Andrés J. Muñoz MartínServicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid

Avances terapeúAcos en el cáncer de páncreas

CONFLICT OF INTEREST• Consultant or advisory role: Celgene, Servier & Astra-Zeneca

Agenda• Estudio POLO.• Otro biomarcadores.• Estudio APACT.• Neoadyuvancia.• Localmente avanzado.• Novedades del tratamiento en 2ª línea.

4

Metastatic pancreatic cancer

Maintenance treatments aim to delay disease progression

following chemotherapy without compromising HRQoL

FOLFIRINOX, leucovorin, fluorouracil, irinotecan and oxaliplatin; HRQoL, health-related quality of life; OS, overall survival; PFS, progression-free survival 1. Conroy T et al. N Engl J Med 2011;364:1817–1825; 2. Von Hoff DD et al. N Engl J Med 2013;369:1691–1703; 3. Hidalgo M et al. Pancreatology 2015;15:8–18; 4. Friedenson B et al. MedGenMed 2005;7:60; 5. Golan T et al. J Clin Oncol 2018;36:4115; 6. Waddell N et al. Nature 2015;518:495–501; 7. Golan T et al. Br J Cancer 2014;111:1132–1138

4–7% harbor a germline BRCA1and/or BRCA2 mutation

(gBRCAm)4,5

Increased benefit from platinum-based chemotherapy6,7

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Key eligibility criteriaMetastatic pancreatic cancer

Deleterious or suspected

deleterious germline BRCA1or BRCA2 mutation

≥16 weeks first-line platinum-

based chemotherapy with no limit

to duration, without progression

(CR, PR or SD)*

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Study design

38% of gBRCAm patients had disease progression,

were ineligible, or declined randomization

Until investigator-

assessed disease

progression or

unacceptable toxicity

Placebo

Olaparib tablets

300 mg bid

or

First-line chemotherapy

4–8 weeks≥16 weeks

Randomization

Follow-up

Maintenance treatment Discontinuation

*There was no maximum limit to the duration of first-line chemotherapy. bid, twice daily; CR, complete response; PR, partial response; SD, stable disease

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Randomized 3:2

No stratification

factors

Olaparib(N=92)

Placebo(N=62)

Screened, n 3315Found to have a gBRCAm, n (%) 247 (7.5)Excluded, n

Disease progression or deathIneligiblePatient or physician decision

93432228

Randomized, n 92 62Treated, n 90 61Discontinued treatment, n (%)

Disease progression by BICRDisease progression by investigator assessmentAdverse eventPatient decisionIneligible

60 (65.2)43 (46.7)12 (13.0)

4 (4.3)1 (1.1)

0

53 (85.5)40 (64.5)9 (14.5)2 (3.2)1 (1.6)1 (1.6)

Continuing assigned treatment at data cut-off*, n (%) 30 (32.6) 8 (12.9)Median follow-up for progression, months (range)† 9.1 (0–39.6) 3.8 (0–29.8)

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Patient disposition

*January 15, 2019. †Censored patients. BICR, blinded independent central review

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4.6%17.4%

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Primary endpoint: PFS by blindedindependent central review*

*Dots indicate censorship. †January 15, 2019. CI, confidence interval

Olaparib

Prob

abili

ty o

f PFS

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50Time since randomization (months)No. at risk

PlaceboOlaparib 92 69 50 41 34 24 18 17 14 10 10 8 8 7 5 3 3 3 3 2 1 1 1 0

62 39 23 10 6 6 4 4 4 2 2 2 2 1 1 0

Placebo

Olaparib(N=92)

Placebo(N=62)

Median PFS, months 7.4 3.8HR 0.53

95% CI 0.35, 0.82; P=0.0038

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Progression-free at data cut-off:†

30 olaparib patients (32.6%)12 placebo patients (19.4%)

Subgroup analyses of PFS*

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*Circle size proportional to number of events. Subgroups in which fewer than five PFS events had occurred per arm were not analyzed. †By BRACAnalysis CDx® test. PBC, platinum-based chemotherapyOlaparib better Placebo better

HR (95% CI)All patients 0.53 (0.35–0.82)

Doublet 1st-line PBCTriplet 1st-line PBC

0.59 (0.24–1.50)0.51 (0.32–0.82)

