Targeted Therapies for Advanced NSCLC - ceconcepts.com to the Future with... · 2016-06-09 · Targeted Therapies for Advanced NSCLC. Current Clinical Developments . Friday, June

Targeted Therapies for Advanced NSCLC

Current Clinical Developments Friday, June 3, 2016

Supported by an independent educational grant from AstraZeneca

Not an official event of the 2016 ASCO Annual Meeting

Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation

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1. Review the molecular pathology of lung cancer and examine its relevance for clinical practice.

2. Outline the safety and efficacy of first-line therapies for advanced NSCLC, including first generation EGFR and ALK inhibitors.

3. Evaluate treatment approaches used to overcome EGFR and ALK resistance in advanced NSCLC, including the safety and efficacy of second- and third-line therapies and recommended molecular testing.

4. Appraise emerging concepts with EGFR TKIs and ALK inhibitors, including their role in adjuvant therapy, combination therapies, and other evolving data.

Learning Objectives

Looking to the Futurewith Targeted Therapies in NSCLC

Tony Mok, MD Li Shu Fan Medical FoundationProfessor of Clinical Oncology Department of Clinical OncologyThe Chinese University of Hong KongHong Kong, China

• I consult for ACA Biosciences, AstraZeneca, AVEO Oncology/Biodesix, BioMarin, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, geneDecode, GlaxoSmithKline, Janssen, Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche/Genentech, SFJ Pharmaceuticals Group, and Vertex

• I am a member of the speakers’ bureaus for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, and Roche/Genentech

• I am a major stock holder in Sanomics Ltd• I am not on any scientific advisory boards

Disclosures

Looking into the Future

"Those that fail to learn from history, are doomed to repeat it."

Winston Churchill

Looking to Next Five Years Based on History of The Past Five

20162011 to 2015 2017 to 2021

2011 to 2015

MADE IT DIDN’T MAKE IT• Crizotinib for ALK positive lung

cancer• Ramucirumab as second line

therapy• Necitumumab for squamous

cell carcinoma• Ceritinib/alectinib as second

line therapy for crizotinib failure

• Osimertinib for T790M positive lung cancer (post TKI failure)

• Nivolumab/pembrolizumab as second line therapy

• MAGE A3 vaccine as adjuvant therapy for resectable lung cancer

• Tecemotide for stage III lung cancer

• Bevacizumab as adjuvant therapy for resectable lung cancer

• Erlotinib as adjuvant therapy for resectable lung cancer

2011 to 2015












Why didn’t we make it?

Why didn’t we make it?

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 60 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1 .0

O v e ra ll S u rv iv a l (M o n th s )

Ove

rall

Sur

viva

l Pro

babi

lity

E r lo tin ib P la c e b o

P la c e b o (1 3 e v e n ts )M e d ia n : n o t re a c h e d

E rlo tin ib (2 2 e v e n ts )M e d ia n : n o t re a c h e d

L o g -ra n k te s t: p = 0 .8 1 5 3

H R : 1 .0 9 (9 5 % C I: 0 .5 4 5 , 2 .1 6 1 )

N u m b e r a t R isk

5 69 4

5 39 1

3 04 3

5 71 0 0

5 91 0 2

5 18 8

5 08 6

4 17 5

2 42 6

57

00

1 41 5

P la c e b oE rlo tin ib

RADIANT

STARTMARGRIT

ECOG1505

EGFR by IHC or FISH

NoneMAGE-A3

expression by IHC

None

Biomarker-Based Adjuvant Studies

2016 2017 to 2021

Kelly K, et al. J Clin Oncol. 2015.

RADIANT EGFRm Subgroup Disease-Free Survival

0 6 12 18 24 30 36 42 48 54 60 660.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Disease-free Survival (Months)

Dise

ase-

free

Surv

ival P

roba

bility

PlaceboErlotinib

Placebo (32 events)Median: 28.5 m

Erlotinib (39 events)Median: 46.4 m

Log-rank test: p=0.0391

HR: 0.61 (95% CI: 0.384, 0.981)

Number at Risk4380

3576

1222

4994

59102

3068

2356

1535

1010

00

00

53

PlaceboErlotinib

The difference is not

statistically significant

Kelly K, et al. J Clin Oncol. 2015.

