highlights in drug therapy of tumors with oncogenic drivers · highlights in drug therapy of tumors...

Highlights in drug therapy of tumors with oncogenic drivers

Luis Paz-Ares

Hospital Universitario Doce de Octubre,

Madrid, Spain

Conflict of Interest Disclosure

Scientific advice and clinical trials

• MSD

• BMS

• Roche

• Astra-Zeneca

• Lilly

• Boehringer

• Clovis

• Pfizer

Topics

• New targets

• Met – Exon 14

• TRK 1

• DLL3 - SCLC

• Important Targets

• EGFR

• ALK, ROS, RET, BRAF

NSCLC - Genotype

NTRK fusions

Tumor Shrinkage Seen in Intermediate <br />and High MET Cohorts

Camidge RD et al. ASCO 2014

NSCLC with MET amplificationResponse to Crizotinib

Crizotinib in MET Amplified NSCLC

AcSé Trial• N = 25

• At 8 weeks – ORR 39%

– 7/18 PRs, 6/18 SD, 5/18 PD

Moro-Sibilot et al. WLCC 2015

MET mutations• Somatic mutations affecting splice

sites of exon 14 of the MET gene (MET ex14) were first reported in primary lung cancer

• MET ex14 alterations were shown to promote RNA-splicing-basedskipping of MET exon 14, whichresults in activation of MET kinaseactivity

• The portion of the protein encodedby exon 14 is required for efficientrecruitment of the ubiquitin ligaseCBL

• Loss of MET exon 14 maintains the reading frame and leads to increased MET stability and prolonged signaling upon HGF stimulation, leading to increasedoncogenic potentialMa et al, Cancer Res 2003

Kong-Beltran et al Cancer 2006Paik et al, Cancer Discovery 2015

MET exon 14 Mutations - Incidence

Disease

Cases with

MET exon

14

Total

casesFrequency

Lower -

Upper 95%

CI

Lung adenocarcinoma 131 4,402 3.0% 2.5 – 3.5%

Other lung neoplasms 62 2,669 2.3% 1.8 – 3.0%

Brain glioma 6 1,708 0.4% 0.1 – 0.8%

Tumors of unknown primary origin 15 3,376 0.4% 0.2 – 0.7%

Female reproductive system

neoplasm0 7,436 0%

0 – 0.05%

Colon and rectum neoplasm 0 3,714 0% 0 – 0.1%

Pancreas neoplasm 0 1,424 0% 0 – 0.3%

All other tumor types 7 13,299 0.05% 0.02 - 0.11%

Adrenal gland cortical carcinoma 1

Kidney renal cell carcinoma 1

Liver hepatocellular carcinoma 1

Skin merkel cell carcinoma 1

Soft tissue rhabdomyosarcoma 1

Soft tissue sarcoma 1

Soft tissue synovial sarcoma 1

Total 221 38,038

Frampton GM al. WLCC 2015

Pt 2 (A)

METex14 alteration (MET c.3028G>C) and multiple others

GCN =6

MET IHC H-score 300

Cabozantinib SD 5.1+ (CR by PERCIST)

Pt 4 (B)

METex14 alteration (MET c.3024_3028del) and multiple others

MET not amplified

MET IHC H-score 300

Crizotinib 3.6 months, PR

Pt 5 (C&D)

METex14 alteration (MET c.3001_3021del) and multiple others

GCN = 3.8

Crizotinib 4.6+ months, PR

Pt 7 (E)

METex14 alteration (MET c.3001_3021del)

MET not amplified

MET IHC H-score 300

Crizotinib 3.1+ months, PR

Paik PK, et al. Cancer Discov 2015

METex14 alterations and response to MET TKI

Selected examples

NTRK Fusions

Doebele et al. Cancer Discovery 2015

Single 5’ (green)Single 3’ (red)