16 weeks to 6 months of 1st-line PBC>6 months of 1st-line PBC

0.69 (0.43–1.12)0.35 (0.17–0.72)

Measurable disease at baselineNon-measurable or no evidence of disease

0.57 (0.37–0.88)0.45 (0.14–1.57)

MaleFemale

0.46 (0.27–0.80)0.66 (0.37–1.19)

Germline BRCA1 mutationGermline BRCA2 mutation

0.40 (0.20–0.85)0.63 (0.39–1.02)

Age <65 yearsAge ≥65 years

0.45 (0.28–0.72)1.02 (0.45–2.60)

Partial or complete response to 1st-line PBCStable disease following 1st-line PBC

0.62 (0.35–1.12)0.50 (0.29–0.87)

Caucasian 0.59 (0.39–0.90)

Absence of biliary stent 0.54 (0.36–0.82)

1st-line FOLFIRINOX variantsOther 1st-line PBC

0.54 (0.35–0.84)0.76 (0.27–2.32)

0.1 1 10

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PFS at prespecified timepoints by blinded independent central review*

*Kaplan-Meier method

53%

34%28%

22%23%

15%10% 10%

0

10

20

30

40

50

60

6 12 18 24

From 6 months onwards, more than twice the proportion of olaparib-arm

patients were progression-free

Pati

ents

free

from

di

seas

e pr

ogre

ssio

n or

dea

th, %

60

50

40

30

20

10

00 6 12 18 24

Time since randomization (months)

Olaparib

Placebo

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OS: interim analysis, 46% maturity*

Olaparib

Prob

abili

ty o

f OS

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50Time since randomization (months)No. at risk

PlaceboOlaparib 92 87 80 71 61 51 46 39 31 28 20 16 14 12 9 6 5 4 4 4 2 1 1 0

62 60 56 50 44 32 29 27 20 18 14 10 8 8 6 6

Placebo

4 1 1 1 1 1 1 0

Final OS analysis planned at 106 events

*Dots indicate censorship. †Crossover to olaparib was not permitted during this study; subsequent therapies were given at the investigators’ discretion

Subsequent treatment with a PARP inhibitor:†

1 olaparib patient (1.1%)9 placebo patients (14.5%)

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Olaparib(N=92)

Placebo(N=62)

Median OS, months 18.9 18.1HR 0.91

95% CI 0.56, 1.46; P=0.68

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PFS2 by investigator assessment: interim analysis, 46% maturity*

*Dots indicate censorship. PFS2, time to second progression

Time to second progression may indicate durability of treatment

benefit beyond disease progression

Olaparib

Prob

abili

ty o

f PFS

2

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50Time since randomization (months)No. at risk

PlaceboOlaparib 92 82 65 56 43 32 27 22 19 13 12 11 8 7 5 4 3 3 3 2 1 1 1 0

62 54 43 36 24 17 12 7 5 4 4 4 3 2 2 1

Placebo

0

Olaparib(N=92)

Placebo(N=62)

Median PFS2, months 13.2 9.2HR 0.76

95% CI 0.46, 1.23; P=0.26

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Objective response* in patients with measurable disease by blinded independent central review

Two olaparib arm patients had a complete response

Both complete responses were ongoing at the data cut-off†

OlaparibN=78

PlaceboN=52

n=18 n=6

Median duration of response

24.9 months

3.7 months

Olaparib

Placebo

Median time to onset of response

5.4 months

3.6 months

Olaparib

Placebo

23.1%

11.5%

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*By modified RECIST v1.1. †January 15, 2019

• Other DDR pathway mutation (ATM, PALB2, etc.)?• And somatic mutations?• All platinum are the same (cisplatin vs. oxaliplatin)?• Other drugs: naliri, irinotecan (topoisomerase inhibitors?)• PARP inhibitors upfront in combination?• 17% patients did not respond to platinum…

27 tumor types were represented, with endometrial, gastric, chol-angiocarcinoma, and pancreatic cancers being the most common

9.4% (22 patients) páncreas9.4% (22 patients) cholangiocarcinoma

14.6% had grade 3 to 5 treatment-related adverse events (grade 5 pneumonia 1 patient)

Study design

Presented By Margaret Tempero at 2019 ASCO Annual Meeting

• Primary endpoint: independently assessed DFS

Presented By Michiaki Unno at 2019 Gastrointestinal Cancer Symposium

NEOLAP is the first prospective randomized study to compare two differentinduction chemotherapy regimens in LAPC.

