Nuevos fármacos anti ALK

Javier de Castro

Cáncer de Pulmón ALK + • Incidencia 2-7%

• 5-6ª dec, No fumador

De Castro J, Clin and Trasl 2013

Respuestas Parciales: ALK+ CPCNP, IMT

Fusión de NPM-ALK descubierta LACG*

PROFILE 1001: Primer paciente

Identificación de Crizotinib

2006 2005 2009 1994 2007

Fusión de EML4-ALK descubierta en CPCNP

2010 2011 2008

Garantía de prioridad de revisión por FDA (Mayo 2011)

Crizotinib aprobado por la FDA (Agosto 2011)

2014

Crizotinib (PF-02341066)

Solomon BJ , N Engl J Med 2014 Camidge, Lancet Oncol 2012

Costa DB, J Clin Oncol 2015

Resistencia Inicial

Progresión SNC

Progresión 11 meses

Major modes of crizotinib resistance in

ALK+ NSCLC Brain metastasis

(new/progression of

existing metastasis)

Loss of ALK/activation of

secondary signalling

pathway

Acquired resistance in

ALK

Gatekeeper

L1196M

Solvent-front

G1202R

R-spine

I1171T/N/S

Non solvent-front;

non-gatekeeper

F1174L/V/C

Crizotinib

ALK mut

ALK amp

No ALK amp or mut

ALK+

Unknown

Bypass tracks

EGFR

CKIT

SRC

IGF1R

About One-Third of Resistant Tumors

Harbor ALK Resistance Mutations

2 4 6 8 10 0

Number of patients

*

Crizotinib resistance mutations

in ALK+ NSCLC

* F1174V Modified from Lovly and Pao. Sci Transl Med 2012

Friboulet et al. Cancer Discov 2014

ASCEND-1

Recruitment closed July 2013

•31 October 2013 data cut-off

used for current analysis

•Study ongoing

*9 ALK+ patients had cancers

other than NSCLC

**All received crizotinib and 5

also received alectinib

Dose escalation phase (n=59) closed May 2012 with RD of 750 mg/day 1Shaw A et al. NEJM 2014;370(13):1189–1197

ALKi: ALK inhibitor; RD: recommended dose

NCT01283516

ALK inhibitor treated**

N=163

ALK inhibitor naïve N=83

Key Objectives: to determine anti-tumor efficacy and

safety of ceritinib

Expansion Phase • Evaluate 750 mg RD

• N=255 patients with ALK+ tumors*

N=246 patients with ALK+ NSCLC tumors

•Global pivotal phase 1 trial including 20 centers across 11 countries1

Shaw, et al. N Engl J Med 2014

ASCEND-1:

Presented by: Dong-Wan Kim ASCO 2014

NCT01283516

Overall Response Rate in ALK+ NSCLC Patients

Treated with Ceritinib (750 mg daily)

Efficacy Parameter

(RECIST 1.0)

ALK inhibitor treated (N=163)

ALK inhibitor naïve

(N=83)

All (N=246)

Complete Response (CR), n (%) 2 (1.2) 1 (1.2) 3 (1.2)

Partial response (PR), n (%) 87 (53.4) 54 (65.1) 141 (57.3)

Stable Disease (SD), n (%) 32 (19.6) 19 (22.9) 51 (20.7)

Progressive Disease (PD), n (%) 16 (9.8) 0 16 (6.5)

Unknown*, n (%) 26 (16.0) 9 (10.8) 35 (14.2)

Overall Response Rate (ORR),

n (%) [95% CI]

89 (54.6) [46.6, 62.4]

55 (66.3) [55.1, 76.3]

144 (58.5) [52.1, 64.8]

*No post-baseline assessment done, or the post-baseline assessment had overall response that was not CR, PR, SD or PD

ASCEND-1

NCT01283516

Progression-Free Survival in Patients

Presented by: E. Felip ESMO 2014

NCT01283516

Adverse Events & Laboratory Abnormalities Regardless of Study Drug Relationship

Presented by: Dong-Wan Kim ASCO 2014

All patients treated with 750 mg (N=255; includes 9 non-NSCLC patients)

Most common adverse events (AE) All grades* (%) Grade 3/4* (%)

Diarrhea 86 6 Nausea 80 4 Vomiting 60 4 Abdominal pain 54 2 Constipation 29 0 Fatigue 52 5 Decreased appetite 34 1 Interstitial lung disease (ILD)/pneumonitis 4 3 Key Laboratory abnormalities All grades* (%) Grade 3/4* (%) Hemoglobin decreased 84 5 Alanine transaminase (ALT) increased 80 27 Aspartate transaminase (AST) increased 75 13 Creatinine increased 58 2 Glucose increased 49 13 Phosphate decreased 36 7 Lipase increased 28 10

QTc prolongation >60ms occurred in 3% of pts. 1 pt at 700mg had QTc >500 ms.