RADIANT EGFRm Subgroup Overall Survival

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 60 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1 .0

O v e ra ll S u rv iv a l (M o n th s )

Ove

rall

Su

rviv

al P

rob

ab

ility

E r lo tin ib P la c e b o

P la c e b o (1 3 e v e n ts )M e d ia n : n o t re a c h e d

E rlo tin ib (2 2 e v e n ts )M e d ia n : n o t re a c h e d

L o g -ra n k te s t: p = 0 .8 1 5 3

H R : 1 .0 9 (9 5 % C I: 0 .5 4 5 , 2 .1 6 1 )

N u m b e r a t R isk

5 69 4

5 39 1

3 04 3

5 71 0 0

5 91 0 2

5 18 8

5 08 6

4 17 5

2 42 6

57

00

1 41 5

P la c e b oE rlo tin ib

CTONG1104 Phase III Trial Adjuvant Gefitinib vs Chemotherapy

EGFR M+ Post-surgical Stage II and Stage III A

NSCLC

Adjuvant gefitinib (24 months)

Adjuvant vinorelbine plus platinum chemotherapy (4 cycles)

Primary:Disease Free

Survival

Secondary:OS

DDFSSafety

QoL

1:1 randomization

• Sample size was estimated to be 220 when HR of DFS; the primary endpoint was estimated to be 0.6; the enrollment period was to be 2 years; the period of follow-up after the final enrollment was to be 5 years; statistically significant level (α) was to be 0.05; the statistical power was to be 80%; the estimated total events is 122 from 208 analysed patients.

NCT01405079

FPI: Sept 15, 2011

24 sites, 41 patients randomized (2012/9)

Stage II-IIIA (N1-N2) NSCLC with EGFR activating mutation (ADJUVANT)

IMPACT: WJOG6410L

Cisplatin80 mg/m2 d1Vinorelbine

25 mg/m2 d1, 8

q3 weeksX 4 courses

Gefitinib250 mg/day for 2

yearsPatients• Completely

resected, stage II-III NSCLC

• EGFR mutation (exon 19 del or L858R)

• NO T790M

Stratification• Institution• Stage• Gender• Age

Endpoints1 ̊ Disease free survival2 ̊ OS Safety Recurrence Pattern

Off studyNo mutation

N=115

N=115

Assumptions:• DFS for chemo 28 months• HR=0.65• Alpha=0.0025(0ne sided), beta=0.2• Necessary DFS events=169• Registration 3y, f/u 5y• Sample size=217

PI: Hitohito Tada, MD

CDDP/VNRMedian PFS=28 monthsMedian DFS=43 monthsHR=0.65

Potential problems with both studies:1. DFS as primary endpoint2. Not powered for overall survival3. Duration of exposure to TKI at 2 years

Gefitinib for Mutation+ Lung Cancer as Adjuvant Chemotherapy (A randomized phase III trial of adjuvant gefitinib versus cisplatin and vinorelbine in completely

resected (stage II-III) NSCLC patients with mutated EGFR)

ALCHEMIST-Screening Study Trial Schema

Trials conducted at sites in theNCI Clinical Trials Networks: NCTN & NCORPNon-squamous NSCLC (n=6000 to 8000 pts)Clinical/Pathologic Stage IB (>4cm), II, IIIAPost-Op cohort with negative surgical margins

Pre-opcohort

Post-opcohort

Completeresection+ standardadj therapyper treatingphysician

CentralEGFR & ALKgenotyping

FFPE tissue &blood specimen

EGFR-mutation:Phase III trial of erlotinibvs placebo x 2 years(n=410) after any adj txALK-rearranged:Phase III trial of crizotinibvs placebo x 2 years(n=360) after any adj tx

Without MolecularAlterations: Followedq6 months x 5 years afterany adj tx

FFPE tissue from biopsydone at recurrence

Advanced genomics at the NCI

ALCHEMISTEGFR Treatment Trial A081105

ResectedNSCLC tissue

tested onALCHEMISTScreening

Trial

Patients withtumors with

an EGFRmutation

RANDOM IZE

Erlotinib150 mg po BID x

2 years

Placebopo BID x2 years

Long TermFollow-up

Long TermFollow-up

1 cycle = 21 days

Primary endpoint is overall survival

ALCHEMISTALK Treatment Trial E4512

Accrual has been slow!!

