non-small cell lung cancer state of the art -...

Non-Small Cell Lung Cancer

State of the Art

Rolf Stahel

University Hospital of Zürich

1 |

Cape Town, 11.2.2017

Individual patient data meta-analysis: sequential vs

concurrent chemo-radiotherapy

3 |

Aupérin, JCO 2010

Chemoradiotherapy: No evidence for advantage with

induction or consolidation chemotherapy in stage III

4 |

Carboplatin-paclitaxel induction

followed by chemoradiotherapyConcurrent PE chemoradiotherapy

followed by docetaxel consolidation

Vokes, JCO 2007 Hanna, JCO 2008

Histological classification is necessary for decision making in

advanced NSCLC

• A diagnosis of “non-small cell lung cancer” is no longer acceptable as

sufficient basis for treatment decisions:

• Cisplatin superior to carboplatin in adenocarcinomaArdizzoni, JNCI 2007

• Benefit of bevacizumab added to first line chemotherapy in non-

squamous cell carcinomaSandler, JCO 2006; Reck; JCO 2009; Zhou, JCO 2015

• Differential effect of pemetrexed in non-squamous vs squamous cell

carcinoma and pemetrexed maintenanceScagliotti, JCO 2008; Paz-Ares, JCO 2013

• Histology will help guide decision about further molecular analysis

6 |

ESMO clinical practice guidelines in metastatic squamous

cell carcinoma: 1st line

7 |

Novello et al, Ann Oncol 2016

Gemcitabine and cisplatin with or without necitumumab in

squamous cell lung cancer

8 |

Thatcher, Lancet Oncol 2015

Magnitunde of Clinical Benefit Scale: Form 2a

(primary endpoint OS, OS < 1 year, non-curative)

9 |

Cherny et al, Ann Oncol 2015

54321

A

B

C

Curative Non-curative

Magnitunde of Clinical Benefit Scale: Second line squamous

cell carcinoma

10 |

ESMO clinical practice guidelines in metastatic squamous

cell carcinoma: 2nd line

11 |


ESMO clinical practice guidelines in metastatic non-squamous


12 |




13 |


Bevacizumab in adenocarcinoma14 |

Sandler, JTO 2008

OS for E4599 all patients and

adenocarcinoma only

BEYOND: Randomized phase III

study from China

Zhou JCO 2015

PARAMOUNT: Overall survival15 |

Paz-Ares, JCO 2013


cell carcinoma: 2nd line

16 |


2nd line NSCLC phase III: Docetaxel vs BSC17 |

MST 7.5 vs 4.7 months

D100 D75

Shepherd, JCO 2000

OS 7.5 vs 6.4 months

Docetaxel plus nintedanib (LUME-Lung 1) or docetaxel plus

ramucirumab (REVEL) versus docetaxel plus placebo for

2nd line treatment of stage IV NSCLC

18 |

LUME-Lung 1: Adenocarcinoma

OS 12.6 vs 10.3 months OS 10.5 vs 9.1 months

Reck, Lancet Oncol 2014

REVEL: all histologies

Garon, Lancet Oncol 2014

Magnitunde of Clinical Benefit Scale: Second line non-

squamous cell carcinoma

19 |

The complexity of PD-L1 diagnostics of NSCLC20 |

Nivolumab:

BMS

Pembrolizumab:

Merck

Atezolizumab:

Roche

Durvalumab:

AstraZeneca

Avelumab: Pfizer

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

Diagnostic

PartnerDako 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(−)

TCPD-L1(+): ≥ 25%

TBC, TC between all >1% and 25%

with moderate or high intensity

Analytical evaluation results: Mean TPS per case based on 3

readers: Tumor cells

21 |

22C3

28-8

SP142

SP263

100

90

80

70

60

50

40

30

20

10

0391 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

Hirsch, AACR 2016

Example of PD-L1 tumor expression22 |

22C3 28-8 SP263 SP142

Not only technical validation, also clinical validation required

Not all animals are created equalHirsch, AACR 2016

Checkmate 017 and 057: 2-years update of OAS

(no biomarker selection),

23 |

Borghael, ASCO 2016

* No biomarker selection

* *

Checkmate 057: OS by PD-L1 Expression24 |

mOS (mos)

Nivo 17.7

Doc 9.0

mOS (mos)

Nivo 19.4

Doc 8.1

mOS (mos)

Nivo 19.9

Doc 8.0

mOS (mos)

