2

Lucio CrinòMedical Oncology Department

University Hospital Perugia, Italy

The optimal therapeutic algorithm for EML4-ALK

+ ve pts

“Anaplastic Lymphoma kinase”(ALK)- rearrangment

• 3-5% of lung adenocarcinomas

ALK signal transduction¹ ALK fusions²

1. Roskoski jr. Pharma research 2013

2. Peters et al. Lung Cancer 2013

Timeline

Mano H Cancer Discovery 2012;2:495-502

Clinical development of Crizotinib for ALK+ NSCLC

*Cisplatin or carboplatin according to investigator’s choice≠Cross-over to crizotinib allowed at PD in the standard arm**Pemetrexed or docetaxel; prior chemo must have been platinum-based chemotherapy ∞May have received Pemetrexed or Docetaxel from previous phase III PROFILE 1007 trial and discontinued treatment due to RECIST-defined progression

StudyPhase

(planned accrual)

HistologyLine of therapy

Study designPrimary endpoint

PROFILE 1014III

(334 pts)Non-squamous 1st

Platinum*-Pemetrexed vs Crizotinib

PFS≠

PROFILE 1007III

(318 pts)NSCLC 2nd

2nd line chemo** vs Crizotinib

PFS

PROFILE 1005II

(400 pts)NSCLC

3rd or more∞

Crizotinib monotherapy

ORR

ORR = overall response rate; PFS = progression-free survival; pts = patients

Study No. of patients RR (%) PFS (mos.)

A8081001 143 60.8 9.7

A8081005 261 59.8∞ 8.1

A8081007 173 65* 7.7

French Temporary Authorization for use of

Crizotinib

230 56.5 Not reported

Crizotinib for ALK+ NSCLC

∞259 pts evaluable for response*Independent radiologic review

Camidge, et al. Lancet Oncol 2012Kim, et al. ASCO 2012

Shaw, et al. NEJM 2013Perol, et al. ECCO 2013

Tumor responses to crizotinib by patient

Median time to response: 8 wk

1. Camidge et al., ASCO 2011; Abs #25012. Riely et al., IASLC 2011; Abs #O31.05

PROFILE 10052PROFILE 10011

Study Design

Key entry criteria

● ALK+ by central FISH testing

● Stage IIIB/IV NSCLC

● 1 prior chemotherapy

(platinum-based)

● ECOG PS 0−2

● Measurable disease

● Treated brain metastases allowed

N=318

Crizotinib 250 mg BID PO, 21-day cycle

(n=159)

Pemetrexed 500 mg/m2 or

Docetaxel 75 mg/m2 IV, day 1, 21-day cycle

(n=159)

PROFILE 1007: NCT00932893

Endpoints

● Primary– PFS (RECIST 1.1,

independent radiology review)

● Secondary– ORR, DCR, DR– OS– Safety – Patient reported

outcomes (EORTC QLQ-C30, LC13)

RANDOMIZE

CROSSOVER TO CRIZOTINIB ON PROFILE 1005

aStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no)

a

aRECIST v1.1

65.3

19.5OR

R (

%)

ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.001

Crizotinib (n=173)

PEM/DOC (n=174)

80

60

40

20

0Treatment

65.7

29.3

6.9

Crizotinib (n=172)

PEM (n=99)

DOC (n=72)

Treatment

80

60

40

20

0

ORR in PROFILE 1007

Crizotinib

(n=172a)

PEM

(n=99b)

DOC

(n=72b)

Events, n (%) 100 (58) 72 (73) 54 (75)

Median, mo 7.7 4.2 2.6

HRc (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)

P <0.001 <0.001

Pro

babi

lity

of s

urvi

val w

ithou

t pr

ogre

ssio

n (%

)100

80

60

40

20

0

0 5 10 15 2025 Time (months)

172 93 38 11 2 0

99 36 12 3 1 0

72 13 3 1 0

No. at riskCrizotinib

PEMDOC

aExcludes 1 patient who did not receive study treatment; bexcludes 3 patients in chemotherapy arm who did not receive study treatment; cvs crizotinib

PROFILE 1007: PFS of Crizotinib vs Pemetrexed or Docetaxel

Shaw, et al. NEJM 2013

Survival curves from PROFILE 1007

PFS OS

Survival in ALK-positive NSCLC with crizotinib versus crizotinib-naive controls

0

0%

20%

40%

60%

80%

100%

Overall survival (years)1 2 3 4

ALK Crizotinib(n=30)

ALK Control(n=23)

Median Survival, mo NR 6

1-yr Survival, % 70 44

WT/WT Control(n=125)

