Treatment of ALK Positive Advanced NSCLC

Fiona Blackhall PhD FRCP Medical Oncologist

Manchester, UK

ESMO – The Christie Preceptorship in Lung Cancer March 2017

Small cell 2017 : Similar incidence in women & men

2017 : at least half of new cases present

with metastatic disease for which average

survival is less than one year

SQ cell Ca ADC

• Possible aetiology in 1927 ? • Damp climate • Dust inhaled from grooming horses • No mention of tobacco smoke exposure !

2017 : ADC > SQCC > small cell

• Molecular basis & diagnosis of ALK positive NSCLC

• Current treatment strategy :

- Role for 1st generation & 1st in class ALK inhibitor, crizotinib

- Role for 2nd & 3rd generation ALK inhibitors

• Major challenges - intracranial metastases

- mechanisms of resistance

• Patient cases

March 2017 ESMO – Christie Preceptorship Lung Cancer 3

Learning Objectives

The EML4-ALK Fusion Gene • First identified in NSCLC cells in 2007

• Small inversion within chromosome 2p results in

fusion of the EML4 & ALK genes • Fusion results in redistribution of the ALK kinase

domain from the cell membrane to cytoplasm

• Ligand dependent activation & transforming activity

• Multiple EML4-ALK fusion variants have been

identified due to truncations of EML4 at different exons

Soda M et al. Nature 2007;448:561–567

Transforming Activity of ALK Fusion Gene

Hallberg & Palmer Ann Oncol Supp 3 2016

• Incidence ~ 2-7% non-squamous NSCLC

• Associated with never-smoker/light former smoking history & younger age

• ESMO guidance - Screen all non – squamous cases

- Other histological subtypes depending on clinical characteristics

6

ALK gene fusion in NSCLC

Diagnosis of ALK gene rearrangement FISH, PCR, IHC

Kerr & Lopez-Rios Ann Oncol supp 3 2016

Schematic diagram of EML4-

ALK fusion

Timeline of Rapid Progress made in treatment of ALK + NSCLC since the 2007 discovery of EML4-ALK Fusions

Solomon & Soria, Ann Oncol Vol 27 Supp 3 2016

Only 4 years between the

discovery of EML4-ALK and the

FDA approval of the 1st in class

ALK inhibitor, crizotinib in 2011

Crizotinib: First-in-human ALK inhibitor

Potent and selective ATP competitive oral

inhibitor of ALK and MET tyrosine kinases

and their oncogenic variants administered at

the MTD of 250 mg PO twice daily

FDA accelerated approval was based on

phase I data for the safety and activity of

crizotinib in an expanded cohort of patients

with advanced ALK-positive NSCLC1

Crizotinib

(PF-02341066) 1Kwak et al. NEJM 2010;363:1693-703

Baseline CT-

scan

2 weeks post

CZT initiation

WATERFALL PLOT OF BEST PERCENTAGE CHANGE IN TUMOUR LESIONS FROM BASELINE IN PATIENTS WITH ALK POSITIVE NSCLC & MEASURABLE DISEASE

TREATED WITH CRIZOTINIB IN THE PHASE 1 PROFILE 1001 STUDY

Camidge et al. Lancet Oncology 2012 10

N=133

Response rate = 61%

Median duration of response = 49 weeks

Phase III PROFILE 1007 & PROFILE 1014 Trials of Crizotinib vs. Chemotherapy

Blackhall & Cappuzzo Ann Oncol Supp 3 2016

PROFILE 1007

Shaw et al.

NEJM 2013

(2nd line)

PROFILE 1014

Solomon et al

NEJM 2014

(1st line)

Response Rate

74 vs 45%

Response Rate

65 vs 20%

Clinical efficacy of Crizotinib for ALK+ NSCLC PROFILEStudy

PhasePa ents

NSCLCALK+ORR(%)

PFS(months)

Author

1001 PhaseI N:14960.8

(95%CI,52.3-68.9)

9.7(95%CI,7.7-12.8)

Camidge2012

1005 PhaseII N:26160(95%CI,53.6-65.9)

8.1(95%CI,6.8-9.7)

Kim2012

1007PhaseIII

(CZTvs.C/D)N:346

65vs.19.5P<0.0001

7.7vs.3.0P<0.0001

Shaw2013

1014 PhaseIII(CZTvs.C+P)

N:34374vs.45P<0.001

10.9vs.7.0P<0.001

Solomon2014

ORR,objec veresponserate;PFS,progressionfreesurvival;CZT,crizo nib;P,pemetrexed;D,docetaxel;C,cispla norcarbopla n.

