:

Chemotherapy and targeted therapies of NSCLC

Rolf Stahel

Comprehensive Cancer Center Zürich

1 |

Berlin, March 23, 2019

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Disclosures

Consultant or Advisory Role in the last two years

I have received honoraria as a consultant at advisory boards from Abbvie,

AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, Roche and Takeda.

Speaker Honoraria in the last two years

I have received honoraria as a speaker from Astra Zeneca, Boehringer

Ingelheim, Lilly, MSD and Roche.

DMC in the last two years

Roche and Takeda

Financial Support of ETOP trials (president and scientific chair)

AstraZeneca, BMS, Boehringer Ingelheim, Genentech, MSD, Roche, and

Pfizer.

2 |

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Lynch, Surgery, 27: 268-285, 1950

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Chemotherapy of NSCLC: a meta-analysis using updated data on

individual patients from 52 randomized trials

4 |

Non-small cell lung cancer collaborative group, BMJ 1995

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Dabate on the use of chemotherapy in advanced NSCLC5 |

BMJ 1994

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Systemic therapy of NSCLC: A pleateau had been reached6 |

Schiller, NEJM 2001

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Phase III randomised trial comparing paclitaxel/carboplatin with

paclitaxel/cisplatin in patients with advanced NSCLC

7 |

Rosell, Ann. Oncol. 2002

Although paclitaxel/carboplatin yielded a similar response rate, the

significantly longer median survival obtained with paclitaxel/cisplatin

indicates that cisplatin-based chemotherapy should be the first

treatment option.

Median survival:

8.2 months for paclitaxel/carboplatin

9.8 months for paclitaxel/cisplatin

(hazard ratio 1.22, 90% CI 1.06–1.40; P= 0.019)

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Phase III randomised trial comparing paclitaxel/carboplatin with

paclitaxel/cisplatin in patients with advanced NSCLC

8 |

Rosell, Ann. Oncol. 2002

Paclitaxel/Cisplatin

Paclitaxel/CarboplatinN

um

be

r o

f p

ati

en

ts

40% of all pts received

6 cycles

70% pts received 4 cycles

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Chemotherapy in addition to supportive care improves survival in

advanced NSCLC: a systematic review and meta-analysis of individual

patient data from 16 randomized controlled trials

9 |

NSCLC Meta-analyses Collaborative Group, JCO 2008

Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI,

0.71 to 0.83; P <= .0001), equivalent to a relative increase in survival of 23%

or an absolute improvement in survival of 9% at 12 months, increasing

survival from 20% to 29%.

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Six versus fewer planned cycles of first-line platinum-based

chemotherapy for NSCLC: a systematic review and meta-

analysis of individual patient data

10 |

Rossi, Lancet 2014

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What can we conclude for the first line therapy of advanced

NSCLC without oncogenic driver mutation

• There is no single platinum-based doublet standard chemotherapy, however

pemetrexed combinations are favoured in non-squamous cell NSCLC

• If platinum-based chemotherapy is indicated, a combination with

bevacizumab is a treatment option in eligible patients with non-squamous

NSCLC. In this case, carboplatin/paclitaxel is the preferred combination

• Pemetrexed maintenance therapy is an option for patients with non-

squamous NSCLC without progression after first line therapy

• Immune checkpoint inhibition with pembrolizumab is becoming a standard for

patients with tumors with strong PD-L1 expression

• For patients with NSCLC with absent or week PD-L1 expression the

emerging treatments include chemotherapy/IO or IO/IO combinations

11 |

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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 use of pemetrexed maintenanceScagliotti, JCO 2008; Paz-Ares, JCO 2013

12 |

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Bevacizumab added to chemotherapy: Initial Phase III trials in

non-squamous NSCLC

13 |

Sandler, NEJM 2006; Reck, JCO 2009; Zhou JCO 2015

Carboplatin-Paclitaxel (OS) Carboplatin-Paclitaxel (OS)

Cisplatin-gemcitabine PFS)

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Cisplatin-pemetrexed vs cisplatin-gemcitabine in advanced

NSCLC

14 |

Overall no difference in PFS or

survival between study arms

Cis/pem bretter than in

non-squamous cell carcinoma

(HR 0.81, p=0.005)

Cis/pem inferior than cis/gem

in squamous cell carcinoma

(HR 1.23, p=0.05)

Scagliotti, JCO 2008

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PARAMOUNT: Pemetrexed maintenance in non-squamous

NSCLC

15 |

Paz-Ares, JCO 2013

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Gemcitabine and cisplatin with or without necitumumab in

squamous cell lung cancer

16 |

Thatcher, Lancet Oncol 2015

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First-line

Stage IV

NSCLC

Stratify:

- Bone mets

- Region

- ECOG PS

- Histology

R

A

N

D

O

M

I

S

E

4-6 cycles chemotherapy

every 3 weeks + BSC

4-6 cycles chemotherapy

every 3 weeks

Denosumab every 3-4 weeks ………………. l i f e l o n g …………………..