ResectedNSCLC tissue

tested onALCHEMISTScreening

Trial

Patients withtumors with

an ALKre-arrangement

RANDOMIZE

Crizotinib250 mg po BID x

2 years

Placebopo BID x2 years

Long TermFollow-up

Long TermFollow-up

1 cycle = 21 days

Primary endpoint is overall survival

ADAURA Phase III Trial Osimertinib vs Placebo

Placebo

Stage IB-IIIAPrimary NSCLC

EGFR mutation positive including

the atypical mutations

WHO PS0,1Completed resection

and adjuvant chemotherapy

Osimertinib

•Primary endpoint: disease-free survival (DFS)•Secondary endpoints: OS, DFS and OS in patients with del19/L858R

2:1 2 yr treatment period

ClinicalTrials.gov Identifier: NCT02511106.

2011 to 2015












What is the reason(s) for success?

Best % change from baseline in target lesionsLDK378 400–750 mg/day

Crizotinib

Ceritinib

Osimertinib

Kwak. N Engl J Med. 2011; Shaw AT, et al. N Engl J Med. 2014; Jänne PA, et al. N Engl J Med. 2015.

• Specific biomarker selection• Expanded phase I program

Should we combine EGFR/ALK TKI with other agent(s)?

Antiangiogenesis Chemotherapy

EGFR/ALK TKI

Immunotherapy

Potential Combination(s)


EGFR/ALK TKI

Immunotherapy


Seto T, et al. Lancet Oncol. 2014.

JO25567 Phase II TrialErlotinib +/- Bevacizumab

Assessed for eligibility

Withdrew before treatment started:Thrombosis: 1Pleural effusion: 1

Randomized (N=154)

Received EB and eligible for analysis

(N=75)

Received E and eligible for analysis

(N=77)

E monotherapy(N=77)

EB combination(N=77)

Seto T, et al. Lancet Oncol. 2014.

JO25567 Phase II Trial PFS by Independent Review

EB E

Median (months)

HR 0.54 (95% CI, 0.36–0.79)

P value*

75 72 69 64 60 53 49 38 30 20 13 8 4 4 077 66 57 44 39 29 24 21 18 12 10 5 2 1 0

00

1.0

EEBNumber at risk Time (months)

4 8 122 6 10 14 18 22 2616 20 24 28

0.2

0.4

0.6

0.8

PFS

prob

abili

ty

9.7 16.0

EB

E

*log-rank test, two-sided

NEJ026 Phase III TrialErlotinib +/- Bevacizumab

Non-sq NSCLCPreviously untreated

Age 20 or aboveEGFR M+

N=214

Erlotinib + Bevacizumab

Recommend Pem/Platinum +

Bevacizumab

RecommendPem/Platinum

Erlotinib

PD1

PD1

Primary endpoint: PFSSecondary endpoint: OS, RR, Safety

RELAY Phase III Trial Erlotinib +/- Ramucirumab

• Age >18• Stage IV NSCLC• EGFR exon

19/21 +ive• T790m -ive• Measurable

disease

N=462

Ramucirumab10 mg/kg

every 2 wks +Erlotinib

150 mg daily

Placebo +Erlotinib

150 mg daily

Primary endpoint: PFS

Started in May 2015


EGFR/ALK TKI

Immunotherapy


Wu YL, et al. Lancet Oncol. 2013.

FASTACT-2 Phase III Trial Intercalated Chemotherapy and Erlotinib

Stage IIIB/IV untreated NSCLC

EGFR Mutation

EGFR Wild Type

Erlotinib (49 patients)Placebo (48 patients)

Prog

ress

ion

free

su

rviv

al (%

)

100

80

60

40

20

0Number at risk

ErlotinibPlacebo

4948

4840

46 45 42 37 33 29 25 22 19 16 11 9 6 4 0035 27 16 8 5 4 4 3 2 2 2 1 1 1

Erlotinib (69 patients)Placebo (67 patients)

Prog

ress

ion

free

su

rviv

al (%

)

100

80

60

40

20

0

Number at riskErlotinibPlacebo

69 564645 0

0165 3

22 2

1 1 1123335967 55 33

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0001

111

1357101536 0

Time (months)38

Cheng Y, et al. WCLC. 2015.

