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