Santiago Ponce Aix

Thoracic Tumors Unit

Medical Oncology Department

University Hospital “12 de Octubre”

H12O-CNIO Lung Cancer Clinical Research Unit

Spanish National Cancer Research Centre (CNIO)

Madrid

¿Cuál es la mejor opción y/o secuencia de tratamiento en el cáncer de

pulmón no microcítico ALK positivo?

Disclosure

I have provided consultation, attended advisory boards and/or provided lectures for thefollowing organizations: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La

Roche, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Pfizer, Celgene

I declare no conflict of interest.

• The most common rearrangement isbetween EML4 and ALK, which producesthe EML4-ALK-fusion protein

• The breakpoint within ALK occurs at exon20 (A20)

• The breakpoint within EML4 can differ, thusgenerating different variants of the fusionprotein

Soda, et al. Nature 2007; Hallberg, et al. Nat Rev Cancer 2013 ; Rikova, et al. Cell 2007

Discovery of ALK Fusion in NSCLC

Dearden, et al. Ann Oncol 2013; . Barlesi, et al. Lancet 2016 ; Johnson, et al. ASCO 2013; Li, et al. PLoS One 2013

Discovery of ALK Fusion in NSCLC

ESPAÑA ?

• 20-30% patients at diagnosis will have with brain mets

• 60-90% patients will progress at CNS, even after crizotinib (60%)

• Brain MRI should be perform baseline instead CT scan

ALK patients: a distinct disease

Kim DW ASCO 2014; Soria JC Lancet 2017; Solomon BJ NEJM 2014; Camidge DR, Lancet Oncol 2012

Profile 1007

Shaw AT, et al. N Engl J Med 2013;368:2385–94

Crizotinib(n=172a)

Pemetrexed(n=99a)

Docetaxel(n=72a)

Median, mo 7.7 4.2 2.6

HRb (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)

P <0.001 <0.001

Pro

bab

ility

of

surv

ival

wit

ho

ut

pro

gre

ssio

n (

%)

100

80

60

40

20

00 5 10 15 20 25

Time (months)

Endpoint

ORR % 65%

Median PFS 7.7 months

Median duration of response 8.0 months

0 5 10 15 20 35

PFS

pro

ba

bil

ity

1.0

0.8

0.6

0.4

0.2

0

HR=0.45 (0.35–0.60)Log-rank p<0.0001

Crizotinib (n=172)

Chemotherapy (n=171)

Time (months)

25 30

10.9 months7.0 months

Endpoint

ORR % 74%

Median PFS 10.9 months

Median duration of response 11.3 months

Profile 1014

Solomon, et al. NEJM 2014

Sub-Optimal CNS disease control with Crizotinib

ITT Treated BM Without BM at baseline

Intracranial Time to Progression Profile 1014

Solomon BJ JCO 2016CNS assessment by CT

ASCEND 4

Soria et al. Lancet 2017

16.6 months8.1 months

PFS in patients without and with BM - Ascend 4

26.3 months8.3 months 10.7 months6.7 months

CNS assessment by CT Soria et al. Lancet 2017

If a TKI is the standard of care in first line, what after?

ASCEND 5

Shaw AT, et al. Lancet Oncol 2017;18:874–86

ALUR: phase III trial of alectinib versus chemotherapy in previously treated ALK+ NSCLC

S.Novello ESMO 2017

Alectinib Arm (N=72)Chemotherapy Arm

(N=35)

PFS (investigator) – ITT Population1

KM estimates of PFS (in months)

Median (95% CI2) 9.6 (6.9, 12.2) 1.4 (1.3, 1.6)

Hazard ratio (alectinib vs. chemotherapy)3 0.15

ALTA

Huber ASCO 2018

ALTA

90180 mg

Median follow-up 18,6m 24,3m

Confirmed ORR 55% 56%

Median PFS* 15.6months 16.7 months

Median DOR* 13.8 months 13.8 months

Median OS 27.6 months 34,1 months

90180 mg

Median follow-up

Confirmed intracranial ORR(measurable brain mets)

67%

Median intracranial PFS(any brain mets)

18.4 months

Median intracranial DOR(measurable brain mets)

16.6 months

Confirmed CRs (non measurable brain mets)

18%

Huber ASCO 2018

Lorlatinib

DOR

One TKI 12.4 m

More One TKI 11.7 m

All 9.3 m

Shaw Lancet Oncology 2017

Addictive effects of multiple ITK s

Tx 1

PFS 1

Tx 2

PFS 2

Tx 3

PFS 3

PFS 1

Tx 1 Tx 2

PFS 2

Can we define a strategy based on molecular biomarkers instead clinical features? or is all about M1 SNC?

Acquired resistance on crizotinib that makes sense to avoid?

OS ?

Addictive effects of multiple ITK s

Tx 1

PFS 1

Tx 2

PFS 2

Tx 3

PFS 3

PFS 1

Tx 1 Tx 2

PFS 2

Can we define a strategy based on molecular biomarkers instead clinical features? or is all about M1 SNC?