A

B

Blood Blood Blood

Progression

Translational research:

Trial treatmentScreening, eligibility and enrolment Follow

-up

FFPE FFPE

(no cross-over to denosumab)

ETOP/EORTC 5-12 SPLENDOUR – Trial design

Primary endpoint:

▪ Overall survival

Secondary endpoints:

▪ Progression free survival RECIST 1.1

▪ Toxicity profile of denosumab CTCAE v 4

▪ Determination of biomarkers for

translational research

Target Sample Size:

▪ 1000 Patients

17 |

ETOP Annual Meeting Barcelona | Completed ETOP Trials

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ETOP/EORTC 5-12 SPLENDOUR – Efficacy results

(OS and PFS)

18 |

ETOP Annual Meeting Barcelona | Completed ETOP Trials

(years)

0 1 2 3 4

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

178 255 82 23 0

177 259 83 29 2

Doublet chemotherapy + best su

Doublet chemotherapy + denos

Overall Score test: p=0.689

Non-parametric Cox model

TreatmentPatients

(N)

Obs.

events

(O)

Median (Years

)

(95% CI)

% at 1 Year

(95% CI)

Hazard Ratio

(95% CI)

P-Value

(Score test)

Doublet

chemotherapy

+ BSC

255 1780.73

(0.63, 0.92)

40.2

(33.8, 46.5) 1.00 0.689

Doublet

chemotherapy

+ denosumab

259 1770.68

(0.62, 0.87)

40.2

(33.8, 46.5)

0.96

(0.78, 1.18)

Log-rank test: p-value=0.689

Overall survival

(months)

0 4 8 12 16 20 24 28 32 36 40

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

98 137 95 53 41 25 15 13 7 3 0

98 138 87 50 36 27 20 17 14 5 2

Doublet + BSC

Doublet + Deno

Bone Metastasis

Overall Score test: p=0.816

Overall survival

Bone metastases

Non-parametric Cox model

TreatmentPatients

(N)

Obs.

events

(O)

Median (Years

)

(95% CI)

% at 1 Year

(95% CI)

Hazard Ratio

(95% CI)

P-Value

(Score test)

Doublet

chemotherapy

+ BSC

137 980.61

(0.51, 0.82)

35.8

(27.5, 44.2) 1.00 0.816

Doublet

chemotherapy

+ denosumab

138 980.62

(0.46, 0.73)

34.4

(26.1, 43.0)

1.03

(0.78, 1.37)

Log-rank test: p-value=0.816 Do n

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Weekly nab-paclitaxel in combination with carboplatin

vs solvent-based paclitaxel plus carboplatin in first line

advanced NSCLC

19 |

Socinski, JCO 2012

Response: Primary endpoint

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Weekly nab-paclitaxel in combination with carboplatin

vs solvent-based paclitaxel plus carboplatin in first line

advanced NSCLC

20 |

Socinski, JCO 2012

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21 |

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NSCLC with oncogenic driver mutations: current status24 |

Tsao, JTO 2016

Activating

mutations

Amplifications

and/or

mutations

Entectinib

Loxo-292

BLUE-6678

Larotrectinib

Gene

translocatons

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Mode of Actions of EGFR TKIs25 |

Liao, Curr Opin Oncol 2015

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26 |

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EGFR-mutated NSCLC: Erlotinib with bevacizumab in first-line27 |

• JO25567: Ph2, randomized, Japanese

multicenter, open-label[a]

Seto, Lancet Oncol 2014; Rosell, Lancet Respir Med. 2017

PFS

BELIEF: Ph2, multicenter, single-arm study, stratified by pretreatment T790M status[b]

PFS

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FLAURA: Osimertinib vs erlotinib or gefitinib as first line treatment of

EGFR-mutated NSCLC: PFS and preliminary OS

28 |

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009Soria NEJM 2018

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FLAURA: CNS activity29 |

Vansteenkiste, ESMO Asia 2017

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Mechanisms of acquired resistance to first-line osimertinib:

Preliminary data from the phase III FLAURA study: Control group

30 |

Ramalingam, ESMO 2018

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Mechanisms of acquired resistance to first-line osimertinib:

Preliminary data from the phase III FLAURA study: Osimertinib group

31 |

Ramalingam, ESMO 2018

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Phase Ib/II study of capmatinib plus gefitinib after failure of EGFR

unhibitor tTherapy in patients with EGFR-mutated, MET factor-

dysregulated NSCLC

32 |

Wu, JCO 2018

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MET exon 14 skip mutation

• Loss of MET exon 14 maintains the reading frame and leads to increased

MET stability and prolonged signaling upon HGF stimulation, leading to

increased oncogenic potential

33 |

Frampton, WLCC 2015 and Cancer Discovery 2015

June 2016 September 2017

60-y/o man with lung adenocarcinoma

with met exon 14 mutation

Crizotinib

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Afatinib in NSCLC with HER2 mutations: Results of the prospective,

open label NICHE trial of ETOP

34 |

Dziadiziuszko, JTO in press

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Trastuzumab emtansine (T-DM1) in patients with previously treated

HER2-overexpressing metastatic NSCLC: Efficacy, safety, and

biomarkers

35 |

Peters, CCR 2018

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Novel NSCLC agents targeting exon 20 insertions in the EGFR and

HER2 genes (standard TKIs are ineffective)

36 |

Tumour responses to poziotinib in HER2 exon 20 mutations2

Best response HER2 (evaluable patients n=12)

Progressive Disease

Stable DiseasePartial Response

Response not confirmed/Follow-up pending

Ma

xim

um

resp

onse

from

baselin

e

ORR: 50%

* **

*

*

30

-60

-15

-45

15

0

-30

80

Tumour responses to TAK-788 in HER2 or EGFR exon 20 mutations1

ORR: 35%

120 40bid

80 120150 80

150120120 80 120

40 bid 180120 120

CR

150 80

40 bid12080

40 bid150 Dose

(mg)

Partial

Response

threshold

Prior TKI: N Y Y N Y N N N N N N Y Y N N N N N N N Y Y N

Prior IO: N N N Y Y Y N N Y N Y Y N N Y Y N N N N Y Y N

80

–100

60

20

–20

–60

–80

40

0

–40

Be

st

ch

an

ge

in

ta

rge

t le

sio

ns (

%)

EGFR exon 20 Insertion mutation

HER2 mutation

Neal, WCLC 2018; Heymach, WCLC 2018

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Dabrafenib plus trametinib in patients with previously untreated

BRAFV600E-mutant metastatic NSCLC: an open-label, phase 2 trial

37 |

Planchard, Lancet Oncol 2017

Response rate 64% Medien PFS 10.4 months Median OS 24.6 months

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38 |

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Crizotinib versus platin-based chemotherapy in fist line treatment of

advanced ALK-positive NSCLC: PRORILFE 1014

39 |

Salomon, NEJM 2014

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Case 1: 52-y/o man

• July 2012:

• Presentation to pneumologists with

cough and dyspnea

• Bronchoscopy demonstrated occlusion of

R main bronchus

• Biopsy: Adenocarcinoma

• PET/CT: right central tumor with contralateral

mediastinal and supraclavicular lymph node

metastases

• Molecular pathology: Neg for EGFR mutation,

40 |

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Case 1: 62-y/o man

• July 2012: Adenocarcinoma of the lung, stage IIIB with bilateral mediastinal

and supraclavicular nodal metastases, EGFR WT

• July – September 2012: Treatment with 3 cycles of carboplatin and

pemetrexed

• September 2012: Start of Crizotinb

41 |

July 2012 September 2012

FISH in initial biopsy:

ALK gene

rearrangement

present

November 2012 March 2017

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Case 1: 62-y/o man

Continuing crizotinib

• March 2017: Stereotactic radiotherapy of the 4 cerebellar lesions

• November 2018: Stereotactic radiotherapy of lesion at nucleus olivaris

42 |

March 2017 October 2018 February 2019

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Alectinib, brigatinib, or ceritinib after crizotinib failure in ALK+ NSCLC patients

43 |

Alectinib Brigatinib Ceritinib

CharacteristicNP287611,a

n = 87

NP286732,3

,a

n = 138

Phase 1/24,5,b,c

n = 25

ALTA5,6,a,c

n = 110

ASCEND-

17,8,b

n = 163

ASCEND-29,a

n = 140

Median follow-up, mo 9.9 21 28.3d 8.3 11.1e 11.3

ORR, n/N (%)

[95% CI]

35/67

(52)

[40–65]

62/122

(51)

[42–60]

19/25

(76)

[55–91]

58/110

(53)

[43–62]

92/163

(56)

[49–64]

50/140

(36)

[28–44]

DCR, n/N (%)

[95% CI]

55/69

(80)

[Not

reported]f

96/122

(79)

[70–86]

22/25

(88)

[69–98]

92/110

(84)

[75–90]

121/163

(74)

[Not

reported]

88/140

(63)

[54–71]

Median DOR, mo

[95% CI]

13.5

[6.7–NE]

