1. 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

2. NSCLC care 21st century “Don Quixotes”
“ Aquel loco caballero que tenía por cordura su escudero”

3. Many important needs in Oncology…
We need to know how we got here…
We need to determine how to move forward…

4. 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 Mar 1;10(2):

5. The State of Cancer Care in America 2014
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.
Progress in 5-year survival
As a result of this progress, more people are surviving
cancer than ever before

6. Responses in ALK+ patients
Drug discovery
EML4-ALK discovery
First clinical tests
Responses in ALK+ patients
NEJM publiction
PHASE III TRIAL
2007
2005
2006
2008
2009
2010
ASCO
ALK+ COHORT
Lovly CM et al. Clin Cancer Res 2014

7. Anaplastic Lymphoma Kinase
ALK:
One of 58 transmembrane receptor tyrosine kinases (RTKs)
1,620 amino acids
Kinase domain between aa
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
LDLa
***Drexler ref still needed?****
Figure from Palmer, Biochem J
ALK:
Located on chromosome 2p23
29 exons, 6,223 bp cDNA, 4.9 kB
Morris SW, et al. Oncogene 1997; 14:
Stoica GE, et al. J Biol Chem 2001; 276:
Stoica Gem et al. J Biol Chem 2002; 277:
Palmer RH, et al. J Biochem. 2009;4201:345–61.
Mehlen P, Bredesen DE. Sci Signaling 4 (157) mr2

8. Transforming Activity of EML4-ALK: a potent oncogenic fusion
Soda M. et.al. Nature 2007;448:

9. ALK oncogenic pathway ALK 2p23 Proliferación Diferenciación
Anti-apoptosis

10. WHY SHOULD WE TEST FOR ALK
WHY SHOULD WE TEST FOR ALK? CRIZOTINIB CLINICAL ACTIVITY Profile 1001, Since 2009….
2009
N: 19
2010
N: 82
2011
N: 119
2012
N: 149
N 261
2013
N 347
2014
N 343
Patients could be tested by any FISH test in any lab, but ALK positivity had to be confirmed by FISH in a central lab.
Brain mets were allowed if treated and stable
1. Kwak EL et al. J Clin Oncol 2009;27:15S abstract 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– Camidge DR et al. J Clin Oncol 2011;29:18S abstract Camidge DR et al. Lancet Oncol Epub ahead of print 6.Kim et al. . Ann Oncol 2012; 23 (suppl 9); Abstr 1225º 7.Shaw A et al. N Engl J Med 2013;368:2385–9 8.Mok T et al. J Clin Oncol 2014; Abstr 8002

11. Phase 1 Crizotinib Study PROFILE 1001
Part 1: MTD determination
Patients:
Clinically selected
Advanced solid malignancies
Refractory to SoC or no SoC available
MTD determined as 250 mg BID
PK data collected
Part 2: Crizotinib 250 mg BID
Patients:
Molecularly defined
No limit on prior regimens
Midazolam drug-drug interaction sub-study
Efficacy and single-/multi-dose PK data collected
ALK-enriched cohort
ALK translocations or gene amplification
Patients with NSCLC
MET-enriched cohort
Met amplification or activating mutations
SoC; standard of care
NCT

12. PATIENTS CHARACTERISTICS: PROFILE 1001
n (N=149) %
Median Age
52.0
(21–86)
Men/Women
73/76
49/51
Ethnic White Asian Otther
Smoking status Never
Former
Present
71 28 <1
Histology Adenocarcinoma Large-cell carcinoma Squamous-cell carcinoma Other
97 <1 1 1
ECOG: ≥2
Number of previous advanced metastatic treatment regimens ≥4
Camidge DR et al. Lancet Oncol (10):1011-9
We always gave data on 119 patients which was cohort presented by Camidge at ASCO 2011
During one of the poster discussions some emphasis was put on the wide age range, which here is 21 to 86,
Don’t remember that we do not only have never smokers. Approx one third is former smoker and this will also be emphasized in 1005
Esst adenocarcinoma, but in a poster from East Asia fe on 392 tissue samples using RT-PCR and validation with sequencing, they found overall 6.1% ALK pos but this in 5 pts with squamous cell CA and 5 pts with adenosquamous CA. (14 were pure adeno)
Updated info shows now 24 pts in first line, which is more than the 13 pts reported by Camidge at ASCO last year
However, till approx one third has 3 or more previous treatment lines
ECOG; Estado funcional del Eastern Cooperative Oncology Group performance status.

