Presentación realizada por la Dra. Dolores Isla del Servicio de Oncología Médica del Hospital Clínico Universitario Lozano Blesa de Zaragoza, en el marco de la I Jornada de actualización e innovación en Oncología que tuvo lugar en el CIBA en enero de 2015.

1. Cáncer de Pulmón
2014
Dolores Isla
Servicio de Oncología Médica
Hospital Clínico Universitario Lozano Blesa de
Zaragoza
Zaragoza, 20 de Enero de 2015

2. CPNM Localizado

5. NEGATIVE

6. Shepherd F, ASCO 2014

7. CPNM Localmente
avanzado

8. • Similar HR compared with the adjuvant approach, with an absolute 5-year OS
improvement of 5%, for all stages: Stage I, 50% to 55%, Stage II, 30% to 35%, Stage III,
20% to 25%
• More conclusive evidence in favour Adjuvant CT

9. CPNM Avanzado

11. Mutaciones mutuamente exclusivas

12. Kris M, JAMA 2014

13. CPNM Avanzado
Mutación EGFR

16. Combined OS analysis: mutation categories
Presented by: James Chih-Hsin Yang
1.0
0.8
0.6
0.4
0.2
0
EstimatedOSprobability
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
1.0
0.8
0.6
0.4
0.2
0
EstimatedOSprobability
Time (months)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0
119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0
Afatinib
Chemo
No of patients
183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0
93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0
Afatinib
Chemo
No of patients
Del19
Afatinib
n=236
Chemo
n=119
Median,
months 31.7 20.7
HR (95%CI),
p-value
0.59 (0.45–0.77),
p=0.0001
L858R
Afatinib
n=183
Chemo
n=93
Median,
months 22.1 26.9
HR (95%CI),
p-value
1.25 (0.92–1.71),
p=0.1600

17. Study Design
Primary endpoint:
PFS (RECIST v1.1, independent review)
Secondary endpoints:
OS, tumor response, QoL, safety
Exploratory endpoint:
biomarker assessment
R
Chemotherapy-naïve
Stage IIIB/IV NSCLC or
postoperative recurrence
Non-squamous
Activating EGFR mutations*
Exon 19 deletion
Exon 21 L858R
PS 0–1
No brain metastasis
E monotherapy
Erlotinib 150mg qd
(n = 75)
EB combination
Erlotinib 150mg qd +
bevacizumab 15mg/kg q3w
(n = 75)
PD
PD
Stratification factors:
sex, smoking status,
clinical stage,
EGFR mutation type
1:1
*T790M excluded
Kato T, et al. J Clin Oncol. 2014;32(Suppl): Abstract 8005.
Phase II

18. PFS by EGFR Mutation Type
EB E
Median, Months 18.0 10.3
HR
0.41
(95% CI: 0.24–0.72)
EB
E
Number at risk
0
1.0
0
Number at risk
EB
E
1.0
0
0
Time, Months
4 8 122 6 10 14 18 22 2616 20 24 28
Time, Months
4 8 122 6 10 14 18 22 2616 20 24 28
0.2
0.4
0.6
0.8
PFSProbability
PFSProbability
0.2
0.4
0.6
0.8
Exon 19 deletion Exon 21 L858R
EB E
Median, Months 13.9 7.1
HR
0.67
(95% CI: 0.38–1.18)
EB E
Median, Months
HR 0.54 (95% CI: 0.36–0.79)
P value*
Primary Endpoint: PFS by Independent Review
0
0
1.0
Number at risk
Time, Months
4 8 122 6 10 14 18 22 2616 20 24 28
0.2
0.4
0.6
0.8
PFSProbability
9.7 16.0
EB
E
*log-rank test, two-sided