12

ESMO MAGNITUDE OF CLINICAL BENEFIT SCALE

Cherny NI, Sullivan R, Dafni U et al. Ann Oncol 26:1547-1573, 2015

Crizotinib (n=171), n (%) Chemotherapy (n=169), n (%)b

AE

Any grade Grade 3/4 Any grade Grade 3/4

Higher frequency (≥5% absolute difference) in crizotinib arm

Vision disorderc 122 (71) 1 (1) 24 (14) 0

Diarrhoea 105 (61) 4 (2) 29 (17) 1 (1)

Oedemac 83 (49) 1 (1) 22 (13) 1 (1)

Vomiting 78 (46) 3 (2) 68 (40) 6 (4)

Constipation 74 (43) 3 (2) 53 (31) 0

Elevated transaminasesc 61 (36) 24 (14) 22 (13) 4 (2)

Upper respiratory infectionc 55 (32) 0 21 (12) 1 (1)

Abdominal painc 45 (26) 0 20 (12) 0

Dysgeusia 45 (26) 0 11 (7) 0

Higher frequency (≥5% absolute difference) in chemotherapy arm

Nausea 95 (56) 2 (1) 103 (61) 3 (2)

Decreased appetite 51 (30) 4 (2) 59 (35) 1 (1)

Fatigue 49 (29) 5 (3) 65 (38) 4 (2)

Neutropeniac 36 (21) 19 (11) 51 (30) 26 (15)

Asthenia 22 (13) 0 42 (25) 2 (1)

Anemiac 15 (9) 0 54 (32) 15 (9) 14

PROFILE 1014 Trial Common AEs of any cause in ≥25% of patients

with ≥5% difference between groups

aNot adjusted for differential treatment duration between arms; bBefore crossover to crizotinib

cClustered term comprising AEs that represent similar clinical symptoms/syndromes

Mok T, et al. Poster presented at ASCO 2014 (Abstract 8002)

aNot adjusted for differential treatment duration between arms; bBefore crossover to crizotinib

cClustered term comprising AEs that represent similar clinical symptoms/syndromes

Mok T, et al. Poster presented at ASCO 2014 (Abstract 8002)

Toxicities associated with crizotinib in Ph I & II Trials

n=255

Common %

Vision 62

Nausea 53

Diarrhoea 43

Vomiting 40

Constipation 27

Oedema 28

Fatigue 20

ALT 13

Rash 10

Common mainly G1/2

• Visual : light trails, flashes, image persistence at edge of visual field (light adaptation)

Other less common

• Renal cysts

• Pneumonitis

• Asymptomatic bradycardia

• Low testosterone (? common)(16/16 crizotinib; 6/19 metastatic NSCLC)

Camidge & Doebele, Nature Reviews 2012; *Weickhardt et al. Cancer 2012

16

PROFILE 1014

Solomon et al.

NEJM

PROFILE 1014 Solomon et al NEJM

17

Patterns of Progression & Mechanisms of Resistance to Crizotinib

Dagogo-Jack & Shaw Ann Oncol Supp 3 2016

19

Chemistry of ALK Tyrosine Kinase Inhibitors

Ceritinib has 20 fold more binding affinity for wild type ALK than crizotinib

Central Nervous System Penetration > for 2nd & 3rd generation ALK inhibitors

2nd & 3rd generation ALK inhibitors are active against crizotinib resistance

mutations

TAE684 Crizotini

b

Lorlatinib

Ceritinib Alectinib

Brigatini

b Models show variation in contact sites between different TKI molecules with the ATP-binding pocket of the wild-type ALK kinase domain

Figure adapted from Hallberg & Palmer Ann Oncol 2016

Clinical efficacy of 2nd generation ALK inhibitors in crizotinib resistant patients

20

Response rates : 38 to 71%

Median PFS : 5.7 to 13.4 months

• July 2013: T2N1M1b ALK + ADC lung, bone & lung mets

• Cis/pem 4 cycles : PR

• Mar 2014 : PD lung & brain (headaches)

• April 2014 : WBRT

• May 2014 to July 2015 : crizotinib 14 cycles : SD [AE low testosterone & bradycardia]

• Aug 2015 Progressive Disease (liver, brain, bone ) : commenced on brigatinib on clinical trial

• October 2015 : Response in all disease sites

• Feb 2017 : Remains on trial with excellent quality of life : recent travel & holiday to Japan

21

Manchester Patient Case 1 : 49 yr old male, 10 pack year smoking history

MRI brain July 2014

ALK inhibitors (ALKi)