Gene PatientsScreened

Positive Cases

Age (Years) Gender Smoking

Status Histology

NTRK1 443 5 - 1.1% 48 to 762M 3F

2 never 2 current

1 unknown

3 ADC1SCC1NE

NTRK2 410 5 - 1.2% 38 to 73 5M3 former 2 current

3 ADC 2 SCC

NTRK3 434 1 - 0.2% 66 1M 1 former 1 ADC

NTRK Fusions in NSCLC


LMNA:NTRK1 response to TRK inhibitor

Study baseline LOXO-101 cycle 5 day 1 LOXO-101 cycle 2 day 1


TRK inhibitors under development


DLL3 is a dominant inhibitor of Notch signaling

• Normally expressed during development in the Golgi

• Aberrantly expressed in SCLC tumor-initiating cells

• Interacts with and inhibits Notch1 in cis

• May mediate Notch inhibition downstream of ASCL1

DLL3 expression by IHC in SCLC

Vanderbilt SC16LD6.5 Trial Case Western

0

50

100

150

200

250

300C

ell

ula

r M

em

bra

ne

H-S

co

re

n = 50

Courtesy of A. Dowlati

n = 106 n = 22

VANDYTMA

(Naïve)

SC16LD6.5TRIAL

(Naïve)

CASE WSTTMA

C/E exposed

60% 70% 75%

22% 12% 10%

18% 18% 15%

High Expression

(DLL3+)

MediumExpression

LowExpression

Courtesy of P. Massion

Rovalpituzumab Tesirine(Rova-T™; SC16LD6.5)

0.001 0.01 0.1 1 100.0

0.5

1.0

1.5

2.0

2.5

DLL3DLL1

DLL4

[Ab], (nM)

Ab

so

rb

an

ce

(A

45

0)

Drug-to-Antibody Ratio (DAR) = 2

Cathepsin-B Cleavable Linker

PBD Dimer Toxin

Rubin et al. WLCC 2015

Rova-T: best response in evaluable patients 0.2 mg/kg q3w and 0.3 mg/kg q6w cohorts (n=60)

-60

-40

-20

0

20

40

60

80

Be

st R

esp

on

se

(R

EC

IS

T)

* LCNEC

**

*

*

*

**

ExpressionH-

ScoreSCLC %

High 180+ 69%

Medium 90-180 12%

Low 0-90 19%

Unknown NA

-60

-40

-20

0

20

40

Be

st

Re

sp

on

se

(RE

CIS

T) *

* LCNEC

Topotecan†

All Pts & dose levels

DLL3+Ph 1b

Cohorts

2nd Line 17% 22% 40%

3rd LineNo

Approved Drug

17% 38%

Rubin et al. WLCC 2015

DLL3+ Tumors (N=28)

Topics

• New targets

• Met – Exon 14

• TRK 1

• DLL3 - SCLC


• EGFR


Resistance to EGFR TKIs

Camidge DR et al. Nat Rev Clin Oncol. 2014;11:473–81

T790M: Severe structural changes in ATP-binding pocket

Michalczyk A et al. Bioorg Med Chem. 2008 Apr 1;16(7):3482-8.

Structural changes of the ATP pocket for greater steric hindrance of methionine compared to threonine

Treonina (~116 A) Metionina (~163 A)

T790M Exon 20 substitution

T790M Inhibitors

100

80

60

40

20

0

−20

−40

−60

−80

−100

SL

D c

han

ge f

rom

baseli

ne (

%)

+ Ongoing

500mg BID HBr

625mg BID HBr

750mg BID HBr

500mg 625mg 750mg Total

n 48 114 77 239

ORR (%) 60 54 46 52

DCR (%) 90 84 82 85

Rociletinib - Update Tiger X

Grade ≥3 treatment-related AEs

observed in >10% of patients, n (%)

AE Rociletinib dose

500mg BID

(n=119)

625mg BID

(n=236)

750mg BID

(n=95)

Hyperglycemia 20 (17) 56 (24) 34 (36)

Goldman JW et al. WLCC 2015

Plasma Testing for T790M has Good Sensitivity and Likely Good Specificity

Tissue*

Total

Positive NegativeInadequate

tissue

Plasma*

Positive 155 23 12 190

Negative 37 12 8 57

Total 192 35 20 247

• When inadequate tissue specimens are factored in, plasma testing identifies as many patients as T790M+ as tissue testing

• T790M tissue-plasma+ are not false positives – T790M confirmed in plasma on subsequent testing in 5/7 samples

Tissue as reference:Positive percent agreement

T790M81% (155/192)

Activating mutations87% (193/221)

24

* patients at all doses

L Sequist et al.,ASCO 2015

T790M

Status:

Plasma

−

n 64

ORR,

%45

DCR,

%83

T790M

Status:

Tissue

−

n 37

ORR,

%35

DCR,

%65

625mg BID

500mg BID

Phase 1 (Dose Escalation)Phase 2 Expansion Cohorts

(Required Central Tissue T790M Testing)

Rociletinib Treatment

(free base rociletinib,

followed by 500, 625, 750, and 1000mg

BID HBr)

750mg BID

2nd-line patients

PD upon 1 immediate prior TKI

>2nd-line patients

PD upon ≥2 TKI or chemotherapy

21-day cycles; escalate to MTD

Key outcome measures

• Safety

• Tolerability

• PK profile

• ORR

The most common treatment-related AEs were similar to those found in the general TIGER-X patient population (e.g., hyperglycemia, fatigue, diarrhea, and nausea)

Rociletinib in NSCLC - Negative Central Testing for T790M in TIGER-X

Wakelee H et al. WLCC 2015

AZD 9291 - AURA 2 Trial

Confirmed objective response Total

ORR† 71% (95% CI 64, 77)

Complete response,‡ n (%)

Partial response,‡ n (%)

Stable disease ≥6 weeks,§ n (%)

Progressive disease, n (%)

2 (1)

139 (70)

41 (21)

15 (8)

DCR92%

(95% CI 87, 95)

Best percentage change from baseline in target lesion – all patients

Complete responsePartial responseStable diseaseProgressive diseaseNot evaluable

100

80

60

20

-20

-40

-60

-80

-100

40

0

Mitsudomi et al, WCLC 2015

Discussion: Martin Reck

AZD9291AURA 21

AZD9291AURA 12

RociletenibTIGERX3

EGF8164

Patients 199 201 243 42

Dose 80 mg 80 mg 500-1000 mg (BID)

75-350 mg (QID)

Line oftreatment

1 TKI / > 1 TKI(1-9)

1 TKI / > 1 TKI(1-11)

1 TKI / > 1 TKI 1 TKI / > 1 TKI

RR 71% 61% 53% 60%

DCR 92% 91% 85% 93%

PFS 8.6 m (median)48% (9 m PFS

rate)

72%(6 m PFS rate)

8 m (median)

1 Mitsudomi 16.08., 2 Yang 16.06, 3 Sequist ASCO 2015, abstr. 8001, 4 Tam ASCO 2015, abstr. 8013

AZD9291AURA21

AZD9291AURA 12

RociletenibTIGERX3

Dose 80 mg 80 mg 500 mg BID

ILD 2% 4% (Gr.3 3%) 1.5%

Hyperglycemia 1% 1% 35% (Gr. 3 17%)

QT-Elongation 5% (Gr. 3 2%) 3% (Gr. 3 0%) 13% (Gr. 3 2.5%)

Rash 23% (Gr. 3 0%) 24% (Gr. 3 0%) Nr

Diarrhea 39% (Gr. 3 1%) 46% (Gr. 3 7%) 33% (Gr. 3 nr)

Discontinuation 4% 4% 2.5%

1. Mitsudomi 16.08., 2 Yang 16.06, 3 Sequist ASCO 2015, abstr. 8001, 4 Tam ASCO 2015, abstr. 8013

Discussion: Martin Reck

Rociletinib Resistance

fsDNA Plasma Monitoring

Z Piotrowska et al., Cancer Discovery 2015

Mechanisms of Resistance to AZD9291 in

EGFR T790M Positive Lung Cancer

• 15 (22%) out of 67 patients, had detectable C797S, all with detectable T790M

• C797S was more common with EGFR exon 19 del (13/43, 30%) vs those with L858R (2/24, 8%, p=0.06)

• 32 of 67 (48%) had no detectable T790M in plasma despite presence of the EGFR-TKI-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism, such as MET or HER2 amplification or BRAF V600E

Thress KS et al. Nature Medicine 2015Oxnard G et al. MINI 17.07

Emergence of HER2 amplification

• 15 cases completed plasma NGS after

resistance to AZD9291 (4 showing C797S)

• One patient treated at 80 mg had an

initial unconfirmed PR (-38%) followed by

new liver metastasis

• Whole genome sequencing of

resistance cfDNA found high level HER2

amplification

Baseli

ne

12

weeks

(PD)

