxel squamous %

Afatinib squamous %

Docetaxel / Ramucirumab %

All 59 87 93 98

Grade 3-4 8 58 57 79

Grade 5 0 2 2 5

Peters, WCLC 2015

Toxicities are observed early in the course of treatment

Reckhamp, WCLC 2015

Nivolumab is safe in PS 2 Community-based real-life trial

• PS 2 patients do not present with more AEs • Short FU (median 10.4 weeks), but most side effects

observed early

Hussein , WCLC 2015

18th ECCO ̶ 40th ESMO European Cancer Congress, September 25-29, 2015, Vienna, Austria

Squamous : EQ-5D Utility Index Mean Scores Over Time While on Treatment

Lung Cancer Norm (UK-based): 0.67b

Mea

n EQ

-5D

Util

ity In

dex

Scor

e

97 50 32 32 21 18 13 13 8 Nivolumab (n = 97)

88 32 9 5 5 4 4 2 1 Docetaxel (n = 89)

0 12 24 30 36 42 48 54 60

1.0

0.9

0.8

0.7

0.6

0.5

0.4

Population Norma

Docetaxel Nivolumab

aBharmal M, Thomas J 3rd. Value Health. 2006;9:262–71. bPickard AS, et al. Health Qual Life Outcomes. 2007;5:70. 39

Higher scores indicate better health status. Only time points that had PRO data available for ≥5 patients in either treatment arm are plotted on the graph.

Week


1) A new generation of expanded phase 1/2 trials for activity evaluation



4) Upfront for checkpoint inhibitors

Mutation load counts, but is not realistic in our daily practice

Rizvi, Science 2015

Efficacy also correlates with the molecular smoking signature characteristic of squamous carcinoma

Intricate role of PD-1 signalling with different cell types

Image from J. Allison

PD-L1 positivity is a flexible concept

Limitations in defining PD-L1 as the biomarker

•PD-L1 “biomarker” is to be defined (mAB, platform & technique, criteria & thresholds, tumour material & sampling)

•PD-L1 expression is dynamic

•PD-L1 is heterogeneous within tissue

•Cytoplasmic vs membranous?

•Quality of the biopsy

•Importance of co-localization with TILs

•We dont know how to handle a continuous variable as a biomarker and need a prospective validation!

PD-L1 as a biomarker

0

2

4

6

8

10

12

0 10 20 30 40 50 60 70 80 90 100

PD-L1 IHC score

‘Negative’ ‘Positive’

Response?

Differential effects depend upon the Dose-response relationship

What do we know about T-cells infiltration in NSCLC

Liu H et al. Cancer Immunol Immunother 2012

Presence of TILs associated with increased recurrence-free survival1

Recu

rren

ce-F

ree

Surv

ival

(%)

Survival Time (Months) 24 36 12 48 60 0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

FoxP3+ cell <3 FoxP3+ cell ≥3 Re

curr

ence

-Fre

e Su

rviv

al (%

) 1.0

0.8

0.6

0.4

0.2

0.0 0.0 10 20 30 40 50 60

Survival Time (Months)

TIL– TIL+

P=0.011

Higher NSCLC-Infiltrating Tregs associated with worse recurrence-free survival2

1. Shimizu K, et al. J Thorac Oncol. 2010 2. Horne ZD, et al. J Surg Res. 2011

TILs must be further characterized. Tissue is a limiting factor!

High Tumor Teff gene signature Is associated with improved

OS benefit with atezolizumab

Teff: CD8A, GZMA, GZMB, IGN-γ, EOMES, CXCL9, CXCL10, TBX21 Schmid, ECCO 2015

PD-L2/B7

• High expression of each component of the axis is associated with improved OS with atezolizumab.

• Blocking PD-1/PD-L1 signaling in highly immunologically dysfunctional tumors my be capable of reversing T-cell exhaustion and improving clinical benefit.

Schmid, ECCO 2015

Response with durvalumab according to PD-L1 and IFNγ mRNA status

Higgs, et al. ECC 2015

Are we ready to select patients ?

Schreiber, Science. 2011

Complexity of immune surveillance and escape might prevent us from identifying a simple & unique predictive biomarker.

Checkpoint inhibitors in « oncogene-addicted » NSCLC ?

MK-3475 N ORRa % (95% CI)

EGRFR mutation 36 14 (5-30)

ALK rearrangement 6 17 (0-64)

Gettinger, ASCO 2014 Garon, ESMO 2014 Horn, WLCC 2013

The real-life study…

ALK treated patients represent a very small subset today. However, ALK protein might represent an interesting neo-antigen. Hussein , WCLC 2015

Need to induce T-cell response •Combinations with other immunotherapy strategies: checkpoints modulators/ TLR agonists / oncolytic viruses /cytokines / vaccines /targeted therapies • What about chemotherapy?