Crizotinib Ceritinib Alectinib Approved

Breakthrough

Therapy

Entrectinib Ensartinib Lorlatinib

Brigatinib

Investigational

Solomon & Soria, Annals of Oncology 2016

Soria ESMO 2016

1st generation ALKi

Current Treatment Algorithm for ALK+ NSCLC

2nd generation ALKi Progressive

disease

ASCEND-4 Soria et al. NEJM 2017

23

PROFILE 1014 Solomon et al. NEJM 2014

ASCEND-4 PFS [95% CI] HR (95%CI) ORR

ceritinib 16.6 (12.6,27.2) 0.55(0.42,0.73)

72.5%

chemoT 8.1 (5.8,11.1) 26.7%

PROFILE PFS [95% CI] HR (95%CI) ORR

crizotinib 10.9 (8.3,13.9) 0.45(0.35,0.60)

74 %

chemoT 7.0 (6.8,8.2) 45%

How does ASCEND-4 compare with PROFILE 1014 ?

Are there differences in • study design • clinical demographics • toxicity • intracranial efficacy

24

Study Design ASCEND-4

Soria et al. NEJM 2017 PROFILE 1014

Solomon et al. NEJM 2014

1:1 randomisation ✔ ✔

Chemotherapy (ChemoT) Platinum/pemetrexed Platinum/pemetrexed

Maintenance pemetrexed ✔ ✖

Crossover on progression ✔ ✔

Stage IIIB/IV ALK+ by

ALK+ by central FISH ✖ ✔

ALK+ by central IHC ✔ ✖

Stratification for

Brain metastases ✔ ✔

PS 0-2 ✔ ✔

Prior treatment ✔ ✔

Clinical Demographics (%) ASCEND-4

Soria et al. NEJM 2017 PROFILE 1014

Solomon et al NEJM 2014

Ceritinib ChemoT Crizotinib ChemoT

Median Age (years) 55 54 52 54

Female 54 61 60 63

Performance Status 2 6.9 5.9 6 5

Never smoker 57.1 65.2 62 65

Ex-smoker 34.9 26.7 33 32

Current smoker 7.9 8.0 6 3

Caucasian 55 52.4 53 50

Asian 40.2 43.9 45 47

Brain Metastases present 31.2 33.2 26 27

27

Toxicity% : All Grades (G3/4)

ASCEND-4 Soria et al NEJM 2017

PROFILE 1014 Solomon et al NEJM 2014

Ceritinib Chemo Crizotinib Chemo

Vision Disorder - - 71 (1) 9 (0)

Diarrhea 84.7 (5.3) 10.9 (1.1) 61 (2) 13 (1)

Edema - - 49 (1) 12 (1)

Vomiting 66.1 (5.3) 36 (5.7) 46 (2) 36 (3)

Nausea 68.8 (2.6) 55.4 (5.1) 56 (1) 59 (2)

Fatigue 29.1 (4.2) 29.7 (2.9) 29 (3) 38 (2)

Elevated transaminases [ALT for ASCEND-4] 60.3 (30.7) 21.7 (2.9) 36 (14) 13 (2)

Discontinuation due to AEs (study drug) % 11.1 (5.3) 16.6 (11.4) 12 (5) 14 (8)

Intracranial Efficacy

28

STUDY (n) ASCEND-4 (n=376) Soria et al. NEJM 2017

PROFILE 1014 (n=343) Solomon et al JCO 2016

Ceritinib ChemoT Crizotinib ChemoT

PFS (mths) overall population 16.6 8.1 10.9 7.0

Brain metastases (BM) present N=61 N=60 N=39 N=40

Prior brain radiotherapy number (%) 24 (40%) 24 (40%) Treated* Treated*

PFS in BM subgroup (mths) [95%CI] PFS in no BM subgroup (mths) [95% CI]

10.7 [8.1,16.4] 26.3 [15.4,27.7]

6.7 [4.1,10.6] 8.3 [6.0,13.7]

9 [6.8,15] 11.1 [8.3,14]

4 [1.5,6.8] 7.2 [6.9,8.3]

Intracranial response rate 73% (22) 27.3% (22) NE NE

Intracranial DCR at 24 weeks 86% 50% 56% 25%

Intracranial Progression number (%) NR NR 25 (15%) 26 (15%)

DCR : Disease control rate (CR,PR,SD), NE : Not evaluated, NR : Not reported *details of prior radiotherapy not known

ASCEND-4 challenges the current treatment algorithm of using a next generation ALKi for treatment after progression on crizotinib