21

weeks

(off tx)

L858R 85% 79% 82%

T790M 42% 0% 1%

EGFR

CNV

6 5 6

ERBB2

CNV

6 11 32

Chromosome 17

log2R

atio

3 Mb region on chromosome

17

log2R

atio

HER2

NEUROD2, PPP1R1B, STARD3, TCAP, PNMT,

PGAP3,

ERBB2, MIR4728, MIEN1, GRB7, IKZF3, ZPBP2

21 weeks

12 weeks (PD)

Baseline

Data source: D. Stetson, A. Markovets, B. Dougherty, Z. Lai, C. Barrett, K. Thress

CNV, copy number variation; PD, progressive disease; PR, partial response; tx, treatmentOral 17.07 – GR Oxnard

32

Long-Hua Guo, Xu-Chao Zhang, Zhi-Hong Chen, Jian Su, Jin-Ji Yang, Chong-Rui Xu, Zhi Xie, Wei-Bang Guo, Hong-Hong Yan, Xue-Ning Yang, Wen-Zhao Zhong, Qiu-Yi Zhang, Yi-Long Wu*, Qing Zhou*

Intratumor Heterogeneity of EGFR Activating

Mutations Analyzed in Single Cancer Cells in

Advanced NSCLC Patients

Guangdong Lung Cancer Institute, Guangdong General Hospital &

Guangdong Academy of Medical Sciences, Guangzhou/China

ORAL 16.07 – Q Zhang

MEK Inhibitors can overcome MAPK pathway

re-activation

TATTON study – ongoing

NCT02143466

EGFR-TKI naïve:

AZD9291 + durvalumab

Dose 2

AZD9291 (qd) + durvalumab (q 2 weeks)

Dose 2 – continuous

AZD9291 (qd) + selumetinib (bid) Asia

Dose 2 – continuous

AZD9291 (qd) + selumetinib (bid) ROW

Dose 2 – intermittent: 4 days on / 3 days off

AZD9291 (qd) + selumetinib (bid) ROW

Dose 2

AZD9291 (qd) + savolitinib (qd)

Acquired resistance to initial EGFR-TKI, cMET negative:

AZD9291 + selumetinib

Acquired resistance to initial EGFR-TKI, cMET positive:

AZD9291 + savolitinib

Dose 2

AZD9291 (qd) + durvalumab (q 4 weeks)

Dose 2

AZD9291 (qd) + durvalumab + tremelimumab (q 4 weeks)

Part A – Dose escalation

(all with acquired resistance to EGFR-TKI)

Part B – Dose expansion

(different lines of treatment)

Acquired resistance to T790M-directed EGFR-TKI, cMET negative:

AZD9291 + selumetinib

Acquired resistance to T790M-directed EGFR-TKI, cMET positive:

AZD9291 + savolitinib

Advance stageNSCLC with

EGFR Mutation

Gefitinib

PDBy RECIST

265 pts

Gefitinib +Alimta/Platinum

Alimta/Platinum

Primary endpoint: PFS

Progression-free survival inT790M mutation-negative patients

Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-

Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS

T790M Subgroup Analysis

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.2

0.3

0.1

0.0

0 2 8 10 14

Pro

bab

ility

of

PFS

Time of randomization (months)Patients at risk:

Gefitinib 46 43 37 20 16 7 4 0Placebo 59 46 38 17 7 4 3 0

4 6 12

Gefitinib (n=46)Placebo (n=59)

Mok T et al. ORAL 17.08

Gefitinib

(n=46)

Placebo

(n=59)

T790M mutation-

negative (n=105)

Median PFS,

months6.7 5.4

HRa (95% CI) = 0.67 (0.43, 1.03); p=0.07

aPrimary Cox analysis with covariatesA HR <1 implies a lower risk of progression with gefitinib

Discussant: T. Mitsudomi

• Retrospective study of 1,522 NSCLC patients diagnosed between 2007-2014

• EGFR mutations were more common in pts with brain metastases than extracranial

metastases or no metastasis (39% vs. 29% vs. 15%, p<.0001)

• The type of EGFR mutation (exon 19 vs. 21) did not correlate with the presence of

brain metastasis

• Patients with brain metastasis were 1.9 times more likely to have an EGFR

mutation than pts with extracranial metastasis (p=0.0002)

• Studies of prophylactic cranial irradiation in pts with earlier stages of EGFR

mutation positive NSCLC may be warranted

Presentation Number: 3282 – Zack Cheng

Encouraging intracranial tumor shrinkage was observed after AZD3759 treatment in an ongoing phase I trial.

