immunotherapy in nsclc: where do we stand€¦ · comparative studies 11 | toxicity gade % of...

Immunotherapy in NSCLC:Where do we stand

Rolf StahelUniversity Hospital of Zürich

1 |

Amsterdam, 26.5.2017

Several PD-1/PD-L1 inhibitors are being evaluated in NSCLC2 |

PD-1 Nivolumab

BMS-936558

Fully human IgG4 mAb Bristol-Myers Squibb Phase III

Pembrolizumab

MK-3475

Humanized IgG4 mAb Merck Phase III

Pidilizumab

CT-011

Humanized IgG1 mAb CureTech Phase II

PDR001 Humanized IgG4 mAb Novartis Phase II

AMP-224 Recombinant PD-L2-Fc fusion

protein

GlaxoSmithKline Phase I

MEDI-0680 Humanized IgG4 mAb Medimmune - AZ Phase I

REGN2810 Humanized IgG4 mAb Regeneron/Sanofi Phase I

PD-L1 Durvalumab

MedI-4736

Engineered human IgG1

mAb

MedImmune - AZ Phase III

Atezolizumab

MPDL-3280A

Engineered human IgG1

mAb

Genentech Phase III

Avelumab

MSB0010718C

Engineered human IgG1 mAb EMD Serono Phase III

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

The complexity of the LD-L1 diagnostics of NSCLC3 |

Nivolumab: BMS

Pembrolizumab: Merck

Atezolizumab: Roche

Durvalumab: AstraZeneca

Avelumab:

Pfizer

Ab Clone 28-8 SP263 22C3 SP142 SP263 73-10

Diagnostic Partner Dako Ventana Dako Ventana Ventana Dako

Scoring Method † % of PD-L1–expressing tumour cells

% of PD-L1–expressing tumour cells

% of PD-L1–expressing

tumour cells or immune cells

% of PD-L1–expressing tumour cells

% of PD-L1–

expressing tumour

cells

Diagnostic Status

Complementary:

testing not required

Companion:

testing required

US/EU: SQ and

NSQ NSCLC

Dx not approved

for NSCLC setting

Dx not approved

for durvalumab in

any setting

Dx not approved

for avellumab in

any settingUS/EU:

NSQ NSCLC

EU:

NSQ NSCLC

Approved IVD

PD-L1 Threshold

US/EU:

All patients

eligible

EU:

All patients

eligible

US: ≥50%

EU: ≥1%NA NA NA

PD-L1 Thresholds

≥1% (pos), ≥5% (strong), or

≥10%

Validated

≥1% (pos)

≥50% (strong)

Validated

TC / IC 3(+)

TC / IC 2(+)

TC / IC 1(+)

TC / IC 0(−)

TC

PD-L1(+): ≥ 25%

TBC, TC between

all >1% and 25%

with moderate or

high intensity

Relationship between level of PD-L1 expression and outcomes in the KEYNOTE-010 trial

4 |

Baas, ASCO 2016

Example of PD-L1 tumor expression5 |

22C3 28-8 SP263 SP142

Not only technical validation, also clinical validation requiredNot all antibodies are created equal

Hirsch, AACR 2016

Analytical evaluation results: Mean TPS per case based on 3 readers: Tumor cells

6 |

22C328-8SP142SP263

1009080706050403020100

391 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37

CasesHirsch, AACR 2016

• Analytical comparison of TPS by case for each assay

• Data points represent the mean score from 3 pathologists for each assay on each case

• No clinical diagnostic cutoff applied

• Conclusion: 3 of 4 assays are analytically similar for tumor cell staining

Checkmate 017 and 057: 2-years update of OAS(no biomarker selection),

7 |

Borghael, ASCO 2016

* No biomarker selection

* *

Checkmate 017 and 057: 2-years update PFS(no biomarker selection)

