ESMO E-Learning Advanced Pancreatic Cancer and … · 2020. 1. 27. · PANCREATIC CANCER SURGERY General considerations Surgery is the only potential curative treatment for pancreatic

ADVANCED PANCREATIC CANCER AND DEVELOPMENT IN ADJUVANT THERAPY

Julien TAIEB

Université de Paris, Hopital Européen Georges Pompidou, Paris, France

INTRODUCTION TO PANCREATIC CANCEREpidemiology

Clinical presentation

Diagnosis

Disease assessment before treatment

Reprinted from Cancer Res, Copyright 2014, 74(11), 2913-2921, Rahib L, et al., Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States with

permission from AACR.

Ferlay J, et al., Acta Oncologica 2016,55(9-10):1158-1160.

INCREASING INCIDENCE AND MORTALITY

At least 150,000 cases/y in Europe and 460,000 new cases diagnosed in the world in 2018

(world cancer research fund)

Higher incidence in Europe and USA

Rapidly increasing incidence in developed countries

May become the 3rd cause of cancer death in 2030

Lung and bronchus

Main modifiable risk factors: Main genetic risk factors:

Chronic pancreatitis Lynch syndrome

Tobacco use Breast and ovarian cancer syndrome

Obesity Peutz Jeghers syndrome

Chronic diabetes Familial adenomatous polyposis

Diet (low fibre) Hereditary pancreatitis

Alcohol abuse Cystic fibrosis

Ataxia telangiectasia

RISK FACTORS

Becker AE, et al. World J Gastroenterol 2014.

PRETHERAPEUTIC ASSESSMENT

Clinical:

◆ ECOG/WHO PS, symptoms (pain, weight loss, diarrhoea)

◆ Nutritional assessment, comorbidities

Imaging:

◆ Thoraco-abdomino-pelvic CT-scan: for diagnosis,

extension, resectability

◆ Liver MRI optional for liver metastases diagnosis

(diffusion)

◆ Pancreatic MRI optional if tumour looks atypical

on CT-scan

Biological

◆ CA 19.9 not useful for diagnosis but bear prognostic

information and useful for follow-up

Biopsy:

◆ No biopsy needed if the tumour is operable

upfront, except if diagnosis is doubtful on

imaging or if clinical presentation is unusual (young age…) or if a neo-adjuvant treatment

proposed (borderline resectable, clinical trials)

◆ Biopsy needed if medical treatment comes first

(locally advanced and metastatic diseases)

PANCREATIC CANCERDisease at presentation

TNM staging

Classification for resectability (resectable, borderline or

locally advanced pancreatic cancer)

HOW TO ASSESS THERAPEUTIC POSSIBILITIES?

Patient

Distant

disease

Local

disease

◆ Age?

◆ Comorbidities?

◆ PS?

◆ Metastases?

◆ Lymph nodes?

◆ Contact with vessels?

◆ Portal hypertension?

DISEASE AT PRESENTATION

5-11 mo 9-16 mo > 2 years15-30 mo

Borderline R0 surgery

Metastatic

disease

60%

Locally advanced

disease

25%

Resectable disease 15%

Overall survival

Courtesy of Pr Pascal Hammel Beaujon Hospital. Clichy France

NEW AJCC 8TH EDITION (2017): TNM AND STAGING

Amin MB, et al: AJCC Cancer Staging Manual, Eighth Edition. New York; Springer International Publishing; 2017.

T1 Tumour 2 cm or less

T1a Tumour 0.5 cm or less

T1b Tumour greater than 0.5 cm but no more than 1 cm

T1c Tumour greater than 1 cm but no more than 2 cm

T2 Tumour more than 2 cm but no more than 4 cm

T3 Tumour more than 4 cm in greatest dimension

T4Tumour involves coeliac axis, superior mesenteric artery and /or

common hepatic artery

N1 Metastases in 1 to 3 nodes

N2 Metastases in 4 or more nodes

M category unchanged

Stage

Stage IA T1 N0 M0

Stage IB T2 N0 M0

Stage IIA T3 N0 M0

Stage IIB T1, T2, T3 N1 M0

Stage III T1, T2, T3 N2 M0

T4 Any N M0

Stage IV Any T Any N M1

DISEASE STAGING

If not metastatic, the tumour has to be classified as resectable, borderline or locally advanced (Isaji S, et al. Pancreatology 2018)

Resectability Status Arterial Venous

ResectableNo arterial tumour contact (celiac axis [CA], superior mesenteric artery [SMA], or common hepatic

artery [CHA]).

