NUEVOS AVANCES DE CRIZOTINIB EN EL TRATAMIENTO PERSONALIZADO DE LOS PACIENTES CON CPNM ALK+ AVANZADO

Rosario García Campelo

Servicio de Oncología Médica

Hospital Universitario A Coruña

NSCLC care21st century “Don Quixotes”

“ Aquel loco caballero que tenía por cordura su

escudero”

Many important needs in Oncology…

We need to know how we got here…

We need to determine how to move forward…

WE ARE LIVING A TRUE THERAPEUTIC

REVOLUTION IN CANCER CARE

• The cancer revolution is a result of long investment in

research to understand cancer’s biology, together with

advances in the way care is delivered to patients every day.

• Today’s patients benefit from a range of important advances,

such as a growing number of approved cancer drugs, more

precise and effective surgical techniques, and comprehensive

supportive care measures.

American Society of Clinical Oncology.J Oncol Pract. 2014 Mar 1;10(2):119-42.

The State of Cancer Care in America 2014

Progress in 5-year survival

As a result of this progress, more people are surviving

cancer than ever before

NEW SCIENTIFIC, TECHNICAL AND ECONOMIC TRENDS ARE

LIKELY TO ALTER ONCOLOGY CARE DELIVERY MORE

SIGNIFICANTLY IN THE NEXT 20 YEARS THAN IN THE LAST 50.

Drug discovery EML4-ALK discovery

First clinical tests Responses in ALK+ patients

NEJM publictionPHASE III TRIAL

20072005 2006 2008 2009 2010

ASCOALK+ COHORT

Lovly CM et al. Clin Cancer Res 2014

● ALK:– One of 58 transmembrane receptor tyrosine kinases (RTKs)– 1,620 amino acids– Kinase domain between aa 1123-1392– 177 kDa (calculated MW)– Primarily expressed in nervous system during development– Major ligands: midkine, pleiotrophin– “Dependence receptor”

• Pro-apoptotic absence of ligand• Anti-apoptotic: ligand binding

● ALK:– Located on chromosome 2p23– 29 exons, 6,223 bp cDNA, 4.9 kB

LDLa

Anaplastic Lymphoma Kinase

Morris SW, et al. Oncogene 1997; 14: 2175-2188Stoica GE, et al. J Biol Chem 2001; 276: 16772-16779Stoica Gem et al. J Biol Chem 2002; 277: 35990-35999Palmer RH, et al. J Biochem. 2009;4201:345–61.Mehlen P, Bredesen DE. Sci Signaling 4 (157) mr2

Transforming Activity of EML4-ALK: a potent oncogenic fusion

Soda M. et.al. Nature 2007;448:561-567

9

2p23

ALK oncogenic pathway

ProliferaciónDiferenciaciónAnti-apoptosis

ALK

WHY SHOULD WE TEST FOR ALK?CRIZOTINIB CLINICAL ACTIVITYProfile 1001, Since 2009….

1. Kwak EL et al. J Clin Oncol 2009;27:15S abstract 3509 2. Bang Y-J et al. J Clin Oncol 2010;28:18S abstract 3 3. Kwak EL et al. N Engl J Med 2010;363:1693–17034. Camidge DR et al. J Clin Oncol 2011;29:18S abstract 25015.Camidge DR et al. Lancet Oncol. 2012 Epub ahead of print6.Kim et al. . Ann Oncol 2012; 23 (suppl 9); Abstr 1225º7.Shaw A et al. N Engl J Med 2013;368:2385–98.Mok T et al. J Clin Oncol 2014; Abstr 8002

2009

N: 19

2010

N: 82

2011

N: 119

2012

N: 149

2012

N 261

2013

N 347

2014

N 343

PATIENTS CHARACTERISTICS: PROFILE 1001

• Camidge DR et al. Lancet Oncol 201213(10):1011-9

n (N=149) %

Median Age 52.0 (21–86)Men/Women 73/76 49/51Ethnic White

Asian Otther

954113

64289

Smoking status Never Former Present

106421

7128<1

Histology Adenocarcinoma Large-cell carcinoma Squamous-cell carcinoma Other

144122

97<111

ECOG: 0 1 ≥2

567518

385012

Number of previous advanced metastatic treatment regimens123≥4

2447311928

1632211319

ECOG; Estado funcional del Eastern Cooperative Oncology Group performance status.