13. An impressive RR and Progression free survival
100
PFS: 9.7 months (IC 95%: 7.7–12.8)
RR: 60.8% 80 60
Progression-free survival (%) 40 20
No. en
riesgo
Time (months)
Camidge DR et al. Lancet Oncol 2012

14. administered continuously
Open-label, Multicenter, Phase II Study of Crizotinib in Advanced ALK-positive Non-Small Cell Lung Cancer
ALK+ NSCLC by central review
ECOG PS: 0–3
≥1 prior line of chemotherapy
Brain metastases that were stable/controlled were allowed
Not eligible for Phase 3 study
Crizotinib 250 mg BID
administered continuously
(21-day cycle)
Primary endpoints: Response rate, safety, and tolerability
Secondary endpoints: OS, TTR, duration of response, disease control rate, PK, biomarkers, PRO/HRQoL (EORTC QLQ-C30 and LC-13)
N=400 (planned)
Kim et al. Ann Oncol 2012; 23 (suppl 9); Abstr 1225O

15. Survival Distribution Function Progression Free Survival time (months)
PROFILE 1005: Progression-free survival in the mature population (n=261)
1.0
Median PFS 8.1 months (95% CI: 6.8–9.7)
28% patients in follow-up for progression
+ Censored 95% Hall-Wellner Band
0.8
ORR: 59.8%
Mature population, n=259 response-evaluable patients
0.6
Survival Distribution Function
0.4
0.2
Progression Free Survival time (months)
n at risk
Kim et al. Ann Oncol 2012; 23 (suppl 9); Abstr 1225O

16. Study Design of PROFILE 1007
Endpoints
Primary
PFS (RECIST 1.1, independent radiology review)
Secondary
ORR, DCR, DR OS
Safety
Patient reported outcomes (EORTC QLQ-C30, LC13)
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
Crizotinib 250 mg BID
PO, 21-day cycle
(n=159)
R A N D O M I Z E
Pemetrexed 500 mg/m2 or
Docetaxel 75 mg/m2
IV, day 1, 21-day cycle
(n=159) b
Say it is validated lung cancer symptom and QOL questionnaire.
N=318
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)
PROFILE 1007: NCT

17. ORRa by independent radiologic review
ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.0001
100
Crizotinib (n=173b)
65.7
29.3
6.9
Crizotinib (n=172c)
Pemetrexed (n=99c)
Docetaxel (n=72c) 40
Chemotherapy (n=174c)
65.3 80 60
ORR (%) 40
19.5 20
aRECIST; bIntent-to-treat population; cAs treated population; ORR=overall response rate
Shaw A, et al. Ann Oncol 2012;23(Suppl9):Abstract 440O
aRECIST v1.1; bITT population; cas-treated population

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

19. The relevance of QoL
Time to deterioration with respect to a composite lung cancer symptom endpoint
Overall change from baseline in symptoms and global QoL
QoL=quality of life; CI=confidence interval Shaw A, et al. N Engl J Med 2013;368:2385–2389

20. PFS (RECIST 1.1, independent radiology review)
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)
Endpoints
Primary
PFS (RECIST 1.1, independent radiology review)
Secondary
ORR, DCR, DR OS
Safety
Patient reported outcomes (EORTC QLQ-C30, LC13)
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 .
Crizotinib 250 mg BID
PO, 21-day cycle
R A N D O M I Z E
Pemetrexed 500 mg/m2 +
Cisplatin75 mg/m2 or
Carboplatin AUC 5-6
IV, day 1, 21-day cycle b
N=334
Estimated Enrollment:334
Study Start Date:January 2011
Estimated Study Completion Date:February 2015
Primary Completion Date:November 2013
ClinicalTrials.gov Identifier:
NCT

21. PROFILE 1014: RR 74% 45% Crizotinib Chemotherapy
Median time to response (months)
1.4
2.8
Median duration of response (months)
11.3
5.3
Mok et al. J Clin Oncol 2014, Abst 8002

22. PROFILE 1014: PFS (ITT Population)
10.9 vs 7 m
Solomon et al. NEJM 2014

23. 2 YEARS SURVIVAL RATE NSCLC
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

24. TOXICITY PROFILE
Solomon et al NEJM 2014
Shaw A et al. NEJM 2013

25. 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 line
32 % 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%