29

Swimmer plot showing PFS for 73 patients treated sequentially with ceritinib after

progression on crizotinib

Gainor et al CCR 2015

• No prospective, randomised data for a sequential 1st generation then 2nd/3rd generation ALKi versus 2nd/3rd generation ALKi first line

• In a retrospective analysis of 73 patients treated sequentially with crizotinib then ceritinib

- combined median PFS of 17.4 (15.5,19.4) months

- comparable with median PFS of 16.6 (12.6,27.2) months in ASCEND-4

• In 23 patients evaluable there was no difference in PFS on ceritinib between those with or without ALK resistance mutations to crizotinib

(median PFS 5.8 vs 6.5 months; P = 0.510)

ASCEND-4 challenges the current treatment algorithm of using a next generation ALKi for treatment after progression on crizotinib

30

Swimmer plot showing PFS for 73 patients treated sequentially with ceritinib after

progression on crizotinib

Gainor et al CCR 2015

• No prospective, randomised data for a sequential 1st generation then 2nd/3rd generation ALKi versus 2nd/3rd generation ALKi first line

• In a retrospective analysis of 73 patients treated sequentially with crizotinib then ceritinib

- combined median PFS of 17.4 (15.5,19.4) months

- comparable with median PFS of 16.6 (12.6,27.2) months in ASCEND-4

• In 23 patients evaluable there was no difference in PFS on ceritinib between those with or without ALK resistance mutations to crizotinib

(median PFS 5.8 vs 6.5 months; P = 0.510)

First Line Head to Head trials of ALK inhibitors

• The J-ALEX trial demonstrated superior survival for the 2nd generation ALKi alectinib compared with crizotinib

• The AE profile for alectinib demonstrated all grade rates of diarrhea, nausea, vomiting, transaminase elevation < 11%

• Results awaited & ongoing trials

- Global ALEX trial of alectinib vs crizotinib

- crizotinib vs brigatinib (ALTA trial)

- crizotinib vs lorlatinib

31

Primary Endpoint: PFS by IRF (ITT Population)Alectinib

(N=103)

Crizotinib

(N=104)

Events, n (%) 25 (24.3%) 58 (55.8%)

Median, mo [95% CI] NR [20.3 - NR] 10.2 [8.2 - 12.0]

P-value <0.0001

HR [99.6826% CI] 0.34 [0.17 - 0.71]

0 6 12 18 27

100

80

60

40

20

0

Pro

gre

ssio

n-f

ree

su

rviv

al ra

te (

%)

24213 9 151

7665

3621

94

1

9386

4940

2714

103102

No. of patients at risk Alectinib

Crizotinib 103 104

Presented by: Hiroshi Nokihara 14

Time (months)

10.2 months

NR

J-ALEX TRIAL Nokihara et al. ASCO 2016

J-ALEX PFS [95% CI] HR (95%CI) ORR

alectinib NR (20.3,NR) 0.34(0.17,0.71)

91.6%

crizotinib 10.2 (8.2,12.0) 78.9%

Alectinib

(N=103)

Crizotinib

(N=104)

Subgroup n Events n Events HR [95% CI]

Overall 103 25 104 58 0.34 [ 0.21 - 0.54 ]

ECOG performance

status

0/1 101 24 102 57 0.33 [ 0.20 - 0.53 ]

2 2 1 2 1 1.41 [ 0.08 - 23.57 ]

Prior chemotherapy 0 66 15 67 35 0.30 [ 0.17 - 0.56 ]

1 37 10 37 23 0.39 [ 0.18 - 0.83 ]

Clinical stage Postoperative recurrence 24 6 26 13 0.49 [ 0.18 - 1.30 ]

Stage IIIB/IV 79 19 78 45 0.31 [ 0.18 - 0.52 ]

Age group ≥75 12 3 10 5 0.28 [ 0.06 - 1.19 ]

<75 91 22 94 53 0.34 [ 0.21 - 0.56 ]

Smoking status Never smoker 56 18 61 33 0.50 [ 0.28 - 0.89 ]

Past or Current smoker 47 7 43 25 0.18 [ 0.08 - 0.42 ]

Brain metastases

at baseline

Yes 14 1 29 16 0.08 [ 0.01 - 0.61 ]

No 89 24 75 42 0.39 [ 0.23 - 0.64 ]

ALK testing method IHC and FISH 96 21 94 52 0.30 [ 0.18 - 0.50 ]

RT-PCR 7 4 10 6 0.80 [ 0.22 - 2.90 ]

