Innovación terapéutica en cáncer de pulmón

Dr A. Artal

Hospital Universitario Miguel Servet

Zaragoza

INMUNOTERAPIA

NINTEDANIB

INMUNOTERAPIA

NINTEDANIB

Study Intervention Target PFS, months OS, months Primary

endpoint

ESCAPE1

(n=926)

CB/PTX/placebo CB/PTX/sorafenib

VEGFR-2, -3, PDGFR-ß, Flt-3,

b-RAF, c-kit

5.4 4.6

HR: 0.99 (0.84–1.16)

10.6 10.7

HR: 1.15 (0.94–1.41) OS

NExUS2

(n=772)

CIS/GEM/placebo CIS/GEM/sorafenib

5.5 6.0

HR: 0.83 (0.71–0.97)

12.5 12.4

HR: 0.98 (0.83–1.16) OS

ZEAL3

(n=534)

Pemetrexed/placebo Pemetrexed/vandetanib

VEGFR, EGFR, RET

2.8 4.1

HR: 0.86 (0.69–1.06)

9.2 10.5

HR: 0.86 (0.65–1.13) PFS

ZODIAC4

(n=1391)

Docetaxel/placebo Docetaxel/vandetanib

3.2 4.0

HR: 0.79 (0.70–0.90)

10.0 10.6

HR: 0.91 (0.78–1.07) PFS

SUN10875

(n=960)*

Erlotinib/placebo Erlotinib/sunitinib

VEGFR-1, -2, -3, PDGFR-ɑ, -ß,

Flt-3, c-kit

2.0 3.6

HR: 0.81 (0.70–0.94)

8.5 9.0

HR: 0.92 (0.80–1.07) OS

VITAL6 (n=913)

Docetaxel/placebo Docetaxel/aflibercept

VEGF-A, -B, PIGF

4.1 5.2

HR: 0.82 (0.72–0.94)

10.4 10.1

HR: 1.01 (0.87–1.17) OS

BETA7 (n=636)

Erlotinib/placebo Erlotinib/bevacizumab

VEGF-A 1.7 3.4

HR: 0.62 (0.52–0.75)

9.2 9.3

HR: 0.97 (0.80–1.18) OS

Fir

st

lin

e

Seco

nd

lin

e

*280 patients received >1 prior treatment lines. CB = carboplatin; PTX = paclitaxel; CIS = cisplatin; GEM = gemcitabine; OS = overall survival; PFS = progression-free survival; HR = hazard ratio;

VEGF = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; RAF = rapidly accelerated fibrosarcoma; PIGF = placental growth factor receptor.

1. Scagliotti G, et al. J Clin Oncol 2010;28:1835–42; 2. Paz-Ares LG, et al. J Clin Oncol 2012;30:3084–92; 3. de Boer R, et al. J Clin Oncol 2011;29:1067–74; 4. Herbst R, et al. Lancet Oncol

2010;11:619–26; 5. Scagliotti GV, et al. J Clin Oncol 2012;30:2070–8; 6. Ramlau R, et al. J Clin Oncol 2012;30:3640–7; 7. Herbst R, et al. Lancet Oncol 2011;377:1846–54.

Nintedanib (BIBF 1120)* – a triple angiokinase inhibitor

• Oral triple angiokinase inhibitor targeting:1,2

– VEGFR 1–3

– FGFR 1–3

– PDGFR α/β

– RET, Src, FLT3

• Preclinical activity:

• Manageable safety profile in combination with:

– Docetaxel3

– Pemetrexed4

– Paclitaxel/carboplatin5

– Gemcitabine/cisplatin6

– Afatinib7

IC50

(nmol/L)

VEGFR

1 / 2 / 3

34/ 21/ 13

PDGFR

α / β

59/ 65

FGFR

1 / 2 / 3

69/ 37/ 108

LUME-Lung 1: Basic study design

BIBF 1120 200 mg BID p.o., Day 2–21 + Docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=655)

Placebo BID p.o., Day 2–21 + Docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=659)

n=1314

RANDOMIZE

Stratification: ECOG PS (0 vs. 1)

Prior bevacizumab (yes vs. no)

Histology (squamous vs. non-squamous)

Brain metastases (yes vs. no)

Stage IIIB/IV

or recurrent

NSCLC patients

after first-line

chemotherapy

(all histologies)

1:1

PD

PD

Number of docetaxel cycles not restricted

Monotherapy allowed after ≥4 cycles of combination therapy

Regions: Europe/Asia/South Africa

Accrual: 23 Dec 2008 to 09 Feb 2011

Reck M, et al. Lancet Oncol 2014; 15: 143

6

Key Inclusion

• Histologically or cytologically confirmed, locally advanced and/or metastatic, stage