8 |

Borghael, ASCO 2016

Checkmate 057: OS by PD-L1 Expression9 |

mOS (mos)Nivo 17.7Doc 9.0






≥1% PD-L1 expression level

Time (Months)

100

90

80

70

60

50

40

30

10

0

20

3024211815129630 27

OS

(%

)

NivoDoc

HR (95% CI) = 0.58 (0.43, 0.79)

≥5% PD-L1 expression level100

90

80

70

60

50

40

30

10

0

20

3024211815129630 27

Time (Months)

HR (95% CI) = 0.43 (0.30, 0.62)

≥10% PD-L1 expression level100

90

80

70

60

50

40

30

10

0

20

3024211815129630 27

Time (Months)

HR (95% CI) = 0.40 (0.27, 0.58)

<1% PD-L1 expression level100

90

80

70

60

50

40

30

10

0

20

3024211815129630 27

Time (Months)

OS

(%

)

NivoDoc


90

80

70

60

50

40

30

10

0

20

3024211815129630 27

Time (Months)


90

80

70

60

50

40

30

10

0

20

3024211815129630 27

Time (Months)

HR (95% CI) = 0.87 (0.63, 1.19) HR (95% CI) = 0.96 (0.73, 1.27) HR (95% CI) = 0.96 (0.74, 1.25)

Based on a July 2, 2015 DBL. Symbols represent censored observations EMA Opdivo Product Characteristics

KEYNOTE 10: Pembrolizumab versus doxetaxel in 2nd lineNSCLC (≥1% of tumor cells PD-L1 positive)

10 |

Herbst, ESMO Asia 2015, Lancet 2016

Less toxicity with immune checkpoint inhibitors in second line comparative studies

11 |

ToxicityGade

% of patients

Check-mate 17 Checkmate 57 KEYNOTE 10

N Doc N Doc P2 P10 Doc

All 59 87 69 88 63 66 35

3-5 8 60 10 54 13 16 79

OAK: A randomized phase III study comparing atezolizumabwith docetaxel in advanced NSCLC

12 |

Barlesi, ESMO 2016

Mutational load and outcome of immune checkpoint inhibitor therapies in NSCLC

13 |

Rizvi, Science 2015

PTML: Predicted total mutation load

Roziak, BMJ Med 2016

Treatment effect on overall suvival in Checkmate 57 and KEYNOTE 10

14 |

Borghaei. NEJM 2015; Herbst Lancet 2015

Case study, R.M. 1952

• June 2015 Diagnosis: Pleomorphic carcinoma RUL, clinical state stage T3N1M1 (bone)

• July-Augurst 2015: 3 cycles of cisplatin and gemcitabine• 28.08.2015 Re-Staging: progression in bone

15 |

08/1506/15

Case study, R.M. 1952

• 29.09.2015 Right upper lobe resection ypT3 ypN1 (1/8)• 06.11.2015 Re-Staging: progression bone, LN

16 |

November 2015 RT Sacrum, paravertebral, Os 14.12.2015 Nivolumab, on the 14.12. and 28.12.2015

Case study, R.M. 195217 |

Emergency hospitalisation 05.01.2016

• PiO2 67%; no fever, ECOG 3-4• CRP 115, LDH 680; Leucocytes 11 G/l

• Methylprednisolon 250mg iv (1d)• Prednison 200mg (2d), 100mg (2d), 50mg (3d), 25mg (3d), 20mg (3d),

10mg (2d), 5mg (2d)• Tazobac +Bactrim

Case study, R.M. 195218 |

Feb 2016, June 2016, Nov 2016, March 2017Nov 2015

Pembrolizumab for patients with melanoma or NSCLC anduntreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial

19 |

Goldberg, Lancet Oncol 2016

Durable clinical benefit in patients PD-L1–Expressing NSCLC who completed pembrolizumab (from KEYNOTE-010)

20 |

Pleateau above 30% emerging Clinical benefit of pembrolizumab is durable after 2 years of treatment

Herbst, WCLC 2016

Immune checkpoint inhibitors in second line NSCLC

• Immune checkpoint inhibition provides a survival benefit as compared to second line chemotherapy

• The safety profile is superior to the safety profile of chemotherapy

• Patient-reported outcomes suggest a stable or improved health status while on treatment

• The optimal duration of therapy is an important issue in need to be addressed

• Biomarker selection also in second line?