JMIT 05 Phase II East-Asian Trial Gefitinib +/- Pemetrexed

• Planned enrollment of 188 patients for 145 PFS events with 70% power to detect an HR=0.79 with a one-sided α level of 0.2

• Tumor samples were collected for biomarker analyses• Patients were followed up approximately every 90 days (±14 days) after study treatment

discontinuation for survival

Inclusion Criteria•Adult patients ≥18 years (≥20 years in Japan and Taiwan)•Confirmed advanced (Stage IV) or recurrent NS NSCLC•Activating EGFR mutations•ECOG PS ≤1•No prior systemic chemotherapy, immunotherapy, or biological therapy

•Enrollment period: February 2012 – August 2013•Data cut-off date: 22 April 2015

Oral gefitinib 250mg daily + pemetrexed 500 mg/m2

IV on Day 1 every 3-week cycle (N=126)

Standard folic acid and Vitamin B12

supplementationN=191

2:1

Oral gefitinib250 mg daily

(N=65)

RANDOMIZE

Until disease progression, unacceptable

toxicity, or another

permitted reason for study discontinuation

Primary Endpoint: PFSKey Secondary Endpoints: Overall survival (OS), Overall response, Disease control rate (DCR), Duration of response (DoR), Quality of life (QoL), Safety

Cheng Y, et al. WCLC. 2015.

JMIT 05 Phase II East-Asian Trial PFS (Primary End Point)

Significantly prolonged median PFS in the gefitinib + pemetrexed arm (15.8 months) vs the gefitinib arm (10.9 months)

Prob

abili

ty

10.90.80.70.60.50.40.30.20.1

00 6 12 18 24 30 36

Progression-Free Survival (Months)

GefitinibGefitinib + Pemetrexed

Median PFS, months (95% Cl)

15.8 (12.6, 18.3)10.9 (9.7, 13.9)

Adjusted HRAdjusted P-value 1-sided=0.01; 2-sided=0.03

0.68 (0.48, 0.96)

Patients at RiskGefitinib + PemetrexedGefitinib

12665 51 17

1828

11

006

69 4997

Han B, et al. ELCC. 2016.

Gefitinib +/- Pemetrexed/Carboplatin Randomized Phase II Study

Advanced NSCLC• Adenocarcinoma• EGFR exon 19/21

mut+• First-line treatment• PS 0-1

RANDOMIZE

Pem/carbo +Gefitinib day 5 to 21

x 6 cycles

Pem/carbo x 6 cycles

N=121 patients

Primary endpoint in

PFS

Gefitinib

PFS 18.8 monthRR 83%

PFS 5.8 monthsRR 33%

PFS 12 monthsRR 66%

Is Pemetrexed + Gefitinib better?

Pem/carbo + Gefitinib: Median PFS 16 months

Gefitinib: Median PFS 10 months Pem/carbo: PFS 6 months


EGFR/ALK TKI

Immunotherapy


What can we expect from anti-PD-1/PD-L1 therapy in patients with EGFR/ALK driver

oncogenes?

PD-1/PD-L1 InhibitorsMGH Retrospective Analysis Characteristic EGFR-Mutant or ALK-Positive

(N=26)EGFR WT or ALK-Negative

(N=28) P Value

Age at DiagnosisMedianRange

54.536-75

64.552-77

.004

Smoking History – no. (%) NeverLight (≤10 pack-years)Heavy (>10 pack-years)

14 (54)6 (23)6 (23)

1 (4)1 (4)

26 (93)

<.001

HistologyAdenocarcinomaSquamous

25 (96)1 (4)

20 (71)7 (25)

.036

Molecular Genotype – no. (%) EGFR MutationALK RearrangementKRAS MutationOther/Unknown

20 (77)6 (23)0 (0)0 (0)

0 (0)0 (0)

10 (36)18 (64)b

<.001

Prior Lines of TherapyMedianRange

30-8

20-4

.006

Prior TKIs – no. (%) 22 (85) 5 (18) <.001

PD-1 vs. PD-L1 InhibitorsPD-1 InhibitorsPD-L1 Inhibitors

21 (81)5 (19)

19 (68)9 (32)

.358

PD-1/PD-L1 InhibitorsResponse by Mutation or Smoking Status

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

EGFR-mutant orALK-positive

EGFR WT/ALKnegative

P=.052

ORR

(%)

Objective Response Rate by Mutation Status

3.8%

25%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

Never/LightSmokers

Heavy SmokersO

RR (%

)