IIIB–IV or recurrent NSCLC

• All NSCLC histologies

• Failure after first-line chemotherapy (adjuvant /neoadjuvant allowed)

• ECOG PS 0 or 1

Key Exclusion

• Prior docetaxel or VEGF/VEGFR inhibitors (other than bevacizumab)

• Active brain metastases or leptomeningeal disease

• Centrally located tumours with radiographic evidence (CT or MRI) of local invasion

of major blood vessels or radiographic evidence of cavitary or necrotic tumours

• History of clinically significant hemoptysis within the past 3 months (greater than

one teaspoon of fresh blood per day)

Major Eligibility Criteria

LUME-Lung 1: Statistical design

Primary objective: PFS (centrally reviewed)

Secondary objectives: OS

PFS (investigator assessment)

Response rate

Safety analysis

PFS: 713 events HR 0.78, power 90%): 1300 patients (10% attrition)

Futility analysis with 50% of events

OS: 1151 deaths (HR 0.85, power 80%)

*Stratified for baseline ECOG PS , tumour histology, brain metastases and prior treatment with Bevacizumab.

LUME Lung 2 was stopped on 18 June 2011 at the recommendation of the DMC

based on a futility analysis using investigator assessed PFS.

LUME Lung 2: DMC futility analysis: investigator based PFS

Baseline variables investigated for LUME Lung 1 + 2

Baseline variables

Race (Asian yes / no)*

Gender* (male / female)

Stage at diagnosis* (<IIIB/IV vs. IIIB vs. IV)

Age (<65 / ≥65 years)*

Smoking history* (ever smoked vs. never smoked)

Adrenal metastasis** (yes / no)

Liver metastasis* (yes / no)

Number of metastatic organs**

Therapy with bisphosphonates* (yes / no)

LDH level** (≤1 vs >1)

Best response to 1st line* (CR,PR,SD vs. PD vs. UNK )

Time since start of 1st line treatment * (continuous variable)

Stratification factors

ECOG performance score

Bevacizumab pre-treatment

Brain metastases at baseline

Tumour histology

* Pre-specified in the protocol or identified from

literature** as potential prognostic or predictive variable.

Kaiser R, et al. Eur J Cancer 2013; 49: 3479

OS Adenocarcinoma

T<9mo

Key secondary endpoint: OS • Stepwise testing

time since start of 1st line therapy (T) <9 months all adenocarcinoma all histologies

• 80% power*, HR 0.80

• Two sided stratified log-rank test, α=0.0494**

• Two-sided stratified log-rank test, α=0.05

Primary endpoint: Independently assessed PFS • All histologies

• 90% power after 713 PFS events, HR 0.78

Statistical Design

p<0.0494 p<0.0494 p<0.0494

1

2

Next analysis step only allowed if PFS confirmed

with all PFS events at time point of OS analysis

OS

OS

*Fixed-sequence order testing implemented prior to database lock to validate biomarker findings from independent study

LUME-Lung 2 (Hanna N, et al. ASCO 2013. Abstract #8034; Hanna N, et al. ESMO 2013. Abstract #3418;

Kaiser R, et al. ESMO 2013 Abstract #3479); Reck M, et al. Lancet Oncol 2014; 15: 143**Overall α=0.05

All adenocarcinoma All histologies

Patient characteristics

Nintedanib Placebo

Age 60 (53-67) 60 (54-66)

Gender (Male) % 72.7 72.7

PS 0/ 1 % 28.5/ 71.3 28.7/ 71.3

Never smoker % 25.2 24.4

Brain met. % 5.8 5.8

Squamous/ Adenoca % 42.1/ 49.2 42.3/ 51.0

Months 1st diagnosis 8.8 (5.4-13.6) 8.6 (5.4-13.6)

Prior platinum % 97.2 97.7

Prior bevacizumab % 4.1 3.5

Best response (CR/ PR/ SD) % 2.0/ 33.1/ 38.5 2.9/ 27.2/ 38.2

PFS, all histologies

13

Squamous HR 0.77

Adenoca HR 0.77

Centrally assessed PFS in T<9m adenocarcinoma

OS

Kaiser R, et al. Eur J Cancer 2013; 49: 3479

Overall Survival: Adenocarcinoma < 9m Since Start of 1st Line

All : 10.1 vs 9.9 m

HR 0.94, p= 0.27

Adenoca: 12.6 vs 10.3 m

HR 0.83, p= 0.03

PD to 1st L 9.8 vs 6.3m

117p HR 0.62, p=0.02

10.9

7.9 m

Best tumour response

Adenocarcinoma, T<9 months (n=405) 16

Adeno <9m Nintedanib Placebo p

Disease control rate 59.2 33.2 0.0009

Obj response 4.9 1.5 0.0001

Overall Survival: Adenocarcinoma Histology

Safety in All Treated Patients

45

40

35

30

25

20

15

10 5

0

Pati

en

ts (

%)