11

47

From 2nd/3rd line crizotinib

2-yr Survival, % 55 12 32

HR = 0.49, p=0.02

Camidge D R , Lancet Oncol 2012; 13: 1011–19

PROFILE 1014 Study Design

Primary Endpoint Met: Crizotinib Superior to Pemetrexed-based Chemotherapy in Prolonging PFSa

T. Mok –ASCO 2014

Secondary Endpoints: ORRa and OS

Emerging issues in management of crizotinib-treated, ALK-positive patients

Crizotinib in ALK-positive

NSCLC

Brain metastases

Therapy for crizotinib-

resistant disease

Treatment beyond

progression

OS from Start of Initial Crizotinib Treatment

Ou et al, Ann Oncol 2014

Median OS (95% CI) CBPD: 29.6 months (23.1−NR) No CBPD: 10.8 months (8.9−14.7)

HR=0.30 (0.19−0.46)p<0.0001

Number at riskContinued 120 104 30 61Did not continue 74 40 8 0

0 5 10 15 20 25 30 35 40Time (months)

100

80

60

40

20

0

Shaded areas are 95% Hall-Wellner confidence bands

Continued crizotinib

Did not continue crizotinibP

rob

abili

ty o

f su

rviv

al (

%)

Otterson, et al. ASCO 2012

Organ sites in which new lesions developed and/or non-target lesions progressed in the Crizotinib-Beyond-PD group

OrganPatients with new lesions and/or non-

target lesions (n=115)No. of patients (%)a

Brain 53 (46)

Liver 30 (26)

Lung 23 (20)

Bone 20 (17)

Pleural effusion 16 (14)

Lymph node 12 (10)

Adrenal 1 (1)

Chest wall 1 (1)

Pelvis 1 (1)

Soft tissue 1 (1)

Spine 1 (1)

Other 21 (18)

aExcluding patients with target lesions only: patients could be counted more than once across organ sites

Most common sites of PD in patients continuing crizotinib beyond PD

Study Population: ALK+ NSCLC With or Without Brain Metastases at Baseline

1. Kim D-W, et al. J Clin Oncol 2012;30(Suppl.) (abstr. 7533); 2. Shaw AT, et al. N Engl J Med 2013;368:2385–2394Crinò et al. Poster presented at European Cancer Congress 2013 (abstract 3413)

Previously untreatedfor BM (n=109)

No BM detected(n=613)

RETROSPECTIVE ANALYSIS of crizotinib-treated patients with or without asymptomatic BM at baseline (n=888)

PROFILE 10051

(open-label,single-arm phase II)

Crizotinib 250 mg BID

PROFILE 10072

(randomized phase III vs. standard chemo)

Crizotinib 250 mg BID

Previously treatedfor BM (n=166)

● Among evaluable patients:

– 20% of patients (22/109) with previously untreated asymptomatic BM had BM classified as target lesions

– 11% of patients (18/166) with previously treated asymptomatic BM had BM classified as target lesions

– 9% of patients (55/613) with no detectable BM at baseline developed symptomatic BM after the start of crizotinib treatment

● Median duration of crizotinib treatment similar in the three groups (22.0–29.3 weeks)

12% 19% 69%

● IC and systemic DCR at 12 weeks: 56–65% in patients with BM at baseline

● IC ORR: 25% in 40 patients with BM classified as target lesions

● Systemic ORR: 46–55% across the three groups

Crizotinib Antitumor Activity in Patients With or Without Brain Metastases at Baseline

 Previously untreated

for BM (n=109) 

Previously treated for BM (n=166)

 No BM detected

(n=613)

  n Outcome   n Outcome   n OutcomeDCR at 12 weeks, % (95% exact CI)                

IC 109 56 (46−66)   166 62 (54−70)     NA

Systemic 109 63 (54−72)   166 65 (57−72)   613 71 (68−75)

ORR, % (95% exact CI)                

IC 109 7 (3−14)   166 7 (4−12)     NA

Patients with target-lesion BM

22 18 (5−40)   18 33 (13−59)     NA

Systemic 109 53 (43−63)   166 46 (39−54)   613 55 (51−59)

Median time to tumor response (range),a weeks

IC 8 6.0 (4.9−12.4)

  12 6.4 (5.9−17.7)     NA

Systemic 58 6.1 (2.0−31.4)

  77 6.1 (3.1−35.3)   336 6.1 (3.0−49.1)

Median duration of responseb (range),a weeks

IC 8 26.4 (6.1−59.3)

  12 NR (6.0−59.9)     NA

Systemic 58 47.9 (5.3−55.0)

  77 55.6 (4.4−95.3)   336 49.0 (4.1−96.1)

Median systemic PFS,b (95% CI),c mo 109 8.3 (6.7−14.0)

  166 13.5 (6.2−16.5)   613 9.9 (8.8−12.2)

NA, not applicable; NR, not reachedaIn patients with confirmed objective response; bKaplan−Meier method; cBrookmeyer−Crowley method

Crinò et al. Poster presented at European Cancer Congress 2013 (abstract 3413)

Emerging issues: brain metastases

aPatients with one intracranial target lesion at baseline (n=33, 7 patients with early death/indeterminate response excluded).Costa DB, et al. Oral presentation at World Congress on Lung Cancer, October 27–30, 2013, Sydney, Australia: Abstract 2932.