Nivo 10.5

Doc 10.1

mOS (mos)

Nivo 9.8

Doc 10.1

mOS (mos)

Nivo 9.9

Doc 10.3

≥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 line

NSCLC (1% of tumor cells PD-L1 positive)

25 |

Herbst, ESMO Asia 2015, Lancet

2016

Relationship between level of PD-L1 expression and

outcomes in the KEYNOTE-010 trial

26 |

Baas, ASCO 2016

Less toxicity with immune checkpoint inhibitors in second line

comparative studies

28 |

Toxicity

Gade

% 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

Case study, R.M. 1952

• 06/15 Diagnosis: Pleomorphic carcinoma RUL,

clinical state stage T3N1M1 (bone)

• 07/15 – 08/15 3 cycles of cisplatin and gemcitabine

• 28.08.2015 Re-Staging: progression in bone

29 |

08/201506/2015

Case study, R.M. 1952

• 29.09.2015 Right upper lobe resection ypT3 ypN1 (1/8)

• 06.11.2015 Re-Staging: progression bone, LN

30 |

Nov 2015 RT Sacrum, paravertebral, Os

14.12.2015 Nivolumab, on the 14.12. and 28.12.2015

Case study, R.M. 195231 |

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. 195232 |

2/2016, 6/2016, 11/201611/2015

Treatment effect on overall suvival in Checkmate 57 and

KEYNOTE 10

33 |

Borghaei. NEJM 2015; Herbst Lancet 2015

First line immunotherapy: Duration of therapy after response?A case of a 70-year old man with stage IV adenocarcinoma of the lung treated with

two doses of atezolizumab

34 |

April 2014:

Pretreatment

September 2014:

2 doses of therapy in

June 2014

March 2015:

Hilar progression

KEYNOTE-024: Pembrolizumab vs platinum-based

chemotherapy as first-Line therapy for advanced NSCLC with

a PD-L1 TPS ≥50%

35 |

Reck, ESMO 2016

KEYNOTE-024: Pembrolizumab vs platinum-based

chemotherapy as first-Line therapy for advanced NSCLC with

a PD-L1 TPS ≥50%

36 |

Reck, ESMO 2016

KEYNOTE-024: Treatment related side effects with

incidence >10%

37 |

0

5

10

15

20

25

30

35

40

45

50

Incid

en

ce,

%

1-2

Grade

3-4

Data cut-off: May 9, 2016.

Pembrolizumab

Chemotherapy

KEYNOTE-024: Immune-mediated adverse events38 |

0

1

2

3

4

5

6

7

8

9

10In

cid

en

ce,

%

1-2

Grade

3-4

Overall incidence

• 29.2% any grade

• 9.7% grade 3-4

• No grade 5 events

Targeted therapy in non-squamous NSCLC lung cancer:

First line TKIs: Superior progression-free survival as compared

to chemotherapy

39 |

Crizotinib

NTRK fusion

Gefitinib

Erlotinib

Afatinib

First TKI versus chemotherapy in oncogenic driver NSCLC40 |

Mok, NEJM 2014Rosell, Lancet Oncol 2012

Aktivating EGFR mutation ALK rearragnement


Second line TKIs: Superior progression-free survival as compared

with chemotherapy

41 |

Crizotinib

NTRK fusion

Gefitinib

Erlotinib

AfatinibT790M: Osimertinib

Ceritinib / AlectinibCrizotinib

Major mechanisms of resistance to EGFR TKIs42 |

Yu, Clin Cancer Res 2013

Osimertinib or platinum-pemetrexed in EGFR T790M–positive

NSCLC

43 |

Mok, NEJM 2016

Crizotinib-resistant ALK-positive NSCLC44 |

Alectinib phase 2 trial

RR 48%

Median PFS 8.1

months

Ceritinib vs chemotherapy

(ASCEND-5)RR 45% vs 8%

Shaw, Lancet Oncol 2016 Scagliotti, ESMO 2016


TKIs in later line beyond mutated EGFR, ALK or ROS rearrangement

45 |

Vandetanib/LevatinibAlectinib

CrizotinibTrastuzumab

Crizotinib

Afatinib

Crizotinib

Dabrafenib/Trametinib

Vermurafenib

NTRK fusion Entrectinib

Gefitinib

Erlotinib

Afatinib

Osimertinib

Ceritinib/AlectinibCrizotinib

46 |

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

non-small cell lung cancer state of the art -...

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