Do we expect a potential role for immunotherapy in

this patient population?

Functional MHC class 1 presentation AND Probably (but not exclusively): -PD-L1 positivity AND/OR -Specific TILs tumour infiltration AND/OR -High mutation load (smoking, mismatch repair…) AND/OR -Expression of potent neo-antigens AND/OR -Others: interferon signature, …?

Are we confident in accurately identifying

these patients?


1) A new generation of expanded phase 1 trials for activity evaluation




Focus on pembrolizumab first line data (Keynote 001)

Median PFS was 6.1 months in all treated patients and 12.5, 4.2 and 3.5 mos in >50%,1-49% and <1% resp. OS was not reached in all treated patients or in patients with ≥50% staining 16.2 months and 10.4 in patients with staining in 1%–49% and <1% of cells,

respectively

Rizvi, ASCO 2015

CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC

Primary endpoint: safety and tolerability Secondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24 wks Exploratory endpoints: OS; efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced disease; ECOG PS 0 or 1

Nivo 3 mg/kg IV Q2W until disease progression or unacceptable toxicitya

Nivo 1 mg/kg IV Q3W x 4 +

Ipi 1 mg/kg IV Q3W x 4

Nivo 1 mg/kg IV Q2W +

Ipi 1 mg/kg IV Q6W


Ipi 1 mg/kg IV Q12W


Ipi 1 mg/kg IV Q6W

Until disease progression or unacceptable toxicitya

• Here, we report results from new cohorts explored to permit synergistic activity and acceptable safety profile of combination treatment with nivolumab and ipilimumab

aPatients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit 59

• There were no treatment-related deaths. Toxicities mailnly GI, hepatic, endocrine, skin, lung

Nivo 1 + Ipi 1 Q3W

(n = 31)

Nivo 1 Q2W + Ipi 1 Q6W

(n = 40)


(n = 38)


(n = 39)

Nivo 3 Q2Wa

(n = 52)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Treatment-related AEs, % 77 29 73 35 74 29 69 28 71 19

Treatment-related AEs leading to discontinuation, % 13 10b 8 8c 5 3d 10 10e 10 10f

Nivolumab Median number of doses (range) Median duration of therapy, wks (range)

4

(1–42) 12.0

(3.0–92.0)

7

(1–26) 16.0

(2.0–59.0)

13

(1–26) 28.7

(2.0–52.0)

8

(1–25) 18.0

(2.0–53.0)

8

(1–62) 16.0

(2.0–129.6)

Ipilimumab Median number of doses (range) Median duration of therapy, wks (range)

NC

1–4g

11.6 (3.0–24.0)

3

(1–9) 17.6

(6.0–59.0)

3

(1–5) 35.7

(12.0–60.0)

2

(1–9) 15.0

(6.0–54.0)

NA

NA

Nivo 1 + Ipi 1 Q3W

(n = 31)


(n = 40)


(n = 38)


(n = 39) Nivo 3 Q2Wa

(n = 52)

Confirmed ORR, % (95% CI) 13 (4, 30)

25 (13, 41)

39 (24, 57)

31 (17, 48)

23 (13, 37)

Confirmed DCR, % (95% CI) 55 (36, 73) 58 (41, 73) 74 (57, 87) 51 (35, 68) 50 (36, 64)

Best overall response, %

Complete response Partial response

Unconfirmed partial response

0 13 3

0 25 3

0 39 5

0 31 8

8 15 0

Stable disease Progressive disease Unable to determine

42 35 6

33 30 10

34 13 8

21 26 15

27 38 12

PFS rate at 24 wks, % (95% CI) 55 (36, 71) NC 63 (44, 76) NC 41 (27, 54)

Median PFS, mos (95% CI) 10.6 (2.1, 16.3) 4.9 (2.8, ) 8.0 (4.2, ) 8.3 (2.6, ) 3.6 (2.3, 6.6)

Median OS, mos (95% CI) NR (11.5, ) NR (8.9, ) NR NR (8.7, ) 22.6 (14.9, )

Median length of follow-up, mos (range)

16.6 (1.8–24.5)

6.2 (0.4–13.1)

8.4 (0.9–12.3)

7.7 (1.1–12.2)

14.3 (0.2–30.1)

Summary of Efficacy

61 NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up. aResults for Nivo 3 Q2W are reported based on a March 2015 DBL