No tumour contact with the superior mesenteric vein (SMV) or portal vein (PV)

or ≤180° contact without vein contour irregularity.

Borderline Resectable

Pancreatic head/uncinate process:

• Solid tumour contact with CHA without extension to CA or hepatic artery bifurcation allowing

for safe and complete resection and reconstruction.

• Solid tumour contact with the SMA of ≤180°• Solid tumour contact with variant arterial anatomy (ex: accessory right hepatic artery, replaced

right hepatic artery, replaced CHA, and the origin of replaced or accessory artery) and the

presence and degree of tumour contact should be noted if present, as it may affect surgical

planning.

Pancreatic body/tail:

• Solid tumour contact with the CA of ≤180°• Solid tumour contact with the CA of >180° without involvement of the aorta and with intact

and uninvolved gastroduodenal artery thereby permitting a modified Appleby procedure [some

panel members prefer these criteria to be in the unresectable category].

• Solid tumour contact with the SMV or PV of >180°, contact of ≤180°with contour irregularity of the vein or thrombosis of the vein but with

suitable vessel proximal and distal to the site of involvement allowing for

safe and complete resection and vein reconstruction.

• Solid tumour contact with the inferior vena cava (IVC).

Unresectable

Distant metastasis (including non-regional lymph node metastasis) Head/uncinate process:

• Solid tumour contact with SMA >180°• Solid tumour contact with the CA >180°Body and tail:

• Solid tumour contact of >180° with the SMA or CA

• Solid tumour contact with the CA and aortic involvement

Head/uncinate process:

• Unreconstructible SMV/PV due to tumour involvement or occlusion (can be

due to tumour or bland thrombus)

• Contact with most proximal draining jejunal branch into SMV

Body and tail:

• Unreconstructible SMV/PV due to tumour involvement or occlusion (can be

due to tumour or bland thrombus)

Tempero MA, et al.J Natl Compr Canc Netw. 2019 Mar 1;17(3):202-210.

DISEASE STAGING

If not metastatic, the tumour has to be classified as resectable,

borderline or locally advanced1

However, imaging has also some limitations

French AFC Cohort (N=1044 patients): CT-scan 97%, US-endoscopy 61%, MRI 46.5%2

Comparison between radiological and pathological examinations:

1. Tempero MA, et al. J Natl Compr Canc Netw. 2019 Mar 1;17(3):202–10; 2. Gilabert M, et al. Medicine 2017;96(24):e7214.

Arterial

involvement, %

Venous

involvement, %Lymph nodes, %

Concordance 97.5 86.5 41.1

Sensitivity 27.3 54 21

Specificity 98 91 86

Positive predictive value 20 47.8 78

Negative predictive value 99 93.2 41

SURGERY OF PANCREATIC CANCERPre-operative work-up

Type of surgery

PANCREATIC CANCER SURGERY

General considerations

Surgery is the only potential curative treatment for pancreatic cancer

If possible: preabilitation with dietetic advice and physical activity

Immunonutrition for 7 days generally recommended

Possible complications (inform your patients):

◆ Exocrine pancreatic insufficiency and maldigestion

◆ Pancreatic fistula (frequent [20 to 50%], generally manageable with increased hospital stay)

◆ Diabetes (20% if not present before, depending on the importance of the pancreatic resection, 100% if total

pancreatectomy)

◆ Wound healing complications and infections

◆ Splenic rupture and thromboembolic complication

PANCREATIC CANCER SURGERY

Biliary stenting

Biliary stent not necessary even if jaundice in the vast majority of patients that will be resected from their

primary tumour

Biliary stent is indicated only if:

◆ Bilirubinemia >250 μmol/L

◆ Renal insufficiency (creatininemia >130 μmol/L)

