The oncologist’s point of view: the promise and challenges of increasing options for targeted therapies in NSCLC Egbert F. Smit Department of Thoracic Oncology, Netherlands Cancer Institute, and Department of Pulmonary Diseases, VUMC, Amsterdam, Netherlands

Patient selection in lung cancer: evolution over time

ADC, adenocarcinoma; NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer. Adapted from Reck M, et al. Lancet. 2013;382:709-19.

1990 Lung cancer

2000 NSCLC SCLC

ADC

ADC and treatable oncogenic alterations

Large cell carcinoma

SCLC

Squamous cell carcinoma

Patient selection in NSCLC: evolution over time

*Non-squamous = adenocarcinoma and large cell carcinoma NSCLC histology. CI, confidence interval; HR, hazard ratio; OS overall survival. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-51.

2008 Non-squamous cell carcinoma Squamous cell carcinoma

Median OS (months)

Pemetrexed + cisplatin 11.8 Gemcitabine + cisplatin 10.4

HR 0.81 (95% CI 0.70–0.94) p = 0.005

Survival time (months)

Prob

abili

ty o

f sur

viva

l

0 6 18 12 24 30

Non-squamous* (n = 1,000) Squamous (n = 473)

Median OS (months)

Pemetrexed + cisplatin 9.4 Gemcitabine + cisplatin 10.8

HR 1.23 (95% CI 1.00–1.51) p = 0.05

Survival time (months) Pr

obab

ility

of s

urvi

val

0 6 18 12 24 30

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

1.0

Timeline for the discovery of relevant alterations in lung cancer

ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; DDR2, discoidin domain receptor 2; EGFR, epidermal growth factor receptor; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homologue; NGS, next-generation sequencing; NRAS, NRAS proto-oncogene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homolog; ROS1, ROS1 proto-oncogene receptor tyrosine kinase.

Adapted from Levy MA, et al. Genome Res. 2012;22:2101-8.

Before NGS NGS era

picking the right gene Difficulty: finding the relevant genes

1984 1997 1990 2002 2004 2005 2007 2008 2010 2012 2011

EGFR HER2

PIK3CA mutations

ALK ROS1

fusions NRAS

mutations

PTEN mutations

KRAS mutations

Lung ADC kinome

623 genes of lung ADC

BRAF mutations

Lung ADC copy numbers

Lung squamous ADC, SCLC exomes & genomes

First lung cancer

genomes

DDR2 mutations

FGFR1 amplifications

Frequencies in real life: French experience

WT, wild type. Barlesi F, et al. Lancet. 2016;387:1415-26.

EGFR 11%

KRAS 29%

BRAF 2%

HER2 1% PIK3CA

2% ALK 5%

Unknown 35%

Full WT 15%

Overall

EGFR 21%

KRAS 27%

BRAF 2%

HER2 1%

PIK3CA 3%

ALK 6%

Unknown 28%

Full WT 12%

Women

EGFR 12%

KRAS 31%

BRAF 2%

HER2 1% PIK3CA

2% ALK 5%

Unknown 32%

Full WT 15%

ADC

EGFR 44%

KRAS 9%

BRAF 3% HER2 4% PIK3CA 4%

ALK 14%

Unknown 13%

Full WT 9%

Never-smokers

Oncogene-driven NSCLC: tailored treatment

PFS, progression-free survival. 1. Adapted from: Rosell R, et al. Lancet Oncol. 2012;13:239-46.

2. Adapted from: Shaw AT, et al. N Engl J Med. 2013;368:2385-94.

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 0

0.2

0.4

0.6

0.8

1.0 Erlotinib (n = 86) Chemotherapy (n = 87)

10.4 5.1

PFS

prob

abili

ty

Time (months) Patients at risk

Erlotinib 86 69 62 43 33 25 19 14 8 7 6 4 3 2 1 0 Chemotherapy 87 52 21 8 5 3 2 1 0 0 0 0 0 0 0 0

Log-rank p < 0.0001

HR (95% CI) 0.3402 (0.2341–0.4944)

Erlotinib vs chemotherapy in EGFR-driven advanced NSCLC1

0

20

40

60

80

100

0 5 10 15 20 25

Number at risk Erlotinib 173 93 38 11 2 0

Chemotherapy 174 49 15 4 1 0

Crizotinib (n = 173)

Chemotheraphy (n = 174)

Events, n (%) 100 (58) 127 (73) Median, mo 7.7 3.0 HR (95% CI) 0.49 (0.37–0.64)

p < 0.001

Crizotinib vs chemotherapy in ALK+ NSCLC2

Time (months)

Prob

abili

ty o

f sur

viva

l w

ithou

t pro

gres

sion

(%)

Number at risk Patients with oncogenic driver No targeted therapy 318 205 110 64 43 20

Targeted therapy 260 225 143 72 36 23 Patients with no driver 360 250 122 59 36 23

Targeted therapy: improved survival, no cure

Kris MG, et al. JAMA. 2014;311:1998-2006.