19. AURA Study

20. Progression-freesurvivalby
T790M(centraltest)status
0 6 12 18 24 30 36 42
Studyweek
Probabilityofprogression-freesurvival
T790M+(95%CI)
T790M-(95%CI)
Dots indicatecensoredobservations,shadedarearepresents95% CIs;progressioneventsthatdonotoccurwithin
14weeks of the lastevaluable assessment(orfirstdose)arecensored. Population: alldosedcentrally confirmedT790M+
andT790M-patients,N=170(115 T790M+,55T790M-;sixpatients forwhom startdateis not yet knownare notincluded)
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Patientsatrisk
T790M+
T790M-
115
55
96
33
78
21
56
15
21
7
6
0
1
0
Responserate* inT790M+(centraltest)
• ORR*=64%(69/107;95%Cl55%,73%)inpatientswith EGFRT790M+NSCLC
• Overalldiseasecontrolrate(CR+PR+SD)=94%(101/107;95%CI88%,98%)
20mg 40mg 80mg 160mg 240mg
N(107) 10 29 34 28 6
ORR 50% 62% 68% 64% 83%
Bestpercentagechangefrombaselineintargetlesion:allevaluableT790M+patients,PartB
*Includesconfirmedresponsesandresponsesawaitingconfirmation;#representsimputedvalues
Population:alldosedcentrallyconfirmedT790M+patientswithabaselineRECISTassessmentandanevaluableresponse(CR/PR,SD,orPD),
N=107(from120T790M+patients;13patientswithacurrentnon-evaluableresponsearenotincluded).D,discontinued;QD,oncedaily
Bestpercentagechangefrom baselineintargetlesion:
T790M+evaluablepatients,expansioncohortsonly(N=107)
40mgQD
80mgQD
160mgQD
240mgQD
20mgQD
40
20
-20
-40
-60
-80
-100
0
##
DD
D D
D
D DD D
DD
D D
DD
D
D D
D D
DD
D

21. Toxicity: Hyperglycemia G3: 22%

24. Mok T, ESMO 2014

25. Mok T, ESMO 2014

26. EGFR TKIs beyond RECIST disease
progression: ASPIRATION study
Park K, ESMO 2014

29. CPNM Avanzado
Translocación ALK/ROS1
Amplificación MET

30. Solomon B, NEJM 2014

31. PFS with crizotinib versus chemotherapy by independent radiologic review (full analysis population).
PFS significantly longer on crizotinib than CT (10.9 vs 7.0 m; HR: 0.45; 95% CI: 0.35–0.60; P<0.0001).
PROFILE 1014
PFS: 10.9 vs 7 m
Solomon B, NEJM 2014

32. ORR: 74% vs. 45%; 95% CI: 20–39; P<0.0001),
PROFILE 1014
COMENTARIO:
•Tratamiento de 1º línea con crizotinib mejoria
significativa de RR y PFS vs QT en CPNM no
escamoso avanzado.
•Tratamiento estándar en primera línea.
Solomon B, NEJM 2014

33. • N= 130 patients
• ORR:
• 58%
• 80 patients who had received crizotinib previously: 56%
• PFS: 7 m.

34. • N= 130 patients
• ORR:
• 58%
• 80 patients who had received crizotinib previously: 56%
• PFS: 7 m.
ONGOING PHASE III
STUDIES 1st-LINE:
•Crizotinib
•QT

35. Alectinib: Crizotinib resistant NSCLC
Phase I/II trial
Gadgeel S, Lancet Oncol 2014
• N= 47 p.
• ORR:
• 55% of the 44 patients
• 52% of the patients with CNS metastases
• Doses: 900 mg twice-daily dose.

36. Alectinib: Crizotinib resistant NSCLC
Phase I/II trial
Gadgeel S, Lancet Oncol 2014
• N= 47 p.
• ORR:
• 55% of the 44 patients
• 52% of the patients with CNS metastases
• Doses: 900 mg twice-daily dose.
ALEX Study:
1st-Line Phase III Study
ALECTINIB vs CRIZOTINIB

37. Crizotinib and ROS1 +
Shaw A, NEJM 2014

38. ASCO 2014

39. Kinase
IC50 (nM)
mean*
Selectivity
ratio
Met 8 –
ALK 40–60 5–8X
ROS 55 7X
RON 80 10X
Axl
294 34X
322 37X
Tie2 448 52X
Abl 1,159 166X
IRK 2,887 334X
Lck 2,741 283X
Sky >10,000 >1000X
VEGFR2 >10,000 >1000X
PDGFRβ >10,000 >1000X
Crizotinib: selectiveCrizotinib: selective
inhibitor ofinhibitor of
ALK, MET and ROSALK, MET and ROS
In archival tumor tissue, MET amplification was determined by FISH
MET not amplified
(not eligible)
•MET/CEP7 ratio <1.8
MET amplified
(intermediate
MET level)
•MET/CEP7 ratio >2.2–
<5.0
MET amplified (high MET
level)
•MET/CEP7 ratio ≥5
MET amplified
(low MET level)
•MET/CEP7 ratio ≥1.8–
≤2.2

40. Smoking status, n (%)
Never smoker
Ex-smoker
Smoker
1 (50)
1 (50)
0
1 (17)
4 (67)
1 (17)
0
6 (100)
0
2 (14)
11 (79)
1 (7)
Low MET,
n=2
Intermediate
MET, n=6
High MET,
n=6
Total,
N=14
•Eficacia en
pacientes con
niveles de MET
intermedios y
altos.
•Tamaño muestral
insuficiente para
extraer
conclusiones.