Sex Female 62 16 63 37 0.31 [ 0.17 - 0.57 ]

Male 41 9 41 21 0.35 [ 0.16 - 0.77 ]

0.01 0.1 1 10 100

Subgroup Analysis of PFS by IRF

Presented by: Hiroshi Nokihara 32

Favors Alectinib Favors Crizotinib Multiple stratified Cox regression using prognostic factors including brain

metastases showed consistent treatment effect (HR = 0.34)

Safety Overview

Alectinib

(N=103)

Crizotinib

(N=104)

Any AEs 100 (97.1%) 104 (100.0%)

Grade 3/4 AEs 27 (26.2%) 54 (51.9%)

Treatment-related deaths 0 0

Serious AEs 15 (14.6%) 27 (26.0%)

Discontinuation of study drug due to AEs 9 (8.7%) 21 (20.2%)

Dose interruptions due to AEs 30 (29.1%) 77 (74.0%)

33 Presented by: Hiroshi Nokihara

Common AEs, ≥20% of Patients in Either Arm All Grade Grade 3/4

Alectinib

(N=103)

Crizotinib

(N=104)

Alectinib

(N=103)

Crizotinib

(N=104)

Constipation 36 (35.0%) 46 (44.2%) 1 (1.0%) 1 (1.0%)

Nausea 11 (10.7%) 77 (74.0%) 0 2 (1.9%)

Diarrhea 9 (8.7%) 76 (73.1%) 0 2 (1.9%)

Vomiting 6 (5.8%) 60 (57.7%) 0 2 (1.9%)

Aspartate aminotransferase increased 11 (10.7%) 32 (30.8%) 1 (1.0%) 5 (4.8%)

Alanine aminotransferase increased 9 (8.7%) 33 (31.7%) 1 (1.0%) 13 (12.5%)

Visual disturbance 1 (1.0%) 57 (54.8%) 0 0

Nasopharyngitis 21 (20.4%) 24 (23.1%) 0 0

Dysgeusia 19 (18.4%) 54 (51.9%) 0 0

Pyrexia 10 (9.7%) 21 (20.2%) 1 (1.0%) 0

Decreased appetite 1 (1.0%) 21 (20.2%) 1 (1.0%) 1 (1.0%)

Presented by: Hiroshi Nokihara 34

Figures from Gainor et al. Cancer Discovery 2016

Will the choice of 1st Line ALKi impact on patterns of progression & mechanisms of resistance ?

The spectrum of ALK resistance mutations varies according to ALK inhibitor

Some mutations confer resistance to ceritinib but not alectinib and vice versa

Some mutations are only sensitive to the 3rd generation ALK TKI lorlatinib

Majority are resistant to crizotinib

The Art of Precision Medicine

36

Shaw et al. NEJM

2016

• 40 yr old lady 5 pack year smoking history

• Stage IV ALK + NSCLC who received platinum/pemetrexed CT with minor response then on progression 1 year later commenced crizotinib

• After 15 cycles she develops symptomatic brain metastases ; extracranial disease remains stable

• What would you do ?

Would you switch ALK inhibitor, treat with WBRT or both ?

37

Manchester Patient Case 2 : How would you treat ?

• She receives WBRT & continues on crizotinib for 15 months

• She then develops intracranial progression with a dominant lesion causing mass effect and midline shift

• What would you do ?

38

June 2015 temporal lobe

lesion causing mass

effect and midline shift

Manchester Patient Case 2 : How would you treat ?

• The neurosurgeons agree to resect !

• 2 months later PD with new bone & liver mets

• Commenced on a clinical trial of brigatinib

• 2 months later response in liver, bone and residual brain metastases

• 16 months later remains stable

39

June 2015 temporal lobe

lesion causing mass

effect , midline shift &

deterioration in symptoms

/ PS

Manchester Patient Case 2 : How would you treat ?

Take Home Message • New targeted therapy treatment paradigms continue to evolve for patients with ALK gene

fusion positive NSCLC with several trials ongoing in the 1st line setting

• Opportunity to combine pragmatism with precision ?

- Crizotinib may be a better tolerated 1st line option in patients where the GI toxicities of ceritinib may be detrimental e.g poor PS, comorbid conditions, very elderly – groups under-represented in trials to date

- Serial tumor tissue biopsy & concomitant evaluation of serial liquid biopsy (mutations in circulating tumor DNA) look set to become routine for precise matching of ALK resistance mechanism to select optimal therapy after failure of first line ALKi treatment

40

Thank you for joining us in Manchester

ESMO – The Christie Preceptorship in Lung Cancer March 2017