◆ Cholangitis (abdominal pain, fever, jaundice)

◆ A neoadjuvant treatment is planned (clinical trial or not)

ANATOMY

Relation of the pancreas with the GI tract, the biliary tract and GI, liver

and splenic vessels is essential to understand pancreatic surgery

PANCREATICODUODENECTOMY

(Whipple procedure)

For tumours located in the head of the pancreas

SPLENOPANCREATECTOMY

For tumours located in the tail of the pancreas

ADJUVANT TREATMENTWhat are the results

How to select the good treatment for each patient

ADJUVANT TREATMENT

A 20-year story

With surgery alone relapse rates are reported to be 85 to 95% within 5 years

Adjuvant therapy to kill residual tumour cells seems fundamental to improve patients outcome

Studies: ESPAC-11:

5FU > observation

CONKO-0012:

Gemcitabine > obs

ESPAC-33:

Gemcitabine = 5FU

ESPAC-44:

Gem+Capecitabine > Gem

2001 2004 2007 2010 2013 2016

DFS OS OSOS

1. From N Engl J Med, Neoptolemos JP, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. 350(12):1200-10. Copyright © 2004 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society.; 2. Reproduced with permission from JAMA 2013;310(14):1473–81.Copyright©2013 American Medical Association. All rights reserved; Oettle H, et al. JAMA

2007;297(3):267–77; 3. Reproduced with permission from JAMA 2010; 304(10):1073-81 Copyright©2010 American Medical Association. All rights reserved; 4. Neoptolemos JP, et al. Lancet 2017. Reproduced under

Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND 4.0). Avalable at: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode; accessed Dec 2019.

ADJUVANT TREATMENT

After the publication of 2 positive trials in the metastatic setting

Both FOLFIRINOX and Gemcitabine+ Nab-paclitaxel have been tested in the adjuvant setting

Etude PRODIGE 24Phase III mFOLFIRINOX

vs. Gem

NCT01526135

Etude APACTPhase III Gem + nab-paclitaxel

vs. Gem

NCT01964430

From N Engl J Med, Conroy T, et al., FOLFIRINOX versus Gemcitabine for Metastatic

Pancreatic Cancer, 364(19), 1817–25. Copyright © 2011 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

From N Engl J Med, Von Hoff DD, Increased Survival in Pancreatic Cancer with nab-

Paclitaxel plus Gemcitabine, 369:1691-1703. Copyright © 2013. Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society

GEMCITABINE1000 mg/m2

3 wk/4, 6 cycles

mFOLFIRINOX/ 2 wk, 12 cycles

1:1

R

Primary objective: DFS

ADJUVANT TREATMENT

FOLFIRINOX in the adjuvant setting (the PRODIGE 24 study)

◆ Oxaliplatin 85 mg/m2

◆ LV 400 mg/m2

◆ Irinotecan 180 mg/m2,*

◆ 5 FU continue 2.4 g/m2 46 h

◆ *Dose modification to 150 mg/m2N=493

◆ Resection R0-1

◆ CA19-9 <180 U/mL within 12 weeks after surgery

◆ Post-op CT-scan mandatory

Stratification:

◆ Centre

◆ Resection margins (R0 vs. R1)

◆ CA19-9 (≤90 U/mL vs. 91-179 U/mL)

◆ pN0 (<12 vs. ≥12) vs. pN1

Conroy T, et al. N Engl J Med 2018;379:2395–406

ADJUVANT TREATMENT


Phase III RCT

N=493 pts

mOS: 54,4 vs. 35,0 monthsmDFS: 21,6 vs. 12,8 months

From N Engl J Med, Conroy T, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer, 379, 2395-2406. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

ADJUVANT TREATMENT


HR for DFS

FOLFIRINOX seems

better in all patients subgroups

(no positive interaction test)

From N Engl J Med, Conroy T, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer, 379, 2395-2406. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society

ADJUVANT TREATMENT


No more haematologic grade 3/4 toxicities with

FOLFIRINOX with the use of G-CSF (done in 60%

of patients)

FOLFIRINOX is responsible of:

◆ More grade 3/4 GI and mucosal toxicities

◆ More severe neuropathy

FOLFIRINOX is manageable and no long lasting

toxicities were reported except neuropathy in a

small proportion of patients (2.9%)

mFOLFIRINOX 12 cycles = standard adjuvant treatment for fit patients

Side effects

(% patients)

mFOLFIRINOX (n=238) Gemcitabine (n=243)P-value

All Grade 3/4 All Grade 3/4

Mucositis 33.8 2.5 14.9 0 <0.001

Diarrhoea 84.4 18.6 49 3.7 <0.001

Fatigue 84.0 11 77.6 4.6 0.003

Vomiting 45.6 5.1 29.0 1.2 <0.001

Alopecia 27.0 - 19.5 - 0.07

Neuropathy 61.2 9.3 8.7 - <0.001

Hand–foot syndrome 5.1 0.4 0.8 - 0.023

More frequent toxicities with FOLFIRINOX

Conroy T, et al. N Engl J Med 2018;379:2395–406

ADJUVANT TREATMENT

Gemcitabine+nab-paclitaxel in the adjuvant setting (the APACT study)

◆ Gemcitabine 1000 mg/m2

◆ Nab-paclitaxel 125 mg/m2


3 wk/4, 6 cycles

Gem+Nab-paclitaxel3 wk/4, 6 cycles

1:1

R

Primary objective: DFS with central review

N=866◆ Resection R0 and R1

◆ Stade II and III

◆ CA19-9 <100 U/mL

Stratification:

◆ Resection R0 vs. R1

◆ pN+ vs. pN-

◆ Region

Tempero MA, et al. ASCO 2019, Abstract #4000

ADJUVANT TREATMENT

Gemcitabine+nab-paclitaxel in the adjuvant setting the APACT study

DFS

19.4 vs. 18.8 mo

HR: 0.88 (95% CI: 0.729, 1.063) p=0.1824

432

434

MonthsAt risk

nab-P +Gem

Gem

DF

S %

391

368

338

309

279

235

236

183

204

157

167

147

138

127

121

116

112

105

99

98

88

88

54

59

43

42

20

15

14

10

2

1

2

Primary objective Phase III RCT

N=866 pts

432

434

MonthsAt risk

Pro

babi

lity

of O

S, %

427

415

420

404

406

384

385

354

366

320

344

301

307

275

284

262

264

249

252

228

219

198

162

153

113

101

73

64

40

29

12

12

OS40.5 vs. 36.2 mo

HR: 0.82 (95% CI: 0.680, 0.996) p=0.045

nab-P +Gem

Gem

3

2 1

Negative trial = gemcitabine+Nab-paclitaxel has failed

Secondary objective

Courtesy of Prof J. Taieb. ASCO 2019

ADJUVANT TREATMENT

Gemcitabine+nab-paclitaxel in the adjuvant setting the APACT study

All Grade > 3 toxicities: 86% vs. 68%

More grade 3/4 haematological toxicities

and fatigue

More severe neuropathy: 15% vs. 0%

Toxic death: 2 pts in each arm

Events, n (%)NAB-P + Gem

(N=429)Gem

(N=423)

Safety summary

Patients with ≥1 grade ≥ 3

TEAE371 (8) 286 (68)

Patients with ≥1 serious TEAE 176 (41) 96 (23)

Grade ≥3 haematologic

TEAEs (occurring in ≥5% of

patients in either treatment

arm)

Any haematologic TEAEs 250 (58) 204 (48)

Neutropenia 212 (49) 184 (43)

Anaemia 63 (15) 33 (8)

Leukopenia 36 (8) 20 (5)

Febrile neutropenia 21 (5) 4 (1)

Grade ≥3 nonhematologic

TEAEs (occurring in ≥5% of

patients in either treatment

arm)

Peripheral neuropathy (SMQ) 64 (15) 0

Fatigue 43 (10) 13 (3)

Diarrhea 22 (5) 4 (1)

Asthenia 21 (5) 8 (2)

Hypertension 17 (4) 27 (6)