Acquired resistance on crizotinib that makes sense to avoid?

OS ?

ALEX

Cadmige ASCO 2018

ALEX

S. Peters N Engl J Med 2017

Pacientes CON metástasis en SNC al inicio†

100

80

60

40

20

0

PF

S (

%)

Duration of PFS (months)9 15 21 276 12 18 24 303Day 1

7.4

(95% CI: 6.6–9.6)

NR

(95% CI: 9.2–NR)

Pacientes SIN metástasis en SNC al inicio

PF

S (

%)

Duration of PFS (months)9 15 21 276 12 18 24 303Day 1

14.8

(95% CI: 10.8–20.3)

NR

100

80

60

40

20

0

Mediana SLP fue de 27,7 meses (95% CI: 9,2–NE) para

alectinib vs 7,4 meses (95% CI: 6,6–9,6) para crizotinib

HR=0,35 (95% CI: 0,22–0,56)

HR 0.40 (95% CI 0.25–0.64)

p<0.0001

HR=0.51 (95% CI 0.33–0.80)

p=0.0024

Alectinib (n=64)

Crizotinib (n=58)

Alectinib (n=88)

Crizotinib (n=93)

Mediana SLP fue de 34,8 meses (95% CI: 22,4–NE) para alectinib

vs 14,7 meses (95% CI: 10,8–20,3) para crizotinib

HR=0,47 (95% CI: 0,32–0,71)

ASCO 2018

Alecensa logró un beneficio de SLP consistente frente a crizotinib,

independientemente de las metástasis de SNC en el momento basal

Beneficio de SLP en pacientes con y sin metástasis en el SNC

S. Peters N Engl J Med 2017

ALEX

ALTA-1

Camidge WCLC 2018

ALTA-1Intracranial PFS

Camidge WCLC 2018

Camidge WCLC 2018

ALTA-1Whole Body BIRC PFS by BM at Baseline

S. Peters N Engl J Med 2017

ALEX

Est

ima

ció

n S

G (

%)

100

80

60

40

20

0

0 2418126 30

Tiempo (meses)

Alectinib (n=152)

Crizotinib (n=151)

Crizotinib

(n=151)

Alectinib

(n=152)

Pacientes con eventos,

n (%)

48 (31,8) 43 (28,3)

SG mediana,

meses (IC 95%)

NR

(NR)

NR

(NR)

HR 0,76

(IC 95%: 0,5–1,15)

No estadísticamente significativo

Cadmige WCLC 2018

ALTA-1Intracranial PFS

Isozaki, et al. Cancers 2015

Rational Biomarker Driven Approach to Best Treatment

Sai-Hong Ignatius Ou ASCO 2018

Rational Biomarker Driven Approach to Best Treatment

Gainor JF, et al. Cancer Discov 2016;6:1118-33

Rational Biomarker Driven Approach to Best Treatment

Gainor JF, et al. Cancer Discov 2016;6:1118-33

Rational Biomarker Driven Approach to Best Treatment

Cellular ALK phosphorylation mean IC50 (nM)Mutation status Crizotinib Ceritinib Alectinib Brigatinib LorlatinibParental BA/F3 763.9 885.7 890.1 2,774.0 11,293.8

V1 38.6 4.9 11.4 10.7 2.3

C1156Y 61.9 5.3 11.6 4.5 4.6

I1171N 130.1 8.2 397.7 26.1 49.0

I1171S 94.1 3.8 177.0 17.8 30.4

I1171T 51.4 1.7 33.6 6.1 11.5

F1174C 115.0 38.0 27.0 18.0 8.0

L1196M 339.0 9.3 117.6 26.5 34.0

L1198F 0.4 196.2 42.3 13.9 14.8

G1202R 381.6 124.4 706.6 129.5 49.9

G1202del 58.4 50.1 58.8 95.8 5.2

D1203N 116.3 35.3 27.9 34.6 11.1

E1210K 42.8 5.8 31.6 24.0 1.7

G1269A 117.0 0.4 25.0 ND 10.0

Gainor JF JCO 2018

Rational Biomarker Driven Approach to Best Treatment

Tracking the evolution of resistance to ALK through longitudinal analysis of circulating tumor DNA

Gainor JF JCO 2018

Rational Biomarker Driven Approach to Best Treatment

Strengths:

- NGS is feasible and can be used with a good

concordance in tissue

Weakness:

-22 patients

-Single center experience

- Inconsistent intervals of blood samples

-Data at PD, no data available at initial TKI

Odegaard J CCR 2018

Rational Biomarker Driven Approach to Best Treatment

High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical

accuracy of Digital Sequencing across all four types of targetable genomic alterations. Digital Sequencing’s clinical

applicability is further supported by high rates of technical success and biomarker target discovery.

Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-

based methodologies.

GRACIAS

sponce@h12o.es