Time (years)

Surv

ival

pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0 0 1 3 2 5 4

Log-rank p < 0.001

No targeted therapy

No driver

Targeted therapy

Patient selection in lung cancer: evolution over time

Adapted from Reck M, et al. Lancet. 2013;382:709-19.

1990 Lung cancer

2000

Established targets Mutation negative/unknown 2015 EGFR ALK ROS1

ADC

ADC and treatable oncogenic alterations

Large cell carcinoma

Small-cell lung cancer

Squamous cell carcinoma

NSCLC SCLC

Unknown oncogenic

driver detected 31%

KRAS 25%

EGFR sensitizing

17%

ALK 7%

EGFR other 4% MET 3% > 1 mutation

3% HER2 2% ROS1 2% BRAF 2% RET 2% NTRK1 1%

PIK3CA 1% MEK1 1%

ADC: targets and therapy

FDA, US Food and Drug Administration; MEK1, mitogen-activated protein kinase 1; MET, mesenchymal-epidermal transition; NTRK1, neurotrophic tyrosine kinase receptor 1; RET, rearranged during transfection. Tsao AS, et al. J Thorac Oncol. 2016;11:613-38.

Only three of these targets have agents

through approval by

the FDA

Key 1 - Phase 1 2 - Phase 2 3 - Phase 3 4 - Approved

EGFR sensitizing • Gefitinib4

• Erlotinib4

• Afatinib4

• Osimertinib4

• Necitumumab4

• Rociletinib3

ALK • Crizotinib4

• Alectinib4

• Ceritinib4

• Lorlatinib2

• Brigatinib2

MET • Crizotinib2

• Cabozantinib2

HER2 • Trastuzumab emtansine2

• Afatinib2

• Dacomitinib2

ROS1 • Crizotinib4

• Cabozantinib2

• Ceritinib2

• Lorlatinib2

• DS-6051b1

BRAF • Vemurafenib2

• Dabrafenib2

RET • Cabozatinib2

• Alectinib2

• Apatinib2 • Vandetanib2

• Ponatinib2

• Lenvatinib2

NTRK1 • Entrectinib2

• LOXO-1012

• Cabozantinib2

• DS-6051b1

PIK3CA • LY30234142

• PQR 3091

MEK1 • Trametinib2

• Selumetinib3

• Cobimetinib1

Dabrafenib−trametinib in previously treated BRAF V600E patients

• One-half of responses (18/36) were ongoing at the time of data cutoff

CR, complete respose; NE, not evaluable; PD; progressive disease; PR, partial response; SD, stable disease.

Maximum change in target lesion by best investigator-assessed confirmed response

NE patients did not have a follow-up scan required for confirmation

−100

−80

−60

−40

−20

0

20

40

Max

imum

redu

ctio

n fr

om

base

line

mea

sure

men

t (%

)

Patients

Best confirmed response CR PR SD PD NE

ORR: 63% (95% CI 49–76)

Duration of response

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Patie

nts

DOR (months)

Number of previous systemic anticancer therapy regimens for metastatic disease

1 2–3

Investigator assessment n = 36

DOR, median (95% CI), months

9.0 (6.9–18.3)

cMET alterations in LUAC

• Polysomy – not sensitive to cMETi

• Amplification – sensitive to cMETi when highly amplified

• Mutation – exon 14 skipping mutations are highly sensitive to cMETi

cMETi, cMET inhibitor; LUAC, lung adenocarcinoma.

Tumour shrinkage seen with capmatinib treatment in intermediate and high MET cohorts

DCR, disease control rate; GCN, gene copy number. Schuler M, et al. Presented at ASCO 2016. Abstract 9067.

Best response n (%)

GCN < 4 (n = 17)

GCN ≥ 4 and < 6 (n = 12)

GCN ≥ 6 (n = 15)

CR 0 0 0 PR 0 2 (17) 7 (47) SD 8 (47) 3 (25) 5 (33) PD 5 (29) 3 (25) 2 (13) Unknown 4 (24) 4 (33) 1 (7) ORR 95% CI 0 2 (17)

2.1–48.4 7 (47)

21.3–73.4 DCR 95% CI

8 (47) 23.0–72.2

5 (42) 15.2–72.3

12 (80) 51.9–95.7

3+

3+

3+ 2+ 3+ 1+ 3+

3+ 0

cMET GCN < 4 n/N (%) = 11/17 (64.7%)