AZD3759 Preclinical and ongoing phase I trial

NCT02228369

Anti-tumor activity

Baseline 6 weeks

Case#13: The patient is a 68 year old male with advanced EGFRm+ NSCLC, immediate prior treatment was pemetrexed. Intracranial tumor reduction of 36% was observed at 6 weeks.

#13

-2

-1

0

1

2

0 10 20 30 40

Lo

g re

la

tiv

e

bio

lu

min

esce

nce

(p

/s)

Study period (day)

Vehicle only

AZD3759 15mg/kg/qd

Erlotinib 15mg/kg/qd

Day0

Erlotinib

15mg/kg/qd

Vehicle

AZD3759

15mg/kg/qd

5 weeks

after treatment

Tumor growth curve in BM model Brain imaging in BM model

Cheng Z et al. WLCC 2015

LUX Lung 7: Randomized IIb Study

Advanced NSCLC

• Adenocarcinoma

• EGFR mut+

• First-line treatment

• PS 0-1

R

A

N

D

O

M

I

Z

E

Afatinib 40mg qd

Gefitinib 250mg qd

1

1

N= 319 patients

Primary endpoint: PFS 13.7 vs 10 months

HR 0.73

Complete

accrual N=319

Aug 16 2013

AZD9291 first-line cohorts by dose

Ramalingam SS et al. MINI 16.07

80 mg

N=30

160 mg

N=30

Total

N=60

Confirmed objective

response rate

67%

(95% CI

47, 83)

83%

(95% CI

65, 94)

75%

(95% CI

62, 85)

Disease control rate

93%

(95% CI,

78, 99)

100%

(95% CI

88, 100)

97%

(95% CI

89, 100)

Best objective

response

Complete response

Partial response

Stable disease

Progressive disease

0

20

8

2

2*

23

5

0

2*

43

13

2

D

DD

D DDDDD

D

D

80 mg

160 mg

D

D

D

1

0

08

07

06

04

02

01

00-

1

0

-

2

0-

4

0-

6

0-

8

0-

1

0

0

5

03

0

-

3

0

DD

Best percentage change in

target lesion size – all

patients

-

9

0

-

7

0

-

5

0

9

0

80 mg

N=30

160 mg

N=30

Total

N=60

Median PFS,‡ months

(95% CI)

NC (12.3, NC)

Maturity: 40%

NC (11.1, NC)

Maturity: 30%

NC (13.7, NC)

Maturity: 35%

Maximum PFS, months 19.2+ 13.8+ 19.2+

Remaining alive and

progression-free,† % (95% CI)

9 months

12 months

83 (64, 93)

75 (55, 87)

80 (60, 90)

69 (48, 82)

81 (69, 89)

72 (58, 82)

1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0

Pro

ba

bili

ty o

f re

sp

on

se

1

5

1

2

630Month

0.6

0.1

Number of

patients at risk:

AZD9291 80 mg

30 26 23

9 1

8

AZD9291 160 mg

22 19 12 3

30 29 27160 mg 23 17 0 0

Censored observation

Censored observation

FLAURA Study Design

Randomize patients 1:1

Enrollment by local*

or central# EGFR mutation testing of biopsy sample

Stratified by:

Asian /non-Asian

Ex19del / L858R

RECIST 1.1 assessment

every 6 weeks until objective

progressive disease

Patients randomized to

standard of care may receive

AZD9291 after progression§

Primary objective:

efficacy by PFS

AZD9291(80 mg p.o. qd)

EGFR-TKI standard of care##: gefitinib (250 mg p.o. qd) or

erlotinib (150 mg p.o. qd)

*With central laboratory assessment performed for sensitivity#cobas™ EGFR Mutation Test (Roche Molecular Systems)##Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation§Patients randomized to the standard of care treatment arm may receive open-label treatment with AZD9291 on central confirmation of

both objective disease progression and T790M positive tumor

OS, overall survival; PFS2, second progression-free survival (time from randomization to second progression); p.o., orally