INTRACRANIAL DISEASE CONTROL RATE AT 12 WEEKS IN PATIENTS WITH BASELINE ASYMPTOMATIC BRAIN METASTASES4BEST PERCENTAGE CHANGE IN INTRACRANIAL TARGET LESIONS

FROM BASELINE (%)

*Patients previously treated for brain metastases.

Best objective response according to RECIST.

** *

*

* **

* **

*

*Progressive disease Stable disease

Partial response Complete response

**

40

20

0

−20

−40

−60

−80

−100

Frequencies of crizotinib resistance mechanisms in ALK+ NSCLC

Unknown 25%

Alk mutation 22-33% L1196M G1202R S1206Y G1269A 1151Tins Others

KIT amplification 10 %

Change in driver mutations5%

Alk amplification6-16%

Increased EGFR signaling30-35%

ALK non-dominant (Bypass tracks)

ALK dominant

Camidge D. R. Nat. Rev. Clin. Oncol. 11, 473–481 (2014) ;

2nd generation ALK-TKIs

Acquired resistance

ALK translocated Crizotinib

All of them seem to be very good

1) Better affinity for ALK2) Better affinity for crizotinib resistant second-site mutated ALK 3) Improvement in pharmacokinetics to brain tissue and CSF

Options at acquired resistance to Crizotinib

Switch to chemotherapy

Crizotinib beyond progression +

CHT or Hsp90I

Crizotinib beyond progression

Ceritinib: Highly Active Treatment <br />Option for ALK-Positive NSCLC

Toxicity Challenges with Ceritinib

Presented By Howard West at 2014 ASCO Annual Meeting

AP26113 IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC

Ceritinib, Alectinib and AP26113, show antitumor activity in ALK+ NSCLC with brain metastasis

Mehra et al., ASCO (2012), abstr 3007Gettinger et al., ESMO (2012), abstr 4390Nishio et al., ESMO (2012), abstr 4410

6 wksBaseline LDK378

AP26113

CH5424802Baseline

8 wksBaseline

33 wks

Tumor Responses to Crizotinib in ROS1-rearranged NSCLC

Shaw AT et al. N Engl J Med 2014.

ORR = 72% (95% CI, 58 to 84)

DOR= 17.6 mos (95% CI, 14.5-not

reached)

PFS= 19.2 mos (95% CI, 14.4-not

reached)

Efficacy of crizotinib in MET-amplified NSCLC

aConfirmed objective responses.bBased on investigator assessment.cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.

Best percent change from baseline in target tumor lesionsa by patient

Low METn=2

Intermediate METn=6

High METn=6

100

80

60

40

20

0

–20

–40

–60

–80

–100

100

80

60

40

20

0

–20

–40

–60

–80

–100

Disease progressionStable diseasePartial responseb

Complete responseb

% C

han

ge

Fro

m B

asel

ine

100

80

60

40

20

0

–20

–40

–60

–80

–100

Threshold for partial responsec

c

Presented By D. Camidge at 2014 ASCO Annual Meeting

Squamous cell cancer

Non-squamous cancer

Platinum + 3rd generation agent

EGFR WT, ALK neg

EGFR mut +

ALK/ROS1 rearranged

EGFR-TKI

ALK-TKI

EGFR WT/ALK neg, clinically selected

EGFR WT/ALK neg, clinically

unselectedPlatinum + Pemetrexed

Platinum-based doublet

+ Bevacizumab

Oncogene addicted

Biologically-unselected non-squamous NSCLC

Istituto Toscano Tumori – Livorno, Italy

First-line therapy for metastatic NSCLC in 2014

Stratification for EGFR, ALK and histology

EGFR Mut+ ALK-/EGFRwt non-squamous

ALK-/EGFRwt squamous

EGFR TKIPlatinum doublet +

bevacizumabOR

platinum + pemetrexed

+/- bevacizumab

Platinum-based doublet

ALK rearranged

Crizotinib

SUMMARY

• Crizotinib is the first-in-class ALK-TKI inhibitor fully approved worldwide

• Consistent response rate, PFS >60% over 8 months, very favourable toxicity profile

• Evidence of clinical benefit in continuous treatment beyond smouldering progression and in brain metastases in selected patients with or without radiotherapy

• Significant activity in ROS1 rearranged patients