15.2

[11.2–24.9]

14.8

[7.9–NE]

13.8

[9.3–NE]

8.3

[6.8–9.7]

9.7

[5.6–12.9]

Median PFS, mo

[95% CI]

8.1

[6.2–12.6]

8.9

[5.6–12.8]b

16.3

[9.2–NE]

16.7

[11.0–NE]

6.9

[5.6–8.7]

7.2

[5.4–9.0]

Dose reduction due to AEs,

n/N (%)

Pooled safety population

57/253 (23)3,g

6/32

(19)h

22/110

(20)

152/246

(62)e

64/140

(46)

Discontinuation due to AEs,

n/N (%)

2/87

(2)

12/138

(9)

4/32

(13)h

9/110

(8)

26/246

(11)e

11/140

(8)

NE = not estimable

1. Shaw Lancet Oncol. 2016; 2. Barlesi 41st Annual Congress, ESMO. Oct 2016, Denmark; 3. Ou S-H J Clin Oncol. 2016; 4. Gettinger Lancet Oncol. 2016; 5. ARIAD data on file; 6. Camidge J Thorac Oncol. 2016; 7. Kim D-W Lancet Oncol. 2016; 8. Kim ASCO 2014. 9. Crinò J Clin Oncol 2016

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First line alectinib versus crizotinib in advanced ALK-positive

NSCLC: Progression-free survival

44 |

Camidge, ASCO 2018

ICB

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Targeting ALK: Precision medicine takes on drug resistance45 |

Lin, Cancer Discovery 2017

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Tyrosine kinase inhibitors targeting ALK

Drug Targets Line

approved

ALK

Line

approved

ROS1

Crizotinib ALK, MET, ROS1, RON 1 1,2

Ceritinib ALK, ROS1 1,2 n/a

Alectinib ALK, RET, 1,2 -

Brigatinib ALK, RET, ROS1, mEGFR 2 n/a

Ensartinib ALK, NTRK, ROS1, MET n/a n/a

Lorlatinib ALK, ROS1 2,3 n/a

Entrectinib ALK, ROS1, NTRK n/a n/a

46 |

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ROS1 rearrangement in NSCLC: Activity of crizotinib

• ROS1 fusion with the transmembrane solute carrier protein SLC34A2

resulting in a constitutive kinase activity in a NSCLC cell lineRikova, Cell 2007

47 |

Shaw, NEJM 2014

Response rate 72% Median PFS 19.2 months

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Newer agents targeting RET fusions48 |

Drilon, ASCO 2018

–

ORR: 77%

40

-100

0

-20

-60

-80

20

-40

Ma

xim

um

ch

an

ge

in

tu

mo

r siz

e (

%)

*

NSCLC

Thyroid

Pancreatic

Tumour type

Tumour responses to LOXO-292 in RET

fusion-positive NSCLC (n=39)4

A phase 1 study of LOXO-292, a potent

and highly selective RET inhibitor, in

patients with RET-altered cancers

Precision targeted therapy with BLU-

667 for RET-driven cancers

Subbiah, Cancer Disc 2018Do n

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Efficacy and safety of entrectinib in patients with NTRK fusion-

positive tumours: pooled analysis of STARTRK-2, STARTRK-1 and

ALKA-372-001

49 |

Demetri, ESMO 2018Pro-survival genes

TRKA

NGF

Ras

Raf

MEK 1/2

ERK 1/2

PLCγ

Ca2+ PKCγ

PI3K

AKT

P

P

P

P

TRKB

BDNF or NT-4/5

P

P

P

P

TRKC

NT-3

P

P

P

P

GSK3β S6K1

IκB

Pro-differentiation genes

Synaptic

plasticity

Transcription factors

Regulation of actin

cytoskeleton

Ubiquitin-

mediated proteolysis

• NTRK1/2/3 genes encode TRK A/B/C proteins, respectively

– NTRK1/2/3 gene fusions are oncogenic drivers 4

0

-30

-50

-90

Bes

t %

chan

ge

from

bas

elin

e

15

-80

-70

-60

-40

-20

-10

20

30

40

-100

50

CRCNSCLCSarcoma

Neuroendocrine tumours

PancreaticThyroidMASC Breast

CholangiocarcinomaGynaecological

NTRK+patients (n=54)

ORR (95% CI) 57.4% (43.2–70.8)

SD 9 (16.7)

PD 4 (7.4)

Non-CR/PD, missing or unevaluable 10 (18.5)

Results per Blinded Independent Central Review (BICR)

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Efficacy of larotrectinib in TRK fusion–positive cancers in adults and

children

50 |

Drilon, NEJM 2018

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Thomas Hart Benton

America Today

Thomas Hart Benton:

“America Today”Do n

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