NCT02296125

Topics

• New targets

• Met – Exon 14

• TRK 1

• DLL3 - SCLC


• EGFR


Next-generation ALK inhibitors

Marsilje, et al. J Med Chem 2013

Crizotinib Ceritinib TAE684

AlectinibBrigatinib ASP3026X-396

New ALK inhibitors should be active against resistance mutations, have proven

CNS activity, improved systemic efficacy and have an acceptable safety profile

Ceritinib in patients with ALK+ NSCLC treated

with prior ALK inhibitors

1. Felip, et al. ESMO 2014; 2. Mok, et al. ASCO 2015

ASCEND-22 Efficacy

(by investigator)

Prior crizotinib

n=140

Median duration of follow-up, months 11.3

ORR, %

[95% CI]

39

[30.5–47.2]

DCR, %

[95 % CI]

77

[69.3–83.8]

Median DoR, months

[95% CI]

9.7

[7.1–11.1]

Median PFS, months

[95% CI]

5.7

[5.4–7.6]

ASCEND-11 Efficacy

(by investigator)

Prior ALK TKI

n=163


ORR, %

[95% CI]

56

[48.5–64.2]

DCR, %

[95% CI]

74

[NR]

Median DoR, months

[95% CI]

8.3

[6.8–9.7]

Median PFS, months

[95% CI]

6.9

[5.6–8.7]

PD

Dose

escalation

Expansion

phase

Expansion groups

• ALK inhibitor naïve

• ALK inhibitor pre-treated

• Non-NSCLC

Ceritinib 50–75mg/day

• Stage IIIB/IV NSCLC

• ALK+ disease according to FISH test

• ECOG PS 0–2

(n=255)

Ceritinib750mg/day

Ceritinib 750mg BID

PD

• Stage IIIB/IV NSCLC

• ALK+ disease

• Prior crizotinib treatment

• Chemotherapy pretreated

(n=140)

Brigatinib in the crizotinib-failure setting

Gettinger, et al. WCLC 2015

Efficacy (by IRC)

Prior crizotinib

n=70


ORR, %

[95% CI]

71

[59–82]

DCR, %

[95% CI]

87

[NR]

Median DoR, months

[95% CI]

9.9

[NR]

Median PFS, months

[95% CI]

13.4

[NR]

Other ALK+ or ROS1+ cancers

• Advanced malignancies

• All histologies except leukaemia (phase I)

• Refractory to available therapies or no standard treatment (phase I)

• ECOG PS 0–1

(n=137)

ALK+ NSCLC(ALK inhibitor naïve)

ALK+ NSCLC(crizotinib resistant)

EGFR T790M+ NSCLC(EGFR TKI resistant)

Phase I Phase II

ALK+ NSCLC (CNS mets)(crizotinib-naïve or -resistant)

Brigatinib30–300mg/day

IRC = independent review committee; NR = not reported

Withdrawal/long-term

follow up or treatment

beyond progression

• Locally advanced ormetastatic NSCLC

• ALK+ disease

• Prior crizotinib treatment

• ECOG PS 0–2

Alectinib 600mg BID

(as determined in the dose-

escalation study1)

Investigator decision

Trial designs: NP28761 and NP28673

1. Gadgeel, et al. Lancet Oncol 20142. Shaw, et al. WCLC 2015; 3. Barlesi, et al. ECC 2015

NP28761 (N. America)2

n=87

NP28673 (Global)3

n=138

Primary endpoint(s) ORR by IRC in RE population

ORR by IRC in RE population

and prior chemo subgroup

(co-primary endpoints)

Key secondary

endpointsCNS ORR; CNS DoR CNS ORR; CNS DoR

NP28761 and NP28673: ORR by IRC

Shaw, et al. WCLC 2015; Barlesi, et al. ECC 2015

NP28761n=67

NP28673n=122

Median follow-up, months 9.9 14.5

ORR, %[95% CI]

52 [39.7–64.6]

51[41.6–60.0]

CR 0 0

PR 52 51

SD 27 28

PD 16 18

Missing or unevaluable 5 3

DCR, %[95% CI]

79[67.4–88.1]

79[70.4–85.6]

Median DoR, months[95% CI]