*All grades (>20%); Grade 3/4 (≥2%).

ASCEND-1

Ceritinib Trials in Progress

• Ongoing Phase III trials

• Ceritinib (LDK378) versus chemotherapy in patients who have received prior chemotherapy and crizotinib (NCT01828112)

• Ceritinib (LDK378) versus chemotherapy in patients who are both chemotherapy-naïve and crizotinib-naïve (NCT01828099)

• Two phase II trials have completed enrolment

• Ceritinib (LDK378) in adult patients previously treated with chemotherapy and crizotinib (NCT01685060)

• Ceritinib (LDK378) in crizotinib-naïve adult patients (NCT01685138)

AF802

Crystal structure of AF802 in complex with ALK

Sakamoto H, , Cancer Cell 2011

1. Seto, et al. Lancet Oncol 2013; 2. Inoue, et al. WCLC 2013; 3. Ou, et al. ESMO 2013; 4. Gadgeel, et al. WCLC 2013

Alectinib: overview of clinical development

Study ID Phase Study design Location Data availability

AF001JP Phase I / II ≥2L crizotinib-naïve

(single-arm)

Japan Published1,2

AF002JG /

NP28761 Phase I / II

≥2L crizotinib-failure

(single-arm)

USA Published3,4

NP28673 Phase I / II ≥2L crizotinib-naïve

(single-arm)

Global Study ongoing

JO28928

(J-ALEX) Phase III

1L / 2L crizotinib-naïve

H2H vs crizotinib

Japan Study ongoing

BO28984

(ALEX) Phase III 1L H2H vs crizotinib Global

Study ongoing

AF-001JP: alectinib in ALK inhibitor-naïve patients

with ALK+ disease (ITT population; by IRC)

*Lymph nodes are identified as target lesion for RECIST evaluation

CR = complete response; NE = not evaluated; PR = partial response; SD = stable disease

31 Jan 2014 cut-off

Alectinib is not approved in Malaysia for the treatment of patients with ALK+ NSCLC

Tamura, et al. CMSTO 2014

0

–30

–50

–100

CR

PR

SD

NE

*

*

*

Ch

an

ge f

rom

baselin

e (

%)

n=46

ORR = 93.5%

Percentage change in tumour size from baseline

1. Seto, et al. Lancet Oncol 2013; 2. Inoue, et al. WCLC 2013

AF-002JG (phase 1/2 alectinib trial): response

in patients previously treated with crizotinib

Gadgeel, et al. Lancet Oncol 2014

Best

ch

an

ge f

rom

baselin

e (

%)

30

20

10

0

–10

–20

–30

–40

–50

–60

–70

–80

–90

–100

300mg

460mg

600mg

760mg

900mg

ORR = 55%

Alectinib is not approved in Malaysia for the

treatment of patients with ALK+ NSCLC

AF-001JP: PFS with alectinib

(ITT population; by IRC)

NR = not reached

31 Jan 2014 cut-off

Tamura, et al. CMSTO 2014

Median treatment duration was 23 months (range 1–33)

Median PFS: 27.7 months

(95% CI: 26.9–NR)

PF

S p

rob

ab

ilit

y

Time (months)

10 20 30 5 15 25 0 35

0.8

0.6

0.4

0.2

0

1.0

27.7

46 43 35 34 31 14 0 0 No. at risk

Phase III studies of 1L alectinib vs

crizotinib

*IHC test is being developed by Ventana as a CDx to alectinib. Sufficient

tumour tissue is required to test for ALK+ disease via IHC and FISH

1. NCT02075840

2. Peters, et al. ESMO 2014; 3.

JapicCTI-132316

Alectinib 600mg BID

Crizotinib 250mg BID

1:1

• Stage IIIB/IV NSCLC

• ALK+ disease according

to IHC test*

• Treatment-naïve

• ECOG PS 0–2

(n=286)