41. CPNM Avanzado
INMUNOTERAPIA

43. • Key results (cont.)
- Strong PD-L1 tumour expression correlated with improved response, PFS and OS
Conclusions
- Pembrolizumab was effective in patients with treatment-naïve or previously treated
advanced NSCLC
- In particular, patients with strong PD-L1 tumour expression may benefit from this
treatment
LBA43: Antitumor activity of pembrolizumab (MK-3475) and correlation with
programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients
(pts) with advanced non-small cell lung carcinoma (NSCLC) – Garon E et al
Strong PD-L1 positivity defined as staining in ≥50% of tumour cells, and
weak PD-L1 positivity as staining in 1–49% of tumour cells. Negative
staining is no PD-L1 staining in tumour cells. Data cutoff: March 3, 2014.
PFS (RECIST v1.1, Central Review)
0 8 16 24 32 40 48
100
80
60
40
20
0
Progression-freesurvival,%
Time, weeks
n at risk
Strong
Weak
Negative
44
53
49
28
43
30
18
17
15
17
12
7
9
6
1
6
0
0
3
0
0
Overallsurvival,%
Strong
Weak
Negative
0 2 4 6 8 10
100
80
60
40
20
0
Time, months
44
53
49
43
51
42
34
34
29
27
22
14
21
18
8
18
11
6
5
5
0
12
8
7
2
9
8
4
30
26
21
32
31
26
38
48
38
38
40
34
5
5
0
14
4
4
0
OS
Garon et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA43

46. Rizvi, ASCO 2014

47. CPNM Avanzado
NUEVOS FÁRMACOS

48. A randomized, multicenter, open-label, phase III study of gemcitabine-
cisplatin (GC) chemotherapy plus NECITUMUMAB (IMC-11F8/LY3012211)
versus GC alone in the first-line treatment of patients (pts) with stage IV
squamous non-small cell lung cancer (sq-NSCLC).
Abstract No:8008.
Nick Thatcher*, Fred R. Hirsch, Alexander V. Luft, Aleksandra Szczesna, Tudor E. Ciuleanu, Wojciech Szafranski,
Mircea Dediu, Rodryg Ramlau, Rinat K. Galiulin, Beatrix Bálint, György Losonczy, Andrzej Kazarnowicz, Keunchil
Park, Christian Schumann, Martin Reck, Luis Paz-Ares, Henrik Depenbrock, Shivani Nanda, Anamarija Kruljac-
Letunic, Mark A. Socinski
Necitumumab:
Ac anti EGFR
Primary Objective: OS (HR 0.80); 545 pacients each arm

49. OS: 11.5m vs 9.9m PFS: 5.7 m vs 5.5m

50. LBA8011: NINTEDANIB (BIBF 1120) plus docetaxel in NSCLC patients
progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-
blind phase III trial – Reck M et al
R
1:1
PD
PDKey patient inclusion criteria
•Stage IIIB/IV or recurrent
NSCLC
•Failure after first-line
chemotherapy
•ECOG PS 0-1
(n=1,314)
Placebo bid PO days 2-21
+
docetaxel 75 mg/m2 IV
day 1 q3w (n=659)
Nintedanib 200 mg bid PO
days 2-21 +
docetaxel 75 mg/m2 IV
day 1 q3w (n=655)
Randomised, double-blind, placebo-controlled, Phase III study
Objective: To evaluate nintedanib plus docetaxel in patients with stage IIIB/IV or
recurrent NSCLC progressing after first-line chemotherapy
Primary endpoint
•PFS
Secondary endpoints
•OS in the total population
•OS in adenocarcinoma
Stratification
• ECOG PS; prior bevacizumab; histology;
brain metastases
Reck M, Lancet Oncol 2014