13.5[6.7–NE]

14.1[10.9–NE]

NP28761 and NP28673: PFS (ITT)

Shaw, et al. WCLC 2015; Barlesi, et al. ECC 2015

NP28761 NP28673

1.0

0.8

0.6

0.4

0.2

0

PF

S e

stim

ate

0 3 6 9

Time (months)

12 15 18 21

Median PFS 8.1 months

Alectinib 600mg

(n=138)

Median PFS 8.9 months

Alectinib 600mg BID

(n=87)

1.0

0.8

0.6

0.4

0.2

0

96 123 15 18 210

Time (months)

Summary of data for alectinib, ceritinib and

brigatinib

Shaw, et al. WCLC 2015; Barlesi, et al. ECC 2015; Felip, et al. ESMO 2014

Mok, et al. ASCO 2015; Gettinger, et al. WCLC 2015; Camidge, et al. ECC 2015

Alectinib Ceritinib Brigatinib

NP28761

(N. American)

n=87

NP28673

(Global)

n=138

ASCEND-1

Prior ALKi

n=163

ASCEND-2

(prior

crizotinib)

n=140

Prior

crizotinib

n=71

RE population n=67 n=122 n=163 n=140 n=70

Median follow-up, months 9.9 14.5 11.1 11.3 13.8

ORR, % 52.2 50.8 56.4 38.6 71

Complete response 0.0 0 1.8 2.9 6

Partial response 52.2 50.8 54.6 35.7 66

Stable disease 26.9 27.9 17.8 38.6 16

Progressive disease 16.4 18.0 9.8 13.6 9

Missing or unevaluable 4.5 3.3 16.0 9.3 4*

Disease control rate 79.1 78.7 74.2 77.1 87

Median DoR, months 13.5 14.1 8.3 9.7 9.9

Median PFS, months 8.1 8.9 6.9 5.7 13.4

Alectinib activity in CNS disease

Data cut-off for both studies 27 April 2015 Gadgeel, et al. WCLC 2015

36%

86%

59%

83%

Prior CNS radiation (n=95)

No prior CNS

radiation (n=41)

Perc

enta

ge

Prior radiation (n=34)

No prior radiation (n=16)

70

60

50

40

30

20

10

0

–10

–30

–40

–50

–60

–70

–80

–90

–100

Sum

of

longest dia

mete

r,

max.

decre

ase f

rom

baselin

e (

%)

–20

Patients

Patients with measurable and

non-measurable CNS disease (n=136)

Patients with measurable CNS disease

(n=50)

100

0

20

40

60

80

CNS ORR CNS DCR

CNS activity of second-gen ALK inhibitors

(IRC assessment)

*Pooled data from the two phase II studies**Data for investigator assessment: 45% ORR, 80% DCR§Disappearance of all lesions

Gadgeel, et al. WCLC 2015 Camidge, et al. ECC 2015; Mok, et al. ASCO 2015

Alectinib* Ceritinib** Brigatinib

Measurable

(n=50)

Measurable

(n=33)

Measurable

(n=15)

CNS ORR, % 64 39 53

Complete response§ 22 3 7

Partial response 42 36 47

Stable disease 26 46 33

Progressive disease 6 0 13

CNS DCR, % 90 85 87

Median CNS DoR, months 10.8 – –

Phase 2 study of dabrafenib + trametinib in previously-treated BRAF V600E Mut+ NSCLC

52

• The median duration of response was not reached

Maxim

um

Perc

ent

Reduction a

t T

ime o

f B

est

Dis

ease A

ssessm

ent

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

Best Confirmed Response PR

SD

PD

a1 patient discontinued at day 23 and did not have any post-baseline scans for efficacy.

D Planchard et al. J Clin Oncol 2015

• Identify the target and provide adequate treatment

• The best treatment first principle!

• The more treatments the longer survival

• Choose the adequate sequence for each patient

and tumor

EGFR TKI + anti-VEGF TKI beyond

progression ?

T790M therapy

BSCPlatin-chemo

Chemo + TKI

EGFR TKI +By –pass Track TKI

Oncogene Addicted Lung Cancer

Some principles !

Re

-bio

psy

Re

-bio

psy

Local

The

rapy

Local

The

rapy

Gracias

[email protected]

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