21 |

Are we ready to use biomarkers for selection of patients fortreatment with immune checkpoint inhibitors in NSCLC?

• PD-L1 expression is a – albeit imperfect - biomarker. It needs further prospective clinical validation in addition to laboratory validation. However, evolving data on the first line use of immune checkpoint inhibitors suggests its use as biomarker to become become routine practice

• Other evolving biomarkers not yet suitable for clinical routine include:

• Co-localization with tumor infiltrating lymphocytes

• Immunologic signatures

• Neoantigen load

• In the presence of oncogenic driver mutations (and in non-smokers) the use of second line chemotherapy is preferable

22 |

ORR by PD-L1 expression levels in first line NSCLC with single agent PD-1 or PD-L1 directed antibody

23 |

OR

R (

%)

CheckMate 012 KN-001 BIRCH JAVELIN Solid TumorDurva(NCT01693562)

5044

28

14

23

58.3

17.410

2619

29

11

27

15.421.420

0

18.7

50

12.2

0

10

20

30

40

50

60

PD-L1 Cutoffs:

23

Results in treatment naïve patients with advancedNSCLC enrolled in KEYNOTE-001

24 |

Hui, ASCO 2016

25 | Phase 3 PD1/PD-L1 combination in 1L advanced NSCLC

Durvalumab

MYSTIC

Atezolizumab

Impower 110

An

ti-P

D-1

/PD

-L1

Nivolumab

CHECKMATE 227

Primary endpoints:

OS, PFS

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Treatment-naïve or recurrent NSCLC

N=1980

Atezolizumab

Gemcitabine + cisplatin or carboplatin

Primary endpoint:

PFS

Stage IV squamous PD-L1+ NSCLC

N=400

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint:

PFSAtezolizumab + bevacizumab + paclitaxel +

carboplatinStage IV non-squamous NSCLC

N=1200

Atezolizumab + carboplatin

+ nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint:

PFSStage IV non-squamous NSCLC

N=550

Atezolizumab

Carboplatin or carboplatin + pemetrexed

Primary endpoint:

PFSStage IV non-squamous PD-L1+ NSCLC N=400

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint:

PFSAtezolizumab + carboplatin + paclitaxel

Stage IV squamous NSCLC

N=1200

Primary endpoint:

PFS

Durvalumab

Durvalumab + tremelimumab

SOC chemotherapy

Advanced NSCLC

N=675

Durvalumab

NEPTUNEDurvalumab + Tremelimumab

SOC chemotherapy

Primary endpoint:

OSFirst-line metastatic NSCLC

N=800

Atezolizumab

Impower 111

Atezolizumab

Impower 130

Atezolizumab

Impower 131

Atezolizumab

Impower 150

Pembrolizumab

KEYNOTE-189Primary endpoints:

PFS

Pembrolizumab + pemetrexed/platinum

Pemetrexed/platinum

Treatment-naïve non-squamous NSCLC

N=580

Nivolumab

CHECKMATE 026

Nivolumab 3 mg/kg IV Q2W

ICCa with potential for crossover

Primary endpoint:

PFS


PD-L1–positive NSCLC

N=495

Pembrolizumab

KEYNOTE-042

Pembrolizumab 200 mg IV Q3W

SOC chemotherapy



N=1240

Primary endpoint:

OSICCa with potential for crossover

Pembrolizumab

KEYNOTE-024

Pembrolizumab 200 mg IV Q3W

Platin-based chemotherapy



N=305

Primary endpoint:

OS

KEYNOTE-024: Pembrolizumab vs platinum-basedchemotherapy as first-Line therapy for advanced NSCLC witha PD-L1 TPS ≥50%

26 |

Reck, ESMO 2016


27 |

Reck, ESMO 2016

Adenocarcinoma molecular pathology workup at University Hospital Zürich, including NGS

28 |


29 |

Reck, ESMO 2016

CheckMate 026: A phase 3 trial of nivolumab vs investigator's choice of platinum-based doublet chemotherapy as first-line therapy for stage IV/recurrent PD-L1 positive NSCLC

30 |

Socinski, ESMO 2016

CheckMate 026: A phase 3 trial of nivolumab vs investigator's choice of platinum-based doublet chemotherapy as first-line therapy for stage IV/recurrent PD-L1–positive NSCLC

31 |

Socinski, ESMO 2016

Impact of tumor mutation burden on the efficacy of first-line nivolumab in advanced NSCLC: An exploratory analysis of CheckMate 026

32 |

Whole exome sequencing a

Tumor DNA

GermlineDNA (blood)

Somatic missense mutations

Tumor exome data

Germline exome data

TMB

Sample size throughout TMB determination

Patients, n (%) Tumor DNA Germline DNA

Randomized 541 (100) 541 (100)

Samples available for DNA extraction a 485 (90) 452 (84)

DNA available for sequencing 408 (75) 452 (84)

Successful preparation of next-generation sequencing library

402 (74) 452 (84)

Passed internal quality control b 320 (59) 432 (80)

Matched tumor-germline exome sequences for TMB analysis c 312 (58)

aSamples were not available for various reasons, including but not limited to lack of patient pharmacogenetic consent, samples exhausted for PD-L1 testing, or poor tissue samplingbInternal quality control failure included factors such as discordance between tumor and germline DNA, too few sequence reads, and low or uneven target region coveragec8 patients with available tumor DNA sequences did not have matched germline DNA sequences

aDNA was sequenced on the Illumina HiSeq 2500 using 2 × 100-bp paired-end reads; an average of 84 and 89 million reads were sequenced per tumor and germline sample, respectively (average 84.6 × and 93 × the mean target coverage, respectively) Peters, AACR 2017

Impact of tumor mutation burden on the efficacy of first-line nivolumab in advanced NSCLC: PFS by mutation burden tertile

33 |

100

90

80

70

60

50

40

30

20

10

00 3 6 9 12

Months15 18 21 24

PF

S (%

)

High

Low

Medium

Mediumn = 49 n = 47

3.6(2.7, 6.9)

Lown = 62

4.2(1.5, 5.6)

9.7(5.1, NR)

Median PFS, months(95% CI)

High

Nivolumab Arm Chemotherapy Arm

Mediumn = 53 n = 60

6.5(4.3, 8.6)

Lown = 41

6.9(5.4, NR)

5.8(4.2, 8.5)

Median PFS, months(95% CI)

High100

90

80

70

60

50

40

30

20

10

00 3 6 9 12

Months15 18

High

Low

Medium

21

• Data for patients with low and medium TMB were pooled in subsequent analysesPeters, AACR 2017

Impact of tumor mutation burden on the efficacy of first-line nivolumab in advanced NSCLC: PFS by TMB subgroup and PD-L1 expression

34 |

32 24 13 12 7 5 2 1

28 18 9 3 2 2 2 0

53 35 23 13 10 8 3 0

41 30 14 10 5 4 2 0

No. at RiskHigh TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 ≥50%

16 13 10 8 8 6 2 0 0

31 17 16 13 8 6 2 1 0

70 33 18 9 7 5 1 1 1

41 21 12 6 2 2 1 0 0

Months

100

75

50

25

0

6 18930 12 15 21

Months

100

75

50

25

0

6 1893

PF

S (

%)