No. en riesgo 149 54 11 0

An impressive RR and Progression free survivalP

rog

ress

ion-

free

sur

viva

l (%

)

100

80

0

60

40

20

Time (months)0 5 10 15 20 25 30

PFS: 9.7 months (IC 95%: 7.7–12.8)

RR: 60.8%

Camidge DR et al. Lancet Oncol 2012

PROFILE 1005: Progression-free survival in the mature population (n=261)

Median PFS 8.1 months (95% CI: 6.8–9.7)28% patients in follow-up for progression

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

0 5 10 15 20Progression Free Survival time (months)

+ Censored 95% Hall-Wellner Band

n at risk 261 175 95 26 2

Kim et al. Ann Oncol 2012; 23 (suppl 9); Abstr 1225O

ORR: 59.8%Mature population, n=259 response-evaluable patients

Study Design of PROFILE 1007

Key entry criteria

● ALK+ by central FISH testinga

● 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

aALK status determined using standard ALK break-apart FISH assay bStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no)

b

aRECIST v1.1; bITT population; cas-treated population

ORRa by independent radiologic review

• aRECIST; bIntent-to-treat population; cAs treated population; ORR=overall response rate• Shaw A, et al. Ann Oncol 2012;23(Suppl9):Abstract 440O

65.3

19.5OR

R (

%)

ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.0001

Crizotinib (n=173b)

Chemotherapy (n=174c)

80

60

40

20

0

65.7

29.3

6.9

Crizotinib (n=172c)

Pemetrexed (n=99c)

Docetaxel (n=72c)

40

0

100

PROFILE 1007 Phase III trial:Crizotinib vs chemotherapy in ALK-positive patients

aIntent-to-treat population; bHR for death in the crizotinib group; QT=chemotherapy; HR=hazard ratio; PEM/DOC=pemetraxed/docetaxel

Shaw A, et al. N Engl J Med 2013;368:2385–2389

Crizotinib(n=173)

Chemotherapy(n=174)

Events, n (%) 100 (58) 127 (73)

Median, mo 7.7 3.0

HR (95% CI) 0.49 (0.37–0.64)

P <0.0001

Crizotinib

(n=173)

PEM/DOCa

(n=174)

Events, n (%) 49 (28) 47 (27)

Median, mo 20.3 22.8

HR (95% CI) 1.02 (0.68 –1.54)b

P 0.539

The relevance of QoL

QoL=quality of life; CI=confidence interval

Shaw A, et al. N Engl J Med 2013;368:2385–2389

Overall change from baseline in symptoms and global QoLTime to deterioration with respect to a composite lung cancer symptom endpoint

A Clinical Trial Testing The Efficacy of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin or Carboplatin in Patients With ALK Positive Non

Squamous Cancer of The Lung (PROFILE 1014)

Key entry criteria

● ALK+

● Stage IIIB/IV NSCLC

● First line treatment

● ECOG PS 0−2

● Measurable disease

● Patients with brain metastases only if treated and neurologically stable .

N=334

Crizotinib 250 mg BID PO, 21-day cycle

Pemetrexed 500 mg/m2 +

Cisplatin75 mg/m2 orCarboplatin AUC 5-6

IV, day 1, 21-day cycle

Endpoints

● Primary

– PFS (RECIST 1.1, independent radiology review)

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

outcomes (EORTC QLQ-C30, LC13)

RANDOMIZE

Estimated Enrollment:334

Study Start Date:January 2011

Estimated Study Completion Date:February 2015

Primary Completion Date:November 2013

b

ClinicalTrials.gov Identifier:NCT01154140

PROFILE 1014: RR

Crizotinib Chemotherapy

Median time to response (months)

1.4 2.8

Median duration of response (months)

11.3 5.3

74%

45%

Mok et al. J Clin Oncol 2014, Abst 8002

PROFILE 1014: PFS (ITT Population)

Solomon et al. NEJM 2014

10.9 vs 7 m

2 YEARS SURVIVAL RATE NSCLC

ECOG1594 JMBD ECOG4599PARAMOUNT AVAPERL PROFILE 10140%

10%

20%

30%

40%

50%

60%

11%19%

23%

32%39%

60%

Schiller J, N Engl J Med 2002; Scagliotti, G. V. et al. J Clin Oncol 2008; Cappuzzo F et al. Lancet Oncol 2010; Ciuleanu TE et al. Lancet 2009; Paz Ares L et al. J Clin Oncol 2013; Barlesi et al. Ann Oncol 2014

TOXICITY PROFILE

Solomon et al NEJM 2014 Shaw A et al. NEJM 2013

THE REASON FOR ALK TESTING SEEMS QUITE CLEAR…

Ph I (1001)

n = 149

Ph II (1005)

n=261

Ph III (1007)

n= 172 (crizo arm)

Ph III (1014)

N=172 (crizo arm)

Line of therapy Any line32 % 2nd line

2nd and beyond 6,6 % 2nd line

2nd line 1st line

ORR % 60.8 59.8 65,3 74

Median duration of response

48.1 wks 41.9 wks 36 wks 49 wks

Median duration of treatment

43.1 weeks 48 weeks 30 weeks NR

Median PFS 9.7months 8.1 months 7.7 months 10.9 months

Survival probability

At 12 months

81% NA 70% 84%

My challenges today…Are we playing in The Champions League?

How should we integrate genetic and clinical information?

Crizotinib Ceritinib, alectinib etc

or platinum/pem

1L 2L

2LWhich ALK inhibitor?