ALGORITHM OF RESECTABLE PANCREATIC CANCER

AND ADJUVANT THERAPY

Resectability

R0 resectable pancreatic cancer

Borderline resectable pancreatic cancer

Clinical trials or CT adapted to the patients condition

(FOLFIRINOX, Gem+ Nab-pacli or Gem)

Clinical trials

Assessing neoadjuvant treatmentsSurgery Tumour response

Adjuvant chemotherapy

Start: maximum 3 mo after surgery

Duration: 6 mo

Modified FOLFIRINOX in fit patients

Gem or Gem/Cap in the others

Switch chemotherapy

Discuss Radiotherapy

Tumour progression

ADVANCED STAGE MANAGEMENTLocally advanced disease

LOCALLY ADVANCED PANCREATIC CANCER

What is the strategy?

Most of these patients are actually metastatic

However a small % may reach curative surgery and potential cure

What we know is that:

◆ We have to start with a systemic chemotherapy (FFCD trial) (Chauffert B, et al, Ann Oncol 2008)

◆ Gemcitabine remains the current standard but FOLFIRINOX is an option as many papers showed good

results (Marthey L, et al. Ann Surg Oncol 2015, Suker M, et al. Lancet Oncol 2016)

◆ We may discuss « closure » radiotherapy after 3 to 6 months chemotherapy in good responders

◆ Only one trial clearly compared chemo vs. chemo followed by radiotherapy and showed equivalence

(Hammel P, et al. JAMA 2016)

IS RADIOTHERAPY USEFUL?

The LAP07 trial

The LAP07 trial was designed to o assess whether

chemoradiotherapy improves overall survival of

patients with locally advanced pancreatic cancer

controlled after 4 months of gemcitabine-based

induction chemotherapy

Total Median OS

Chemo 136 16.4

Radio+chemo 133 15.2

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Time since the first randomisation (months)

Ove

rall

surv

ival

pro

babi

lity Logrank p=0.8295

HR (95% CI) = 1.03 (0.79; 1.34)

136

133

136

133

133

131

117

113

94

87

70

66

55

45

39

34

24

26

14

18

12

12

8

9

4

9

4

8

4

6

Number at risk

ChemotherapyChemo +

radiotherapyConclusion:

No significant difference in overall survival

with chemoradiotherapy compared with

chemotherapy alone

Figure courtesy of Prof J. Taieb. ASCO 2019

ALGORITHM OF TREATMENT FOR

LOCALLY ADVANCED PANCREATIC CANCER

Locally advanced pancreatic cancer

Systemic chemotherapy first

(FOLFIRINOX, Gem+Nab-pacli, gemcitabine, clinical trials)

PS>2, non eligible for chemotherapy

Best supportive care

Disease progressionDisease control

Second line treatment

Multidisciplinary assessment

Resectable

Surgery

Non resectable

Continue

chemotherapy

Radiation therapy

Non eligible

for chemotherapy

Eligible

for chemotherapy

ADVANCED STAGE MANAGEMENTMetastatic disease

IMPROVEMENT IN OS SINCE 20 YEARS

However OS remains poor for metastatic pancreatic cancer

Gemcitabine: 5-6 mo1997

FOLFIRINOX : 11-12 mo2010

Gemcitabine; option «doublet »2005

Gemcitabine + Abraxane : 9-10 mo2013

Before 1997: 3-4 mo

os

FIRST-LINE TREATMENT FOR METASTATIC DISEASE

FOLFIRINOX the PRODIGE 4 study


3 wk/ 4, 6 cycles

mFOLFIRINOX/ 2 wk, 12 cycles

1:1

R

Primary objective: OS

◆ Oxaliplatin 85 mg/m2

◆ LV 400 mg/m2

◆ Irinotecan 180 mg/m2,*

◆ 5 FU continue 2.4 g/m2 46 hN=342

Conroy T, et al. N Engl J Med 2019.