P=.122

Objective Response Rate by Smoking Status

4.5%

21.9%

PD-1/PD-L1 InhibitorsPFS by Mutation Status

Months

EGFR Mut or ALK+EGFR WT or ALK -

Median 95% CI 1.93 months 1.87-2.30 months2.20 months 1.93-5.80 months

P=0.041Hazard Ratio 0.577

Progression-Free Survival

Months

Endpoint

Surv

ival

Pro

babi

lity

(%)

No. at Risk

Group 1

Group 2

26

28

3 1 1 1 1 0

0233610

ALK TKI with Immunotherapy Cohorts

[-1 dose cohort] ceritinib 300 mg daily + nivolumab (3 mg/kg every 2 weeks) [1st dose cohort] ceritinib 450 mg daily + nivolumab (3 mg/kg every 2 weeks)

[starting doselevel]

[2nd dose cohort] ceritinib 600 mg daily + nivolumab (3 mg/kg every 2 weeks)

Dose-escalation phase Dose expansion phase

N=30Nivolumab + Ceritinib

(at MTD or RDE)ALK inhibitor-treated

(ALK inhibitor aslast therapy excluding ceritinib)

N=30Nivolumab + Ceritinib

(at MTD or RDE)ALK inhibitor naïve

N=3-6Ceritinib 300 mg +

Nivolumab3mg/kg


Nivolumab 3mg/kg


Nivolumab 3mg/kg Dose Level 1

Starting Dose

2nd Dose Level

TATTONMulti-Arm Osimertinib Phase IB Trial

Ahn M, et al. ELCC. 2016.

Part A – dose escalationPatient with progression on any EGFR TKI Part B – dose expansion

Osimertinib + durvalumab (anti-PD-L1 mAb) First-line: osimertinib + durvalumab

Osimertinib + selumetinib (MEK1/2 inhibitor)

T790M-directed EGFR-TKI progressors, cMET negative: osimertinib + selumetinib

>Second-line, cMET negative: osimertinib + selumetinib

Osimertinib + savolitinib (MET inhibitor)

>Second-line, cMET positive: osimertinib + savolitinib

T790M-directed EGFR-TKI progressors, cMET positive: osimertinib + savolitinib

TATTON Phase IB TrialOsimertinib + Durvalumab


Characteristic, n

Part A Part BOsimertinib 80 mg daily/durvalumab

3 mg/kg every 2 weeks(N=10)

Osimertinib 80 mg daily/durvalumab10 mg/kg every 2

weeks (N=13)

Osimertinib 80 mg daily/durvalumab

10 mg/kg every 2 weeks (N=11)

GenderMale/Female 3/7 6/7 6/5

Age, median (range), years 67 (46-78) 58 (44-73) 57 (46-70)

Treatment location and ethnicityAsia/USAJapanese/Asian Black/White

6/43/5/1/1

7/62/8/1/2

10/15/6/0/0

SmokerCurrent/Former/Never/Unknown 0/3/7/0 1/1/9/2 1/5/5/0

Therapy line, median (range) 3.5 (2-10) 3 (2-5) N/A: all treatment naïve

Immediate prior therapyGefitinib/Erlotinib/Afatinib/Other 4/1/3/2 2/5/1/5 N/A: all treatment naïve

EGFRmEx19 del/L858R/Unknown 6/4/0 5/7/1 8/2/1

T790M statusNegative/Positive 7/3 7/6 11/10

TATTON Phase IB TrialOsimertinib + Durvalumab: Toxicity


AE by preferred term, occurring in >3 patients at any dose, n

Part A Part B

Osimertinib 80 mg daily/durvalumab

3mg/kg every 2 weeks (N=10)

Osimertinib 80 mg daily/durvalumab10mg/kg every 2

weeks (N=13)

Osimertinib 80 mg daily/durvalumab10mg/kg every 2

weeks (N=11)

Any Grade Grade >3 Any Grade Grade >3 Any Grade Grade >3

Rash (grouped terms) 5 1 6 0 7 0

ILD (grouped terms) 2 1 4 1 7* 3

Diarrhea 3 0 3 0 5 0

Pyrexia 2 0 2 0 4 0

Stomatitis 1 0 1 0 4 0

Nausea 3 0 5 0 3 0

Anemia 4 0 4 1 1 0

Vomiting 7 1 2 0 0 0

Decreased appetite 3 1 4 0 1 0

TATTON Phase IB TrialOsimertinib + Durvalumab: Tumor Response


Investigator-assessed ORR was 67% (6/9) and 21% (3/14) in patient with T790M positiveAnd T790M negative NSCLC, respectively, and 70% (7/10) in EGFRm treatment-naïve patients