• CNS efficacy• Tolerability• Resistance mechanism

3LIs there a role for a 3rd

line ALK inhibitor?• CNS disease• Resistance mechanism

Shaw A. ESMO 2014

Novel ALK inh

1L

MIS RETOS..Mi día a día…y supondo que el de muchos de vosotros…

Mujer 24 años, dx el pasado 31/10/2014 Adenocarcinoma

pulmón estadio IV, M1 hepáticas,

cerebrales, pulmonares, óseas,

DP bilateral, pericárdico..

EML4-ALK+

9 Septiembre 2011

Aprobación FDA

23 Octubre 2012

Aprobación EMA

AEMPS

12 Noviembre 2012

Mayo 2014 CF farmacia CHUAC

Comisión uso medicamentos de alto impacto Noviembre 2014

Febrero 2015Comisión Central Autonómica pendiente

CR

IZO

TIN

IB R

EG

UL

AT

OR

Y

TIM

EL

INE

PARTIAL RESPONSE AFTER 5 WEEKS ON CRIZOTINIB THERAPY

PARTIAL RESPONSE AFTER 5 WEEKS ON CRIZOTINIB THERAPY

Beyong first line…SOME KEY QUESTIONS

• Why did 26% of the patients who received crizotinib in PROFILE 1014 not have a response?

• Are there combinations of agents that might convert good partial responses to durable complete responses?

• Is crizotinib still active after PD?

• Brain mets management

Mechanisms of therapeutic resistance to kinase inhibitors.

Lovly C M , and Shaw A T Clin Cancer Res 2014

Novel potent HSP90 inhibitors

HSPs are a family of chaperone proteins that shepherd the aberrantly expressed EML4-ALK proteins to their subcellular location and substrates1

Ipi-504 have demonstrated a RR of 67% in ALK+ NSCLC patients2

Ganestepib in ALK+: PFS 8.1 m3

AUY 922 in ALK+: RR 32% (previously treated; 50% in crizotinib-naïve)

HSP90 inhibitors alone or in combination with other therapy have the potential to overcome acquired resistance to crizotinib: Crizotinib+Ganetespib (NCT01579994) Crizotinib+AT13387 (NCT01712217) LDK378+AUY922 (NCT01772797)

RR=response rate; PFS=progression free survival

1. Crystal A and Shaw A. Clin Cancer Res 2012;18:4479–4481; 2. Sequist LV, et al. J Clin Oncol 2010;28:4953—4960;

3. Socinski MA, et al. Clin Cancer Res 2013;19:3068—3077; 4. Felip E, et al. Ann Oncol 2012;23(Suppl 9):Abstract 4380

Slide 30

Presented By Scott Gettinger at 2014 ASCO Annual Meeting

29.6m10.8m

CBPD

No CBPD

74%

55%

RR

Serie 1

Ou et al. Lancet Oncol 2014

IS CRIZOTINIB ACTIVE BEYOND PROGRESSION?Clinical outcome of patients who continued Crizotinib Beyond Progressive Disease in PROFILE 1001 and 1005: 174 P

THE BRAIN:A Sanctuary site in ALK+ NSCLC

Brain mets at any point in course of disease

Shaw et al, TLO 2011 52% ALK+ crizotinib naive 47% ALK+ crizotinib treated

Shaw et al, NEJM 2013PROFILE 1007

35% ALK + crizotinib naive

Solomon et al, NEJM 2014PROFILE 1014

45% ALK+ crizotinib naive

Brain mets on treatment

Weickhardt et al, ASCO 2012 46% as site of first progression (85% had CNS as sole site of first progresson)

Costa et al, JCO 2011 At CNS progression CSF:plasma ratio=0.0026 (<0.3% gets into brain)

Crizotinib in PROFILE 1005 and PROFILE 1007 275 p with asymptomatic BM

• Intracranial DCR at 12 weeks: 56% if untreated BM 62% if previously treated BM

• Intracranial ORR (only 40 patients with BM identified as a target lesion at the basal moment) 18% if untreated BM 33% if previously treated BM

Costa D, et al. J Clin Oncol 2015

Systemic progression-free survival (PFS) by presence or absence of brain metastases (BM) at baseline (BL) The presence of BM at BL does not significantly affect systemic PFS to crizotinib

Costa D, et al. J Clin Oncol 2015

PROFILE 1014: Higher Intracranial DCR with Crizotinib in Patients with Previously Treated Brain Metastases

Crizotinib (n=39) Chemotherapy (n=40)

DCR, disease control rate (% CR + PR + SD)aPearson χ2 test

12 weeks 24 weeks

DC

R (

95%

exa

ct

CI;

%)

Difference: 40% (95% CI: 21–59)

Pa=0.0003

Difference: 31% (95% CI: 11–52)

Pa=0.006100

80

60

40

20

0

Solomon et al. Ann Oncol 2014; Abst 1225O

I have never accepted the incurability of cancer. And I have remained hopeful, not because of

wishful thinking –that´s not progress– but because for the factual evidence of progress

Sidney Farber, MD