Bes

t % c

hang

e fr

om

base

line

−20

60 40 20 0

−40 −60 −80

−100

80 3+ 2+

3+

3+ 3+

3+ 3+

Bes

t % c

hang

e fr

om

base

line

cMET GCN ≥ 4 and < 6 n/N (%) = 7/12 (58.3%)

−20

60 40 20

0

−40 −60 −80

−100

80

3+ 3+

3+ 3+ 3+ 3+ 2+ 3+ 3+

2+ 3+ 3+

cMET GCN ≥ 6 n/N (%) = 12/15 (80.0%)

Bes

t % c

hang

e fr

om

base

line

−20

60 40 20

0

−40 −60 −80

−100

80

cMET exon 14 skipping mutations are sensitive to cMET inhibitors

TKI, tyrosine kinase inhibitor. Awad MM, et al. Presented at ASCO 2017. Abstract 8511.

0 12 24 36 48 60 0

0.2 0.4 0.6 0.8 1.0

0 12 24 36 48 60 0

0.2 0.4 0.6 0.8 1.0

OS from date of stage IV diagnosis

Time (months)

Time (months) O

S pr

obab

ility

O

S pr

obab

ility

Received a MET TKI

N = 27

Never received a MET TKI

N = 34

Median OS (95% CI) 8.1 months (5.3–NR)

Median OS (95% CI) 24.6 months (12.1–NR)

ROS1 rearrangement

cd74, cluster of differentiation antigen 74; FISH, fluorescent in-situ hybridization. Awad MM, et al. N Engl J Med 2013;368:2395-401.

FISH

Sequence of the CD74-ROS1 fusion transcript

Cytologic analysis of a pleural effusion

Crizotinib in ROS1-rearranged LUAC: results from a phase 1 extension cohort (n = 50)

DoR, duration of response. Shaw AT, et al. N Engl J Med. 2014;371:1963-71.

ORR: 72%

−100

−80

−60

−40

−20

0

20

40

60

80

100

Cha

nge

from

bas

elin

e (%

)

0 30 35 5 10 15 20 25 40

A M *

Time (months)

3 patients (6%) CR 33 patients (66%) PR 9 patients (18%) SD

PD SD PR CR

DoR

Ceritinib has activity in crizotinib-resistant ROS1-rearranged LUAC

Lim SM, et al. J Clin Oncol. 2017;35:2613-8.

Cha

nge

from

bas

elin

e in

sum

of

long

est t

umou

r dia

met

ers

(%) 100

80 60 40 20 0

−20 −40 −60 −80

−100

PD SD PR CR

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

0.2

0.4

0.6

0.8

1.0

Duration (months)

PFS

(pro

port

ion)

All Crizotinib-naive

PFS 9.3 months (95% CI 0–22) 19.3 months (95% CI 1–37)

Lorlatinib in ROS1 + NSCLC

Solomon BJ, et al. Presented at Proc ASCO 2016. Abstract 9009.

1 prior TKI No prior TKI Ongoing treatments

ROS + patients

0 10 20 30

−10 −20 −30 −40 −50 −60 −70 −80 −90

−100

Bes

t cha

nge

from

bas

elin

e (%

)

E768

A883 S891 M918

L790 Y791

• G533

• C609 • C611 • C618 • C620 • C630 • C634

RET rearrangements

Mulligan LM. Nat Rev Cancer. 2014;14:173-86.

• Real frequency unknown

• 1–2% of LUAC

• Responses observed • vandetanib • sorafenib • regorafenib • alectinib • cabozantinib

MEN2A FMTC

Y791

G691

V804

Mod

ifyin

g va

riant

s

FMTC MEN2B

FMTC

Papillary thyroid carcinoma

Lung adenocarcinoma

Chronic myelomonocytic leukaemia

FGFR1OP-RET

BCR-RET

KIF5B-RET

BCR

FGFR10P

KIF5B

RET-PTC1

713 CCDC6

RET-PTC3

101

NCOA4 238 713

713

426 713

713 375

575

Cabozantinib phase 2 in RET-rearranged LUAC

Drillon A, et al. Lancet Oncol. 2016;17:1653-60.

0 6 12 18 24 30 36 48 42 Time from start of treatment (months)

Number at risk (number censored) 25 (0) 15 (5) 7 (5) 6 (5) 6 (5) 6 (5) 4 (7) 1 (8) 0 (9)

0

20

40

60

100

80

OS

(%) 0

20

−100

− 80

40

− 20

− 40

− 60

Max

imum

redu

ctio

n fr

om

base

line

mea

sure

men

t (%

) PR SD

Best confirmed response

HER2 mutation and amplification are distinct molecular targets

CEP17, chromosome enumeration probe 17.

Li BT, et al. Presented at ASCO Annual meeting 2017. Abstract 8510.