◆ Metastatic

◆ Chemotherapy naïve

◆ PS 0 or 1

◆ 18-75-year-old

◆ Bilirubinemia <1.5 xN



PFS

6.4 mo vs. 3.3 mo 11.1 mo vs. 6.8 mo

OSORR = 31% vs. 9%; DCR = 70% vs. 51%

From N Engl J Med, Conroy T, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, 364(19), 1817–25. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from




The FOLFIRINOX regimen

was favoured in all subgroups

From N Engl J Med, Conroy T, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer,

364(19), 1817–25. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from


FIRST LINE TREATMENT FOR METASTATIC DISEASE


From N Engl J Med, Conroy T, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, 364(19), 1817–25. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from


IS MAINTENANCE POSSIBLE WITH FOLFIRINOX?

The PRODIGE 35 study

PFS OS

De-escalation from FOLFIRINOX to LV5FU2 after 3 to 6 mo of induction is possible without impairing PFS nor OS

ITT population FOLFIRINOX Maintenance FIRGEM

PFS (mo) 6.3 5.7 4.5

9 mo PFS (%) 32 29 16

12 mo PFS (%) 15 15 13

ITT population FOLFIRINOX Maintenance FIRGEM

OS (mo) 10.1 11.0 7.3

9 mo OS(%) 74 75 60

12 mo OS(%) 43 44 28

Months Months

FIRGEM: FOLFIRI.3 followed by gemcitabine.

Dahan L, et al. ASCO 2018; Abstract #4000.

Pro

babi

lity

of

prog

ress

ion-

free

sur

viva

l

Pro

babi

lity

of s

urvi

val


Gem+ Nab-paclitaxel (the MPACT study)

Von Hoff DD, et al., N Engl J Med 2013.

◆ Gemcitabine 1000 mg/m2

◆ Nab-paclitaxel 125 mg/m2


7w/8 then 3 w/4, 6 cycles

Gem+Nab-paclitaxel3w/4 , 6 cycles

1:1

R

Primary objective: OS

n=842◆ Metastatic

◆ Chemotherapy naive

◆ KPS ≥70

◆ Measurable tumour

◆ Bilirubinemia normal

Stratification:

◆ PS

◆ Liver metastases

◆ Country

Months

PF

S

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0

0.0

0 3 6 9 12 15 18 21 24

At risk

nab-P + Gem:

Gem:

431

430

281

209

122

51

62

23

24

10

8

6

4

4

2

0

0

0

nab-P + Gem

GemHR = 0.69

95% CI: 0.581, 0.821

P=0.000024

PFS

Months

OS

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0

0.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39

nab-P + Gem:

Gem:

431

430

357

340

269

220

169

124

108

69

67

40

40

26

27

15

16

7

9

3

4

1

1

0

1

0

0

0

nab-P + Gem

GemHR = 0.72

95% CI: 0.617; 0.835)

P=0.000015

OS



ORR= 29% vs. 8%; DCR= 48% vs. 33%

5.5 mo vs. 3.7 mo 8.5 mo vs. 6.7 mo

From N Engl J Med, Von Hoff DD, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine, 369:1691-1703. Copyright © 2013. Massachusetts Medical Society. Reprinted with permission from




0.125 0.25 0.5 1.0 2.0

Favours nab-P + GEM Favours GEM

All patientsAge <65 yearsAge ≥65 years

Femalemale

KPS 70-80KPS 90-100

Primary tumour location: headPrimary tumour location: other

Liver metastasesNo liver metastases

1 metastatic site2 metastatic site3 metastatic site

>3 metastatic sitesNormal CA 19-9

CA 19-9 ULN to < 59 x ULNCA 19-9 ≥ 59 x ULN

AustraliaEastern EuropeWestern Europe

North America

HR

The combination Gem+ Nab-paclitaxel

was favoured in all subgroups

except normal CA 19.9


Massachusetts Medical Society..