All CTCAE grades ≥15% incidence

CTCAE grades ≥3 ≥1% incidence

Nintedanib + docetaxel

Placebo + docetaxel

50

45

40

35

30

25

20

15

10 5

0

50

HBP, bleeding, intestinal perforation: No differences

First positive trial of a targeted agent in second line therapy of NSCLC

along with standard chemotherapy

LUME-Lung1 met its primary endpoint: PFS (HR 0.79, p=0.0019) in all

histologies

Nintedanib + Docetaxel significantly improved OS in adenocarcinoma

histology (HR 0.83, p=0.0359, median OS 10.3 to 12.6 m)

Patients with a poor prognosis (time since start of 1st line therapy <9

months) also experienced significant OS improvement

AEs with Nintedanib + Docetaxel were generally manageable with dose

reductions and symptomatic treatment

Summary

Absolute benefit was small, increased toxicity in a palliative setting,

absence of biomarkers

INMUNOTERAPIA

NINTEDANIB

Reconocimiento

Presentación de antígenos

Activación de linfocitos T

Destrucción celular

Anti- N RO (%) IrRO(%)

Nivolumab PD1 129 17.1 21.7

MK3475 PD1 221 15 21

MPDL3280A PD-L1 85 23 -

BMS936559 PD-L1 207 10 -

MEDI4736 PD-L1 26 15 -

Eficacia

Criterio de repuesta/ progresión

• RECIST vs irRECIST

• Dificultad recuperación en FFPE

• Heterogeneidad tumoral

• Prevalencia

• Influencia de tratamientos previos

• Criterio de positividad (1/ 5/ 10/ 50%?)

• Positividad en céls. tumorales o linfocitos

• Diferentes pruebas (problemas metodológicos + intereses

comerciales)

Concordancia?

Respuestas en tumores PD-L1 negativo (8-15%)

PD-L1como biomarcador

Toxicidad

Anti- N AE (%) G3-4 (%) Neumonitis (%)-G34-G5

Nivolumab PD1 129 53 5 6-2-2p

MK3475 PD1 221 48 6 1-1-0

MPDL3280A PD-L1 85 66 11 ?-0-0

BMS936559 PD-L1 207 61 9 0-0-0

MEDI4736 PD-L1 26 34 0 0-0-0

N PDL1+

RO AE

8007 Rizvi MK3475 Pembrolizumab

42 +>1% 1 L 22% sq

57% 10mg/Kg/ 21d 10mg/Kg/14d

20/31 DCR 70/63

80% 1p N

8020 Garon MK3475 217 >1L 23

8021 Brahmer MEDI4736 155 >1L +25% -3%

45% 3%SAE No N - C

8022 Rizvi Nivolumab + Erlotinib

21 >TKI 15% 0 N

8023 Antonia Niv 3+ Ipi 1 Niv 1+Ipi1

49 +19 -14

50% G3-4 3p N 3-4

8024 Gettinger Nivolumab 20 1L 30 Sq 22 No 36 +50, -0%

SAE 2% 0N

ASCO 2014

Ensayos en combinación

Línea

QT Nivolumab 1ª CDDP-Gem CDDP-Pem CBDCA-Tax

MK-3475 1ª CDDP-Pem CBDCA-Tax±Bev

MPDL3280A T. sólidos CBDCA-Tax±Bev Nab-paclitaxel Pem±Bev FOLFOX

T. dirigidas Nivolumab Erlotinib

MK-3475 Erlotinib Gefitinib

MPDL3280A Erlotinib Cobimetinib (Mek)

Línea

Inmunoterapia Nivolumab 1ª Ipilimumab

MK-3476 2ª Tremelimumab

MEDI0680 T. sólidos MEDI4376

Nivolumab T. sólidos Il-21

Nivolumab Anti-CD137 Anti-KIR

Cuestiones pendientes

Anti PD-1 o anti PD-L1 Actividad parece semejante

Duración del tratamiento Indefinido vs 1-2 daños

Respuestas en re-tto y post-tto

Combinación QT (dosis y esquema, inmuno-

supresión vs antígenos, MHC,…)

Valor del “priming” (agentes

hipometilantes y HDACi)?

Inmunoterapia (vacunas, citoquinas,

céls. dendríticas)

Bevacizumab (inmunosupresor,

infiltración LT)

RT

Mecanismos de resistencia, activación LT,…