0 12 15 2421

High TMB, PD-L1 ≥50%


Low/medium TMB, PD-L1 1–49%




Low/medium TMB,

PD-L1 1–49%

High TMB, PD-L1 ≥50%

Nivolumab Arm Chemotherapy Arm

Peters, AACR 2017

Randomized phase-2 study of carboplatin and pemetexed with orwithout pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G

35 |

Langer, ESMO 2016

Randomized phase-2 study of carboplatin and pemetexed with orwithout pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G

36 |

Langer, ESMO 2016

Phase 1 CheckMate 012 study design: First-line nivolumab± ipilimumab in NSCLC

37 |

• Updated datad presented here are based on median follow-up durations of 22 months (monotherapy) and 16 months (combination cohorts)

– Overall additional follow-up relative to previous reports: monotherapy, +~18 months;1 combination cohorts, +6 months2

Primary endpoint: safety and tolerabilitySecondary endpoints: ORR (RECIST v1.1) and PFS rate at 24 weeks assessed by investigatorsExploratory endpoints: OS, efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology), no prior chemo therapy for advanced disease, ECOG PS 0 or 1

Nivolumab 3 mg/kg IV Q2W aNivolumab 3 mg/kg IV Q2W

+Ipilimumab 1 mg/kg IV Q12W b

Nivolumab 3 mg/kg IV Q2W+

Ipilimumab 1 mg/kg IV Q6W b

Until disease progression c or unacceptable toxicity

ClinicalTrials.gov number NCT01454102; aTreatment allocation not randomized; bTreatment allocation randomized; earlier cohorts evaluated other dosing schedules/regimens2

cPatients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefitdBased on a September 2016 database lock1. Gettinger S, et al. J Clin Oncol 2016;34:2980–2987; 2. Hellmann MD, et al. Lancet Oncol 2016 Dec 5. [Epub ahead of print].

Gettinger, WCLC 2016

Phase 1 CheckMate 012 response rate by tumor PD-L1 expression:38 |

Hellmann, Lancet Oncol 2016

Phase 1 CheckMate 012 OAS by tumor PD-L1 expression:39 |

39

Based on a September 2016 database lock

All treated patients (n = 77) ≥1% PD-L1 (n = 46) ≥50% PD-L1 (n = 13)

1-year OS rate: 76%

100

80

60

40

20

0

OS

(%

)

0 6 12 18 24 30 36 42 48

100

80

60

40

20

00 6 12 18 24 30 36 42 48

1-year OS rate: 87%

100

80

60

40

20

00 6 12 18 24 30 36 42 48

1-year OS rate: 100%

Nivo 3 Q2W + ipi 1 Q6/12W

1-year OS rate: 73%

100

80

60

40

20

0

Months

OS

(%

)

0 6 12 18 24 30 36 42 48

100

80

60

40

20

0

Months0 6 12 18 24 30 36 42 48

1-year OS rate: 69%

100

80

60

40

20

0

Months0 6 12 18 24 30 36 42 48

1-year OS rate: 83%

All treated patients (n = 52) ≥1% PD-L1 (n = 32) ≥50% PD-L1 (n = 12)

Nivo 3 Q2W

• Data are based on median follow-up durations of 16 months (combination cohorts) and 22 months (monotherapy)


Phase 1 CheckMate 012 treatment related adverse events:40 |

• The safety profile of nivolumab plus ipilimumab with longer follow-up was similar to that reported previously1

Based on a September 2016 database lock; select AEs are those with potential immunologic etiology; aAll treatment-related pulmonary events were pneumonitis; rxn = reaction 1. Hellmann MD, et al. Lancet Oncol 2016 Dec 5. [Epub ahead of print].