FOLFIRINOX VS. GEM+ NAB-PACLITAXEL

Efficacy1 Safety2

1. Conroy T, et al. N Engl J Med 2011; 2. Von Hoff DD, et al., N Engl J Med 2013.

FOLFIRINOX Gem+ Nab-pacli

Performance status PS2 <1% KPS 70-80: 40%

ORR 31.6% 29%

PFS 6.4 mo 5.5 mo

with gem 3.3 mo 3.7 mo

2nd Line 47% 38%

OS 11.1 mo 8.5 mo

with gem 6.8 mo 6.7 mo

FOLFIRINOX Gem+ Nab-pacli

Neutropenia 45.7% 38%

+ febrile 5.4% 3%

Thrombopenia 9.1% 13%

Anaemia 7.8% 13%

Neuropathy* 9% 17%

Diarrhea 12.7% 6%

Alopecia 11.4% 50%

METASTATIC PANCREATIC CANCER

Rare subtypes: BRCAness. Some pancreatic cancers are BRCA mutated and as

shown in ovarian cancer may be more sensitive to platinsalts and PARP inhibitors

Waddelletal,Nature2015

POLO studyNCT02184195

Phase III

Maintenance

Olaparib

Reprinted by permission from Springer Nature, Nature, Whole genomes redefine the mutational landscape of pancreatic cancer, Waddell N, et al., Copyright 2015

GERMLINE BRCA2 MUTATED PANCREATIC CANCER

The POLO study

◆ Pancreatic adenocarcinoma

◆ Germline Mutated BRCA 1/2

◆ Treated with a first line platinum

◆ Without disease progression

within 16 weeks Placebo

Olaparib 300 mg x 2 /d

3:2

RPrimary objective:

Progression free survivalN=145

GERMLINE BRCA MUTATED PANCREATIC CANCER

The POLO study

7.4 vs. 3.8 moHR = 0.53

(95% CI: 0.35, 0.82; p=0.004)

OSPFS

From N Engl J Med, Golan T, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer, 381(4):317–27. Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from


18.9 vs. 18.1 moHR = 0.91

(95% CI: 0.56, 1.46; p=0.68)

Hazard ratio (95% CI) HR (95% CI)

All patients 0.53 (0.35, 0.82)

1st-line FOLFIRINOX variants 0.54 (0.35, 0.84)

Other 1st-line PBC 0.76 (0.27, 2.32)

Doublet 1st-line PBC 0.59 (0.24, 1.50)

Triplet 1st-line PBC 0.51 (0.32, 0.82)

16 weeks to 6 months of 1st-line PBC 0.69 (0.43, 1.12)

>6 months of 1st-line PBC 0.35 (0.17, 0.72)

Partial or complete response to 1st-line PBC 0.62 (0.35, 1.12)

Stable disease following 1st-line PBC 0.50 (0.29, 0.87)

Measurable disease at baseline 0.57 (0.37, 0.88)

Non-measurable or no evidence of disease 0.45 (0.14, 1.57)

Germline BRCA1 mutation 0.40 (0.20, 0.85)

Germline BRCA2 mutation 0.63 (0.39, 1.02)

Age <65 years 0.45 (0.28, 0.72)

Age ≥65 years 1.02 (0.45, 2.60)

Male 0.46 (0.37, 0.80)

Female 0.66 (0.35, 1.19)

Caucasian 0.59 (0.39, 0.90)

Absence of biliary stent 0.54 (0.36, 0.82)

0.1 1 10Placebo betterOlaparib better

GERMLINE BRCA MUTATED PANCREATIC CANCER

Kindler HL, et al. Presented at ASCO 2019, Abstract #LBA4. By permission of Prof Kindler.

IMMUNOTHERAPY FOR METASTATIC

PANCREATIC CANCER

Poor results of PC patients in basket studies due to poor local immune cells except for MSI+ tumours

Dense fibrotic stroma physical barrier

Exclusion of

anti-tumour T cells

Infiltration by

immunosuppressive cells

M2 macs+++, T reg, MDSC

Potential explanations to poor results of

Checkpoint inhibitors in PC patients:

Type of response, n (%)1Pancreas

N=8

Complete Response 2 (25)

Partial Response 3 (37)

Stable Disease 1 (12)

Progressive Disease 0 (0)

Non Evaluablea 2 (25)

Objective Response Rate (%) 62

Disease Control Rate (%)b 75

aPatients were considered not evaluable if they did not undergo a 12 week scan due to clinical progression; bThe rate of disease control was defined as the percentage of patients who had a complete response, partial response or stable disease for 12 weeks or more.