Best

per

cent

age

chan

ge fr

om b

asel

ine

in ta

rget

lesi

on si

ze (%

)

Best percentage change in target lesion size

Part A T790M positive Part A T790M negative Part B First-line therapy

40

20

0

-20

-40

-60

-80

-100

Long List of Early Trials

• Durvalumab + Gefitinib in EGFR mut+ NSCLC

• Durvalumab + Osimertinib in EGFR mut+ NSCLC [part of TATTON]

• Nivolumab + Erlotinib in EGFR mut+ Erlotinib failure [part of Checkmate 012]

• Nivolumab + Ceritinib in ALK translocated Crizotinib failure

• Atezolizumab + Erlotinib in EGFR mut+ NSCLC

• Atezelizumb + Alectinib in ALK translocated Crizotinib failure

• Pembrolizumab + Rociletinib in EGFR mut+ Erlotinib failure

• Pembrolizumab + Afatinib in EGFR mut+ Pembrolizumab failure

• Pembrolizumab + Crizotinib in ALK translocated NSCLC

• Pembrolizumab + Dabrafenib/Trametinib in KRAS mut+ NSCLC

ClinicalTrials.gov. March 29, 2016.

Looking into the Future

ARCHER 1050 Phase III Study Dacomitinib vs Gefitinib

Advanced NSCLC• Adenocarcinoma• EGFR exon 19/21

mut+• First-line treatment• PS 0-1

RANDOMIZE

Dacomitinib45 mg daily

Gefitinib250 mg daily

1

1

N=440 patients

Primary endpoint in

PFS14.8 vs 9.5

months

Stratification- Race- Exon 19 v 21

Completed accrual in March 2015

FLAURA Phase III Study Osimertinib vs Gefitinib or Erlotinib

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

Osimertinib (80 mg po daily)

EGFR-TKI standard of care##: gefitinib

(250 mg po daily) or erlotinib (150 mg po

daily)

*With central laboratory assessment performed for sensitivity#cobasTM 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

Targeting EGFR MutationsFuture Advanced stage NSCLC

EGFRm(by tissue or blood)

Gefitinib Erlotinib+/-Bev Afatinib DacomitinibOsimertinib

OsimertinibRociletinibHMI 61713

PD

Chemo +/-Bev

T790m+ T790m-

Rebiopsy

Continue TKI beyond RECIST

PD

Anti-C797S Tx

? role of ICI

ASCEND-4 Phase III Study Ceritinib vs Chemotherapy

Ceritinib 750 mg(N=174)

Pemetrexed/cisplatinOR

Pemetrexed/carboplatin every 3 weeks

(N=174)

Pemetrexedevery 3 weeks

Eligibility criteria:• ALK-positive locally

advanced/metastatic non-squamous NSCLC

• No prior treatment for advanced disease

RANDOMIZE

Primary endpoint = PFS

Eligibility criteria:• ALK-positive

locally advanced/metastatic NSCLC

• No prior treatment for advanced disease

RANDOMIZE

Alectinib 600 mg BID (N=143)

Crizotinib 250 mg BID (N=143)

Primary endpoint = PFS by IRR*J-ALEX

ASCO 2016

ALEX Phase III Study Alectinib vs Crizotinib

*Closed by IDMC at preplanned interim analysis after primary end-point of PFS met.

Targeting ALK TranslocationsFuture

Crizotinib/ceritinib/alectinib CNS met

Alectinib/ceritinib if prior

crizotinib

Re-biopsy

Y

N

Gate-keeper mut

2nd

generation according to sensitivity

Chemo

Others G1202R

Loratinib

Summary • Biomarker driven adjuvant studies

− EGFR: Two Asian studies on DFS, ALCHEMIST study on OS− ALK: ALCHEMIST study on OS (slow)

• Combination strategies − With anti-angiogenesis: NEJ26− With chemotherapy: FASTACTII, pemetrexed/carboplatin− With immunotherapy: uncertain efficacy/toxicity

• Second/third generation TKI as first line therapy− EGFR: dacomitinib, osimertinib− ALK: ceritinib, alectinib

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Targeted Therapies for Advanced NSCLC - ceconcepts.com to the Future with... · 2016-06-09 · Targeted Therapies for Advanced NSCLC. Current Clinical Developments . Friday, June