• Median DOR was not reached in any arm • Unconventional immune-related responses were observed in arms Nivo 3 Q2W + Ipi 1 Q12W (n = 2), Nivo 3 Q2W + Ipi 1 Q6W (n = 1) and

Nivo 3 Q2W (n = 3)

Efficacy by Tumor PD-L1 Expression

62

≥1% PD-L1 expression <1% PD-L1 expression

Nivo 1 + Ipi 1 Q3W

(n = 12)

Nivo 1 Q2W

+ Ipi 1 Q6W

(n = 21)

Nivo 3 Q2W

+ Ipi 1 Q12W

(n = 21)

Nivo 3 Q2W

+ Ipi 1 Q6W

(n = 23)

Nivo 1 + Ipi 1 Q3W

(n = 13)

Nivo 1 Q2W

+ Ipi 1 Q6W

(n = 7)

Nivo 3 Q2W

+ Ipi 1 Q12W (n = 9)

Nivo 3 Q2W

+ Ipi 1 Q6W

(n = 7)

ORR, % 8 24 48 48 15 14 22 0

mPFS, wks (95% CI)

11.5 (7.1, )

21.1 (11.4, )

34.6 (15.9, 35.3)

NR (15.4, )

34.0 (8.9, )

NR (10.1, )

23.1 (4.0, )

10.3 (7.4, 12.7)

PFS rate at 24 wks, % (95% CI)

42 (15, 67)

40 (18, 61)

74 (48, 88)

65 (42, 81)

57 (25, 80)

NC

39 (9, 69)

0

NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up

• All patients had available pretreatment tumor samples; 76% (113/148) had samples evaluable for PD-L1 expression • Median DOR was not reached in any arm, regardless of PD-L1 expression

Phase Ib GP28328 Atezolizumab and chemotherapy study design

• Primary endpoint: safety (including dose-limiting toxicities) • Secondary endpoints: pharmacokinetics; best overall response; objective response rate (ORR); duration of

response (DOR); progression-free survival (PFS) • Date of cut-off: 10 Feb 2015; median safety follow-up: 128.5 days (4.2 months)

Atezolizumab 15mg/kg i.v. q3w + carboplatin AUC=6 i.v. q3w + paclitaxel 200mg/m2 i.v. q3w (4–6 cycles)*

Atezolizumab 15mg/kg i.v. q3w + carboplatin AUC=6 i.v. q3w (4–6 cycles) + pemetrexed 500mg/m2 i.v. q3w

(maintenance pemetrexed permitted)*

Solid tumours ECOG PS 0–1 (n=58 NSCLC cohort at data cut-off; n=25

per arm planned)

Atezolizumab 15mg/kg i.v. q3w + carboplatin AUC=6 i.v. q3w + nab-paclitaxel 100mg/m2 i.v. q1w (4–6 cycles)*

Arm C: NSCLC

Arm D: NSCLC

Arm E: NSCLC

Camidge, WCLC 2015

Summary of response by RECIST v1.1 (response-evaluable patients*)

• Data are preliminary; ~25 patients will be included in each arm for final analysis

Arm C – cb/pac (n=8)

Arm D – cb/pem (n=17)

Arm E – cb/nab (n=16)

All NSCLC patients (n=41)

Overall response, n (ORR %) 4 (50.0) 13 (76.5) 9 (56.3) 26 (63.4)

[95% CI for ORR] [15.7–84.3] [50.1–93.2] [29.9–80.3] [46.9–77.9]

Complete response, n (%) 0 (0) 0 (0) 4 (25.0) 4 (9.8)

Partial response, n (%) 4 (50.0) 13 (76.5) 5 (31.3) 22 (53.7)

Stable disease, n (%) 4 (50.0) 1 (5.9) 4 (25.0) 9 (22.0)

Progressive disease, n (%) 0 (0) 2 (11.8) 2 (12.5) 4 (9.8)

Missing or not evaluable, n (%) – 1 (5.9) 1 (6.3) 2 (4.9)

Depth of response and changes in tumor burden by treatment arm

Arm C – cb/pac (n=8) Arm D – cb/pem (n=17) Arm E – cb/nab (n=16)

No unexpected toxicity!