ALEX (BO28984)1,2

J-ALEX3

Alectinib 300mg BID

Crizotinib 250mg BID

1:1

• Stage IIIB/IV NSCLC

• ALK+ disease according

to IHC, FISH or RT-PCR

• Treatment-naïve or

received 1L chemo

• ECOG PS 0–2

(n=200)

Primary endpoint

•PFS (independent review)

Primary endpoint

•PFS (investigator assessed)

Innovative features

•Regularly scheduled

brain MRI to assess time

to CNS progression

•QoL measured

post-progression

R

R

ASCEND-1

NCT01283516

Efficacy of Ceritinib in Patients with Brain Metastases

Presented by: A. Shaw ESMO 2014

$Eastern Cooperative Oncology Group Performance Status ≤1; *Remaining patients either had CT scans or scans that were not available.

ALK, anaplastic lymphoma kinase gene; CT, computerised tomography; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer

Of 246 ALK+ NSCLC patients enrolled in the ASCEND-1 trial and treated

with ceritinib 750 mg/day, 124 had brain metastases at study entry, as per

investigator assessment.

Among the 124 patients with brain metastases at study entry, 26 were ALK

inhibitor naïve while 98 had previously been treated with an ALK inhibitor

Most patients had adenocarcinoma

histology, were aged <65 years

and had good

performance status$

Caucasian and Asian

represented the

predominant races and

accounted for 98% of the

patient cohort

NCT01283516

Overall Intracranial Response Rate for Patients with Measurable Brain Metastases at Baseline

Presented by: Dong-Wan Kim ASCO 2014

Best Overall

Response

n (%)

ALK inhibitor

treated

N=10

ALK inhibitor

naïve

N=4

All patients N=14

Complete response 0 1 1

Partial response 4 2 6

Stable disease 3 0 3

Progressive disease 0 0 0

Unknown 3 1 4

OIRR [95% CI]

4 (40.0) [12.2, 73.8]

3 (75.0) [19.4, 99.4]

7 (50.0) [23.0, 77.0]

CI, confidence interval; OIRR, overall intracranial response rate

ASCEND-1

*Intracranial PFS calculated as time to progression in brain + deaths due to any cause. Analyses include patients evaluated by MRI (n=74) and CT (n=20)

ALK, anaplastic lymphoma kinase; CI, confidence interval; NE, not estimable; NSCLC, non-small cell lung cancer; PFS, progression-free survival

Intracranial PFS* with Ceritinib in Patients with ALK+ NSCLC

with Baseline Brain Metastases Evaluable by MRI/CT

Median: non-estimable (95% CI 7.4, non-estimable)

Intracranial* PFS rate at 12 months: 54.9% (95% CI 21.8, 79.0)

Median: 6.0 months (95% CI 4.2, 9.4)

Intracranial* PFS rate at 12 months: 24.5% (95% CI 13.6, 37.2)

Number of patients still at risk

Time (Months) 0 3 6 9 12 15 18 21

NSCLC with prior ALKi 75 46 29 20 9 5 0 0

NSCLC ALKi naïve 19 13 10 7 3 1 1 0

100

90

80

70

60

50

Pro

ba

bil

ity (

%)

40

30

20

10

0

0 3 6 9 12 15 18

Time (Months)

21

NSCLC with prior ALKi (N = 75)

NSCLC ALKi naïve (N = 19)

Mehra et al Miami SNO 14 Nov. 2014

AF-002JG:

alectinib activity against brain metastases

OIRR = overall intracranial response rate

Alectinib is not approved in Malaysia for the treatment of patients with ALK+

NSCLC Gadgeel, et al. Lancet Oncol 2014

Patients with brain metastases at baseline (n=21)

Best intracranial response, %

OIRR 52

CR 29

PR 24

SD 38

PD 10

Ch

an

ge

fro

m b

ase

line

(%

)

0.6

0.4

0.2

0

–0.2

–0.4

–0.6

460mg

600mg

760mg

900mg

–0.8

Patients with measurable brain

metastases at baseline (n=9)

Plasma/CSF levels of alectinib may

explain clinical activity seen against

CNS metastases

Alectinib is not approved in Malaysia for the treatment of patients with

ALK+ NSCLC

Gadgeel, et al. Lancet Oncol 2014

(n=5)