14 104 0

21

8 1118

3 5 3

37

5

21

5 3 5

332

2

4

05

5

05

50

8 5

0

5

00

10

20

30

40

50

60

2

2

2 3

3

Pat

ient

s w

ith a

n ev

ent,

% Nivo 3 Q2W(n = 52)

Nivo 3 Q2W + Ipi 1 Q12W(n = 38)

Nivo 3 Q2W + Ipi 1 Q6W(n = 39)

15

Grade 1−2 Grade 3−4


Projected read-out of many phase 3 anti PD1/PD-L1combination trials in first-line advanced NSCLC (>15’000 patients)

41 |

2016 2017 2018 2019 2020

Nivolumab

monotherapyPDL1+

CheckMate-026

Q3 2016

Pembrolizumab

monotherapy>50% PDL1+

Keynote 024

Q2 2016

MYSTIC

Q1 2017

Durvalumab ±

tremelimumab

vs SoC

Pembrolizumab +

platinium /

pemetrexed

(non-squamous)Keynote 189

Q3 2017

Avelumab mono

vs Pt doublet

PD-L1+JAVELIN lung 100

Q1 2018

Atezolizumab +

chemo

±bevacizumab

vs chemo +

bevacizumabIMpower 150

Q1 2017

Nivolumab mono

vs

Nivolumab mono

vs

Niv + Ipi vsNiv + Pt doublet

vs Pt doubletCheckMate-227

Q1 2018

Pembrolizumab

monotherapy>1% PDL1+

Keynote 042

Q2 2018

Atezolizumab

Q2 2018

Atezolizumab

monotherapy

all histologiesPDL1+

Impower 110

Q2 2018

Atezolizumab +

chemoIMpower 130 (non-

SCC)

Impower 131 (SCC)

Q3 2018

Durvalumab

±

tremelimuma

b vs SoCNEPTUNE

Q4 2018

Ipilimumab +

paclitaxel +

carboplatin

squamousCA184-153

Q3 2019

PD1/PDL1

Monotherapy

CTLA4 + PD1

PD1 or PDL1

CT Combo

Legend

Other Immune checkpoints: Exploration of combinations

42 |

• Combination with inhibitoryantibodies

• Lag-3, TIM Combination with agonisticantibodies• CD137, OX40, CD40, GITR

Pardoll, Nat Review Cancer 2012; Dempke, Eur J Caner 2017

Immune ons:

• Adjuvant immunotherapy after complete resection of stagesIB-IIIA NSCLC

• Immunotherapy combined with chemo-radiotherapy of stageIII disease

• SCLC• Thymic carcinomas

43 |

PEARLS: A randomized, phase 3 trial with pembrolizumab versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapyPEARLS).

Co-primary endpoints:• DFS in the PD-L1 strong sub-group • DFS in the overall population

(co-primary endpoint)Stratification factors:• Stage (IB* vs II vs IIIA); • Adjuvant CT (no adjuvant CT versus

adjuvant CT)• PD-L1 status• Region

44 |

NICOLAS: A feasibility trial evaluating anti-PD1 nivolumabconsolidation after standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC, amendment 1

Primary Endpoint:• Grade ≥3 pneumonitisSample Size:• 43 patients

45 |

Auswahl-Voruntersuchung,

Eignung und Aufnahme

Nivolumab:480 mg Q4Wfür bis zu 1 Jahr

StadiumIIIA / BNSCLC

Chemo Zyklus 1

Chemo Zyklus 2

Chemo Zyklus 3 Strahlentherapie

Strahlentherapie

Chemo Zyklus 3

Chemo Zyklus 1

Chemo Zyklus 2

Auswahl durch den

Prüfer

bis PD

Ganzkörper-FDG-PET

CT-Scans Jahr 1 : alle 9 Wochen, Jahr 2 : alle 12 Wochen, nach 2 Jahren : alle 6 Monate

Nivolumab: 360 mg Q3W, 4 Dosen

Nivolumab: 240 mg Q2W, 8 Dosen

46 |

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009

immunotherapy in nsclc: where do we stand€¦ · comparative studies 11 | toxicity gade % of...

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