Cáncer de Pulmón 2014

Dolores IslaServicio de Oncología Médica

Hospital Clínico Universitario Lozano Blesa de Zaragoza

Zaragoza, 20 de Enero de 2015

CPNM Localizado

NEGATIVE

Shepherd F, ASCO 2014

CPNM Localmente avanzado

• 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

CPNM Avanzado

Mutaciones mutuamente exclusivas

Kris M, JAMA 2014

CPNM AvanzadoMutación EGFR

Combined OS analysis: mutation categories

Presented by: James Chih-Hsin Yang

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed O

S p

roba

bilit

y

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

Est

imat

ed O

S p

roba

bilit

yTime (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

Del19Afatinibn=236

Chemon=119

Median, months 31.7 20.7

HR (95%CI), p-value

0.59 (0.45–0.77), p=0.0001

L858RAfatinib n=183

Chemon=93

Median,months 22.1 26.9

HR (95%CI), p-value

1.25 (0.92–1.71), p=0.1600

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

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 12 2 6 10 14 18 22 26 16 20 24 28

Time, Months

4 8 12 2 6 10 14 18 22 26 16 20 24 28

0.2

0.4

0.6

0.8

PFS Proba

bility

PFS Proba

bility

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 12 2 6 10 14 18 22 26 16 20 24 28

0.2

0.4

0.6

0.8

PFS P

roba

bility

9.7 16.0

EB

E

*log-rank test, two-sided

AURA Study

Progression-free survival by T790M (central test) status

0 6 12 18 24 30 36 42 Study week

Pro

babi

lity

of p

rogr

essi

on-f

ree

surv

ival

T790M+ (95% CI)

T790M- (95% CI)

Dots indicate censored observations, shaded area represents 95% CIs; progression events that do not occur within 14 weeks of the last evaluable assessment (or first dose) are censored. Population: all dosed centrally confirmed T790M+ and T790M- patients, N=170 (115 T790M+, 55 T790M-; six patients for whom start date is not yet known are not included)

0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Patients at risk T790M+ T790M-

115 55

96 33

78 21

56 15

21 7

6 0

1 0

Response rate * in T790M+ (central test)

• ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC

• Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%)

20 mg 40 mg 80 mg 160 mg 240 mg

N (107) 10 29 34 28 6

ORR 50% 62% 68% 64% 83%

Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B

*Includes confirmed responses and responses awaiting confirmation; #represents imputed values Population: all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD), N=107 (from 120 T790M+ patients; 13 patients with a current non-evaluable response are not included). D, discontinued; QD, once daily

Best percentage change from baseline in target lesion: T790M+ evaluable patients, expansion cohorts only (N=107)

40 mg QD

80 mg QD

160 mg QD

240 mg QD

20 mg QD

40

20

-20

-40

-60

-80

-100

0

# # D D

D D

D

D D D D

D D

D D D D

D D D

D D

D D D

Toxicity: Hyperglycemia G3: 22%

Mok T, ESMO 2014

Mok T, ESMO 2014

EGFR TKIs beyond RECIST disease progression: ASPIRATION study

Park K, ESMO 2014

CPNM AvanzadoTranslocación ALK/ROS1

Amplificación MET

Solomon B, NEJM 2014

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

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

• N= 130 patients• ORR:

• 58% • 80 patients who had received crizotinib previously: 56%

• PFS: 7 m.

• N= 130 patients• ORR:

• 58% • 80 patients who had received crizotinib previously: 56%

• PFS: 7 m.

ONGOING PHASE III STUDIES 1st-LINE:

•Crizotinib

•QT

Alectinib: Crizotinib resistant NSCLCPhase 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.

Alectinib: Crizotinib resistant NSCLCPhase 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

Crizotinib and ROS1 +

Shaw A, NEJM 2014

ASCO 2014

Kinase

IC50 (nM)

mean*

Selectivity

ratio

Met 8 –

ALK 40–60 5–8X

ROS 55 7X

RON 80 10X

Axl294 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: selective Crizotinib: selective inhibitor of inhibitor 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

Smoking status, n (%)

Never smokerEx-smokerSmoker

1 (50)1 (50)

0

1 (17)4 (67)1 (17)

06 (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.

CPNM AvanzadoINMUNOTERAPIA

• 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 p ooled 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

0Pro

gres

sio

n-f

ree

surv

ival

, %

Time, weeksn at riskStrong

Weak

Negative

44

53

49

28

43

30

18

17

15

17

12

7

9

6

1

6

0

0

3

0

0

Ove

rall

surv

ival

, %

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

Rizvi, ASCO 2014

CPNM AvanzadoNUEVOS FÁRMACOS

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

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

LBA8011: NINTEDANIB (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lun g 1, a randomized, double-blind phase III trial – Reck M et al

R1:1

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

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, monthsAll patientsAdenocarcinomaSCC

3.44.02.2

2.72.82.6

0.79 (0.68–0.92)0.77 (0.62–0.96)0.77 (0.62–0.96)

0.00190.01530.0200

OS, monthsAll patientsAdenocarcinomaSCC

10.112.68.6

9.110.38.7

0.94 (0.83–1.05)0.83 (0.70–0.99)1.01 (0.85–1.21)

0.27200.03590.8907

Reck M, Lancet Oncol 2014

Lancet 2014

• Phase III 2nd-Line Study

• NSCLC: Squamous / Non-

Squamous

• N= 1253 p.

• Primary Objective: OS: +

• Toxicities were manageable

+

ESMO 2014

LUX-Lung 8: PFS, independent reviewE

stim

ated

PF

S p

roba

bilit

y

0

Time (months)

0.4

0.8

1.0

0.6

0.2

01 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 1Erlotinib 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

¿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

¿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,…

¿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)