Extrapolated Ctrough

in CSF = 2.69nmol/L

Unbound systemic

Ctrough = 3.12nmol/L

In-vitro IC50 for

ALK inhibition in

cell-free assays

= 1.9nmol/L

Co

nc

en

tra

tio

n o

f a

lec

tin

ib in

CS

F (

nm

ol/

L) 15

10

5

0

0 2 4 6 8 10

Unbound alectinib in plasma (nmol/L)

r2=0.75

CNS penetration and the P-gp

transporter

• Lipid-soluble solutes that can freely diffuse through the capillary endothelial

membrane may passively cross the BBB

• BBB is reinforced by a high concentration of P-gp, a drug-efflux-transporter protein

Misra, et al. J Pharm Pharm Sci 2003

Lipid soluble

crizotinib

BBB = blood-brain barrier; P-gp = protein P-glycoprotein

Crizotinib Ceritinib Alectinib

May 2012 Nov 2012 Oct 2014

WT G1269A

I1322M 1151 T-ins G1202R

Culture in absence of drug

Culture with crizotinib

G1269A

I1322M

WT G1269A

I1322M 1151 T-ins

G1202R

Tre

at

wit

h

ceri

tin

ib

Culture with ceritinib

G1202R

I1322M

Culture in absence of drug

Modeling the Evolution of Resistance

Ceritinib is not approved in the EU Ryohei Katayama and Tahsin Khan.

Unpublished data

ALK mut

ALK amp

No ALK amp or mut

ALK+

Unknown

Bypass tracks

EGFR

CKIT

SRC

IGF1R

About Two-Thirds of Resistant

Tumors do not Harbor ALK

Resistance Mutations

Heterogeneidad de los mecanismos de

resistencia

Friboulet, et al. Cancer Discov 2014

IHC (KIT)

IHC (SCF)

pEGFR

Pre-crizotinib Resistant (BAC) Resistant (solid)

Ki67

EGFR and CKIT May Mediate Crizotinib

Resistance

Katayama, et al. Sci Transl Med 2012

Current and Emerging Combinations

Mechanism Strategy

EGFR activation ALK + EGFR inhibitors

MET amplification ALK + C-MET inhibitors

Multiple mechanisms (or unknown) ALK + hsp90 inhibitors

ALK + chemotherapy

ALK + anti-angiogenesis

ALK + immunotherapy

ALK + CDK4/6 inhibitor

CRIZOTINIB QUIMIOTERAPIA

CRIZOTINIB QUIMIOTERAPIA

CERITINIB

ALECTINIB

NUEVOS AGENTES

CERITINIB/ALECTINIB

QUIMIOTERAPIA

Inmunoterapia ?

D’Incecco et al, B J Cancer 2015

*Up-regulation of PD-L1 by EGFR Activation Mediates the Immune Escape in

EGFR-driven NSCLC: Implication for Optional Immune Targeted Therapy for

NSCLC Patients with EGFR Mutation. Chen et al. J Thorac Oncol 2015

ALK TKI Sponsor

ROS1

Activity Status

Ongoing

Studies Reference

Ceritinib

(LDK378)

Novartis Yes FDA approved

(4-29-2014)

Phase 3 Shaw, et al. NEJM 2014;

Kim, et al. ASCO 2014

Alectinib

(CH5424802)

Roche No Investigational

(Breakthrough Therapy

Designation)

Approved in Japan

Phase 3 Seto, et al. Lancet Onc

2013; Gadgeel, et al.

Lancet Onc 2014

AP26113 Ariad Yes Investigational Phase 2 Gettinger, et al. ASCO 2014

X-396 Xcovery Yes Investigational Phase 1 Horn, et al. ASCO 2014

TSR-011 Tesaro Unk Investigational Phase 1/2 Weiss, et al. WCLC 2013

NMS-E628 Ignyta Yes Investigational Phase 1/2a De Braud, et al. ASCO 2014

CEP-37440 Teva Unk Investigational Phase 1 NCT01922752

PF-06463922 Pfizer Yes Investigational Phase 1/2 Zou, et al. EORTC-AACR-

NCI 2013

Next generation ALK inhibitors

Ceritinib and alectinib are not approved in the EU

All other agents on this slide are: experimental use, not authorised

Cáncer de Pulmón ALK +

una entidad clínica diferente

Crizotinib

altamente eficaz

Progresión 11 m/ SNC

Nuevos inhibidores de ALK

Ceritinib

Alectinib

Nuevas Opciones

Nuevas secuencias

Kris MG, JAMA 2014