51. Key efficacy data: PFS and OS
• Key results
– Patient characteristics were balanced between the two groups (~70% were <65 years of age; 73%
male; ~50% had adenocarcinoma; ~25% were never smokers; ~95% had received prior platinum-
based therapy)
– Incidence of grade ≥3 AEs for nintedanib+docetaxel vs. placebo+docetaxel was 71.3% vs. 64.3%
– Grade ≥3 AE occurring in ≥1% with nintedanib+docetaxel included: decreased neutrophils, ALT
increased, diarrhoea, fatigue, dyspnoea, AST increased, pneumonia, asthenia, chest pain and appetite
decreased
Nintedanib+
docetaxel
Placebo+
docetaxel HR (95% CI) p value
PFS, months
All patients
Adenocarcinoma
SCC
3.4
4.0
2.2
2.7
2.8
2.6
0.79 (0.68–0.92)
0.77 (0.62–0.96)
0.77 (0.62–0.96)
0.0019
0.0153
0.0200
OS, months
All patients
Adenocarcinoma
SCC
10.1
12.6
8.6
9.1
10.3
8.7
0.94 (0.83–1.05)
0.83 (0.70–0.99)
1.01 (0.85–1.21)
0.2720
0.0359
0.8907
Reck M, Lancet Oncol 2014

52. Lancet 2014
• Phase III 2nd-Line Study
• NSCLC: Squamous / Non-
Squamous
• N= 1253 p.
• Primary Objective: OS: +
• Toxicities were manageable
+

53. ESMO 2014

54. LUX-Lung 8: PFS, independent review
EstimatedPFSprobability
0
Time (months)
0.4
0.8
1.0
0.6
0.2
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
No. of patients
Afatinib 335 266 127 96 54 45 28 25 16 15 8 8 4 2 2 1
Erlotinib 334 256 112 72 43 34 15 12 6 5 0 0 0 0 0 0
Afatinib Erlotinib
Total randomised, n (%) 335 (100) 334 (100)
Patients progressed/died 202 (60) 212 (64)
Median PFS, months 2.4 1.9
HR 0.82
95% CI (0.68–1.00)
Log-rank p value 0.0427
CI, confidence interval; HR, hazard ratio

55. ¿Qué hemos aprendido en 2014?
• Adyuvancia:
– Erlotinib no mejora la SLP en p. EGFR + por FISH o IHQ.
– EGFR-TKI en p. mutación EGFR + ¿?
• Localmente avanzado:
– QT neoadyuvante a Cirugía mejora un 5% la SG a 5 años.
• Mutación de EGFR:
– Afatinib mejora la OS frente a QT (pooled analysis)
– Erlotinib + Bevacizumab mejoran PFS vs Erlotinib
– Deleción exon 19 mejores resultados
– Resistencia adquirida (T790M +): EGFR-TKI 3ª generación (AZD9291,
CO-1686) son eficaces.
– Tras PR a Gefitinib, continuar con Gefitinib + QT no mejora SG vs QT
– Criterios RECIST pueden no ser útiles, EGFR-TKI pueden aportar
beneficio en PR clinicamente no agresiva

56. ¿Qué hemos aprendido en 2014?
• Translocación de ALK:
– Crizotinib mejor SLP y RR que QT en 1ª línea
– Ceritinib eficaz en pacientes previamente tratados y sin tratamiento
previo, y activo en pacientes con M1 SNC (también Crizotinib)
– Alectinib activo en p. pretratados, tb con afectación SNC
• Traslocación ROS1:
– Crizotinib es activo
• Amplificación de MET:
– Historia de tabaquismo
– Crizotinib eficaz en p. con amplificación MET por FISH
• Inmunoterapia:
– Inh PD1/PL1: Activos en CPNM avanzado pretratados y 1ª línea
– Mayor actividad en PD-L1 +
– Por definir el mejor método para determinar PD-L1, cómo evaluar la
eficacia,…

57. ¿Qué hemos aprendido en 2014?
• Nuevos Fármacos:
– Necitumumab mejora SG y SLP en 1ª línea
– Nintedanib mejora SLP y SG en adenocarcinomas en 2ª línea
– Ramucirumab mejora SG y SLP en 2ª línea
– Afatinib en ca escamoso en 2ª línea mejora SLP respecto de Erlotinib
(discretamente)