Max

imum

SLD

redu

ctio

n fr

om b

asel

ine

(%)

100

50

0

–50

–100

9 –7

Complete response Partial response Progressive disease Stable disease

–12

–31 –31 –38 –41 –42 –47 –50 –53 –57 –57 –57 –58

–69 Max

imum

SLD

redu

ctio

n fr

om b

asel

ine

(%)

100

50

0

–50

–100

–16 –22 –23 –25

–43 –45

–64

–84


0 42 84 126 168

Time on study (days)

210 252 294 336 378 420 450

–100

–80

–60

–40

–20

0

20

40

60

80

100 PD (n=2) PR/CR (n=13) SD (n=1) Progression* Discontinued New lesion

Max

imum

SLD

redu

ctio

n fr

om b

asel

ine

(%)

100

50

0

–50

–100

11 9


–17

–21 –21 –22 –43

–67 –72 –72 –76

–86 –87

–100 –100

0 42 84 126 168


210 252 294 336 378 420 450

–100

–80

–60

–40

–20

0

20

40

60

80

100 PD (n=2) PR/CR (n=9) SD (n=4) Progression* Discontinued New lesion

Cha

nge

in S

LD fr

om b

asel

ine

(%)

0 42 84 126 168


210 252 294 336 378 420 450

–100

–80

–60

–40

–20

0

20

40

60

80

100 PR/CR (n=4) SD (n=4) Progression* Discontinued New lesion

Cha

nge

in S

LD fr

om b

asel

ine

(%)

Cha

nge

in S

LD fr

om b

asel

ine

(%)

Chemotherapy combination trials GP28328

PhIb solid tumours (incl. 1L NSCLC) atezo + chemo

(n=58)

KEYNOTE-021 PhI/II 1L NSCLC

pembro + chemo (n=49)

CheckMate 012 PhI 1L NSCLC

nivo (N) + chemo (n=56)

CheckMate 012 PhI 1L NSCLC

nivo (N) + ipi (I) (n=49)

Atezo + carbo/

pac

Atezo + carbo/ pem

Atezo + carbo/ abrax

Pembro + carbo/

pac

Pembro + carbo/ pem

N10 + gem/ cis

N10 + pem/ cis

N10 + carbo/

pac

N5 + carbo/

pac

N1 q3w +

I1 q3w

N1 q2w +

I1 q6w

N3 q2w +

I1 q12w

N3 q2w +

I1 q6w

n 8* 17* 16* 25 24 12 15 15 15 31 40 38 39

ORR, %

Grade 3–4 treatment-

related AEs

69% 35% 45%

71% 54% 85% 32% 38% 25% 47% 73% 29%

29%

35%

29%

28%

0

25

50

75

100

50

77

56

28

58

33 47 47 43

13 25

39 31

Refs.

Camidge, et al. WCLC 2015

Giaccone, et al. ECC 2015

Papadimitrakopoulos, et al. ASCO 2015

Gettinger, et al. ESMO 2014

Rizvi, et al. WCLC 2015

Phase III trials in 1st-line advanced NSCLC (selected)

Nivolumab

Pembrolizumab

MEDI4736

SOC=standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed August 2015.

KEYNOTE-042 Pembrolizumab

SOC chemotherapy Primary endpoint: OS PD-L1+ NSCLC

N = 1240

Primary endpoints: OS, PFS

Treatment-naïve or recurrent NSCLC N = 1980 CheckMate 227

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Primary endpoint: PFS Treatment-naïve or recurrent PD-L1+ NSCLC N = 535 CheckMate 026

Nivolumab

Investigator’s choice chemotherapy

KEYNOTE-024 Pembrolizumab

Platinum-based chemotherapy Primary endpoint: PFS PD-L1 strong NSCLC

N = 300

Atezolizumab

IMpower 111 Atezolizumab

Gemcitabine + cisplatin or carboplatin Primary endpoint: PFS Stage IV squamous PD-L1+ NSCLC

N = 400

IMpower 150

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint: PFS Stage IV non-squamous NSCLC N = 1200

Atezolizumab + bev. + paclitaxel + carboplatin

IMpower 130 Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel Primary endpoint: PFS Stage IV non-squamous NSCLC

N = 550

IMpower 110 Atezolizumab

Carboplatin or carboplatin + pemetrexed Primary endpoint: PFS Stage IV non-squamous PD-L1+

NSCLC N = 400

IMpower 131

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint: PFS Stage IV squamous NSCLC N = 1200

Atezolizumab + carboplatin + paclitaxel

Primary endpoint: PFS Advanced NSCLC N = 675

MYSTIC

MEDI4736

MEDI4736 + tremelimumab

SOC chemotherapy

IPI + Paclitaxel/Carboplatin IPI

Pbo + Paclitaxel/Carboplatin Pbo Primary endpoint: OS Squamous NSCLC

N = 920 CA184-104

IPI + Paclitaxel/Carboplatin IPI

Pbo+ Paclitaxel/Carboplatin Pbo Primary endpoint: OS Squamous NSCLC

N = 867 CA184-153

Ipilimumab

Anti-

PD-1

/PD

-L1

Anti-

C

TLA-

4

Thanks for your attention

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