Li BT, et al. J Thorac Oncol. 2016;11:414-9.

HER2 amplification Testing FISH

(HER2/CEP17 ≥ 2)

N = 175

5/175 = 3% (95% CI 1–7)

“Overlap” testing HER2 mutation and

HER2 amplifications

N = 145

0/175 = 0% (95% CI 0–3)

HER2 mutation Testing

Fragment analysis and mass spectrometry genotyping

(insertions, deletions, indels, recurrent point mutations

L755S, D769H, V777L, V777M)

N = 145

4/145 = 3% (95% CI 1–7)

TDM-1 in LUAC with HER2 ins mutations

Li BT, et al. Presented at ASCO Annual meeting 2017. J Thorac Oncol. 2016;11:414-9.

Adapted from: Arcila ME, et al. Clin Cancer Res. 2012;18:4910-8. Kris MG, et al. JAMA. 2014;311:1998-2006.Stephens P, et al. Nature. 2004;431:525-6.

2% of lung cancers Most common HER2 mutation

is insYVMA

1 0 12 11 10 9 8 7 6 5 4 3 2

TDM-1 in LUAC with HER2 ins mutations

RECIST, Response evaluation criteria in solid tumours.

Li BT, et al. Presented at ASCO Annual meeting 2017. J Thorac Oncol. 2016;11:414-9.

Median PFS: 4 months (95% CI 3.0 to NR, n = 18 with 13 events) Median DoR: 5 months (95% CI 3.0 to NR, n = 8 with 6 events)

PFS ORR by RECIST v1.1

ORR 44% (8/18; 95% CI 22–69), study met primary endpoint

0

75

−75

−50

−25

25

50

% B

est r

espo

nse

per R

ECIS

T v1

.1

Patients

HER2 mutant lung cancer responses

Confirmed PR SD/PD

Time since treatment start (months)

Prob

abili

ty o

f PFS

0

1.0

0.8

0.6

0.4

0.2

0 10 8 6 4 2

Time on treatment (months)

HER

2 m

utan

t pat

ient

s re

ceiv

ing

ado-

tras

tuzu

mab

em

tans

ine

1

1

2

3

3

3

4

4

4

4

4

5

5

6

6

8

9

11

Treatment ongoing Response Response and treatment ongoing

• Oncogene addiction – ~ 25% of ADC – almost no squamous cell carcinoma

• Oncogene expedience – most ADC – vast majority of squamous cell

carcinomas

How about squamous cell lung cancer?

Potential therapeutic targets in squamous NSCLC

Perez-Moreno P, et al. Clin Cancer Res. 2012;18:2443-51.

FGFR1 amplification 22%

DDR2 mutation 4%

PIK3CA amplification 33%

MET amplification 5%

MET mutation 1%

BRAF mutation 2%

Others

Unknown

FGFR1 amplifications in SCC of the lung: from discovery to clinical evaluation

SCC, squamous cell carcinoma; SQLC, squamous lung cancer.

1. Weiss J, et al. Sci Transl Med. 2010;2:62ra93. 2. Heucamp LC, et al. Sci Transl Med. 2012;4:141ra91. 3. Malchers F, et al. Cancer Discov. 2014;4:246-57.Nogova L, et al. Presented at ASCO 2014. Abstract 8034.

Chromosome 8p geography

FIM trial BGJ398 in FGFR1-ampl. SQLC

Genomic discovery1 Pre-clinical validation1 FISH diagnostics2

Clinical evaluation

Understanding response on the molecular level3

n = 153

BGJ398 has clinical activity at doses ≥ 100 mg/day

HNSCC, head and neck squamous cell carcinoma. Sequist L, et al. Presented at AACR 2014. Abstract CT326.

RR FGFR1 amplified lung: 16% (RR FGFR-altered bladder: 40%)

Bes

t % c

hang

e fr

om b

asel

ine

(sum

of l

onge

st d

iam

eter

s of

targ

et le

sion

s)

0

80 60 40 20

−20 − 40 − 60

Bladder Breast Lung Cholangiocarcinoma HNSCC Other

Conclusion

• Targeted therapies extend survival over conventional chemotherapy (with improved QoL) in NSCLC

• Identification of patients for targeted therapies is key

• This can only be done by proper sequencing techniques – no clinical factor predicts reliably

• Calls for close cooperation between pathologists and treating physicians

Thank you for your attention!

Thermo Fisher Scientific and its affiliates are not endorsing, recommending, or promoting any use or application of Thermo Fisher Scientific products presented by third parties during this seminar. Information and materials presented or provided by third parties are provided as-is and without warranty of any kind, including regarding intellectual property rights and reported results. Parties presenting images, text and material represent they have the rights to do so.