• Sequential FOLFIRINOX was not significantly superior to 4-month nab-P+Gem induction chemotherapy in terms of conversion rate (primary endpoint) and other secondary efficacy endpoints (ORR, CA 19-9 response, pathologicalresponse, PFS, OS).

• Both induction chemotherapy regimens were tolerable and consistent with their known safety profile.• Secondary tumor resection after obligatory surgical exploration was associated with significant survival benefit and

appears highly recommendable in patients with LAPC.

• Estudio fase III HALO 301: negativo 1ª líneaGem-NABP vs. Gem-NABP + PEGPH20 (median OS 11.5 m vs. 11.2 m, HR=1.00, p=0.9692)

• Estudio fase III RESOLVE: negative 1ª líneaGem-NABP vs. Gem-NABP + ibrutinib (medianOS 10.8 m vs. 9.7 m, HR=1.1, p=0.3225)

• Estudio fase III ARMO: negativo 2ª líneaFOLFOX vs. FOLFOX + IL-10peg

2019 MALAS NOTICIASPARA EL CÁNCER DE PÁNCREAS

Per-protocol of NAPOLI-1

Chen LT et al. EJC 2019

NALIRI EN 2ª LÍNEA 2019

Final analysis NAPOLI-1 OS NALIRI-FU/LV vs 5FU/LV6.2 vs 4.2 months, HR 0.75; 95% CI: 0.57-0.99; p = 0.039

PFS NALIRI-FU/LV vs 5FU/LV3.1 vs 1.5 months, HR 0.57; 95% CI: 0.43-0.76; p < 0.0001

ORR NALIRI-FU/LV vs 5FU/LV17% vs 1%; p < 0.0001

Estimated 1 yr-OS NALIRI-FU/LV vs 5FU/LV26% vs 16%

NALIRI EN 2ª LÍNEA 2019

Elderly patients of NAPOLI-1

Macarulla T et al. Journal of Geriatric Oncology 2019

QoL NAPOLI-1

NAPOLI-1 análisis QoL: las características basales estaban bien balaceadas en

ambos grupos

No se observaron cambios apreciables en el estado de salud global ni en la

escala funcional entre los dos brazos

Los pacientes tratados con nal-IRI+5-FU/LV no presentaron deterioro en el

estado de salud global, puntuación de escala funcional y puntuación de escala

de síntomas en comparación con 5-FU/LV

Análisis Q-TWIST Nal-IRI+5-FU/LV supuso un aumento significativo y clínicamente relevante en

la ganancia de calidad de vida ajustada a la supervivencia vs. 5-FU/LV

Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin

Richard A. Hubner, et al. EJC 2019

NALIRI EN 2ª LÍNEA 2019

Nomogram for predici-ng survival NAPOLI-1

Chen LT et al. Cancers 2019ESMO GI 2019

Phase III – First-line

CONCLUSIONES HITOS PÁNCREAS 2019• Análisis molecular se debe considerar como estándar de práctica clínica: dos biomarcadores en enfermedad

avanzada: BRCA1/2 germinal & MSI…biológico (olaparib y pembrolizumab) más selección de quimioterapia (platino).

• Olaparib de mantenimiento tras inducción con platino (al menos 16 semanas, sobre todo tras 24 semanas/12 ciclos de FOLFIRINOX) se puede considerar un estándar de tratamiento.

• La combinación de gemcitabina más nab-paclitaxel en adyuvancia se puede posicionar como tratamiento de referencia en pacientes no candidatos a tratamiento con mFOLFIRINOX.

• La neoadyuvancia en tumores resecables se está perfilando como un nuevo tratamiento estándar, a la espera de los ensayos clínicos aleatorizados con los esquemas actuales de poliquimioterapia.

• Aún no despejada cual es el mejor esquema de tratamiento en la enfermedad localmente avanzada: poliquimioterapia tratamiento de elección, ¿biomarcadores?

• Los nuevos datos publicados en 2019 refuerzan el papel de la combinación de NALIRI-5FU/LV como tratamiento de referencia de 2ª lÍnea en cáncer de páncreas avanzado (guía clínica ASCO).