27. HOW WE ACHIEVE AN OS MILESTONE IN ALK+ NSCLC PATIENTS?
MEDIUM
TKI
Chemo
SMALL
LARGE
Chemo
TKI
Chemo
TKI
LARGE

29. ADENOCARCINOMA

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

31. Is there a role for a 3rd line ALK inhibitor? • Resistance mechanism
How should we integrate genetic and clinical information? 1L 2L 3L
Is there a role for a 3rd line ALK inhibitor?
• CNS disease
• Resistance mechanism
Crizotinib
Ceritinib, alectinib etc
or platinum/pem 1L 2L
Which ALK inhibitor?
• CNS efficacy
• Tolerability
• Resistance
mechanism
Novel ALK inh
Shaw A. ESMO 2014

32. 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 2015
Comisión Central Autonómica pendiente
CRIZOTINIB REGULATORY TIMELINE

33. CELL BLOCK
BAL: CITOCENTRIFUGADO
BLOQUE CITOLOGICO DE BAL

35. PARTIAL RESPONSE AFTER 5 WEEKS ON CRIZOTINIB THERAPY

36. PARTIAL RESPONSE AFTER 5 WEEKS ON CRIZOTINIB THERAPY

37. 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

38. Mechanisms of therapeutic resistance to kinase inhibitors.
Mechanisms of therapeutic resistance to kinase inhibitors. Resistance to targeted therapies can be classified as primary resistance or acquired resistance. Primary resistance is defined as a de novo lack of treatment response and can be mediated by tumor intrinsic factors, such as concurrent genetic alterations within the drug target or within other signaling molecules, and by patient-specific factors, such as drug–drug interactions. Conversely, acquired resistance refers to disease progression after an initial response to the targeted therapy. Acquired resistance develops while the patient is still receiving the targeted therapy, implying that the tumor has developed an “escape” mechanism to evade continuous blockade of the target. These “escape” mechanisms include target modification (gene amplification, second-site mutations, splice variants), the emergence of bypass signaling tracks, histologic transformation, as well as other less well-characterized mechanisms such as increased growth factor production. Examples of strategies to overcome acquired resistance, which are discussed in more detail within the text, include alternative doses or schedules of the targeted inhibitor, development of more potent “next-generation” inhibitors, dual blockade of the initial target with two or more target-specific agents, and combination drug strategies designed to suppress compensatory signaling loops.
Lovly C M , and Shaw A T Clin Cancer Res 2014

39. 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 (NCT )
Crizotinib+AT13387 (NCT )
LDK378+AUY922 (NCT )
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 39

40. Acquired and intrinsic Resistance in ALK+ NSCLC
Most patients develop resistance to crizotinib4,5
Usually within 1–2 years
CNS relapses are common6
Mechanisms of resistance are diverse4,5
ALK resistance mutations
Alternative signaling pathways
Refs:
Kim, S., et al., JTO 2013 Apr 8:415-22
Huang, D et al., Genomics 2013 Feb 20
Katayama R et al., Sci Translational Med 4 120ra17 (2012)
Doebele et al., Clin CA Research 2012
1. Camidge DR, et al. Lancet Oncol 2012;13:1011–1019; 2. Kim D-W, et al. ESMO 2012 (Abstr 1230PD); 3. Shaw AT, et al. ESMO 2012 (Abstr LBA1_PR); 4. Katayama R, et al. Sci Transl Med 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res 2012;18:1472–1482; 6. Takeda M, et al. J Thorac Oncol 2013;8:654–657.

41. Presented By Scott Gettinger at 2014 ASCO Annual Meeting
Slide 30
Presented By Scott Gettinger at 2014 ASCO Annual Meeting

42. IS CRIZOTINIB ACTIVE BEYOND PROGRESSION
IS CRIZOTINIB ACTIVE BEYOND PROGRESSION? Clinical outcome of patients who continued Crizotinib Beyond Progressive Disease in PROFILE 1001 and 1005: 174 P
29.6m
10.8m
Ou et al. Lancet Oncol 2014

44. Brain mets at any point in course of disease Brain mets on treatment
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 2013
PROFILE 1007
35% ALK + crizotinib naive
Solomon et al, NEJM 2014
PROFILE 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= (<0.3% gets into brain)

45. 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

46. 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

47. PROFILE 1014: Higher Intracranial DCR with Crizotinib in Patients with Previously Treated Brain Metastases
Crizotinib (n=39)
Chemotherapy (n=40)
Difference: 40% (95% CI: 21–59) Pa=0.0003
Difference: 31% (95% CI: 11–52) Pa=0.006
100 80 60
DCR (95% exact CI; %) 40 20
12 weeks
24 weeks
DCR, disease control rate (% CR + PR + SD)
aPearson χ2 test
Solomon et al. Ann Oncol 2014; Abst 1225O

48. 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