1. Le DT, et al. Science 2017;357(6349):409–13.

Image courtesy of Dr Cindy Neuzillet, Curie Institute Saint-Cloud

IMMUNOTHERAPY FOR METASTATIC

PANCREATIC CANCER

Ongoing combination trials

Taieb J, et al. Ann Oncol 2017.

Drugs Study Phase Estimated numbers NCT number

GVAX + CRS-207 +/- nivolumab 2 108 02243371

ACP-196 +/- pembrolizumab 2 76 02362048

Gem/Nabpacli +/- durvalumabt/tremelimumab 2 180 02879318

Durvalumab + pexidartinib 1 58 02777710

Tremelimumab, durvalumab, SBRT (in 3 combos/arms) 1 60 02311361

Epacadostat, Pembro, CRS-207 2 70 03006302

NRG1 GENE FUSIONS

NRG1 Gene fusions are recurrent, clinically actionable gene

rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma

Occurrence not well documented but <5%

Efficacy of afatinib in NRG1 gene fusion KRAS metastatic pancreatic cancer patients

Reprinted from Clin Can Res, Copyright 2019, Jones MR, et al. doi: 10.1158/1078-0432.CCR-19-0191 NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal

adenocarcinoma, with permission from AACR.

In an expert centreMolecular profiling and therapeutic options for first line metastatic pancreatic cancer

BEYOND GEMCITABINE FIRST LINE

Few randomised trials

40 to 50% of patients will receive a second line therapy after progression with a 1st line regimen

Author, year Treatment n PFS (mo) OS (mo)

Oettle H, et al.

J Clin Oncol 2014

5FU 84 2.0 HR=0.68

p=0.019

3.3 HR=0.66

p=0.0105FU+Oxali 76 2.9 5.9

Von Hoff DD, et al. WCGIC

2014

5FU

398

1.5 HR=0.56

p<0.001

4.2 HR=0.67

p=0.0125FU+MM-398 3.1 6.1

MM-398 2.7 4.9

Gill S, et al.

2014

5FU

FOLFOX

2.9

3.1

NS 9.1

6.1

NS

Yoo C, et al.

2009

FOLFOX

FOLFIRI.3

2

1.5

NS 4.2

3.7

NS

Mainly in the era of gem-based first line treatments

BEYOND FIRST LINE

The NAPOLI 01 study

OS: 6.1 vs. 4.2 mo, p=0.012

Phase III

N=417, post-Gemcitabine

5FU/AF vs. Nal-IRI

vs. 5FU/AF + Nal-IRI

Primary endpoint:

OS

Reprinted from The Lancet, 387(10018), Wang-Gillam A, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global,

randomised, open-label, phase 3 trial, 545-557, Copyright 2016, with permission from Elsevier.

FUTURE DIRECTIONS

◆ Target Cancer Stemcell

(Napabucasin)

◆ Target BRCAness

◆ Target Ras or interaction

domains with binding partners

◆ Metformin

◆ L-asparaginase

◆ Hydroxychloroquin

◆ Physical activity

◆ TGF-b (evofosamide)

◆ Notch/DDL4 (demcizumab)

◆ Wnt/B-catenin (OMP-54F28)

◆ Lysyl-oxidase inhibitors (simtuzumab)

◆ Recombinant human hyalorunidase

◆ Gvax /CRS207

◆ Anti-CLTA4, Anti-

PD1/PDL1 + CCR2

targeting or anti-TGFb or

other co treatments

Adapted from Neuzillet C, Pharmacol Ther 2015;155:80–104.

Other

Metabolism

Stroma

Immunity/

Inflammation

SURVEILLANCE

References

After surgery: clinical examination, CA19-9 & Thorax/Abdomen/Pelvis-CT-scan

◆ At least every 6 months for 2 years

◆ At least every 12 months from 2 to 5 years

In patients with advanced disease and patients on treatment whatever disease stage: clinical examination,

CA19-9 & TAP-CT

◆ Every 2 to 3 months in advanced disease

◆ Every 2 months neoadjuvant patients

◆ Every 3 months in adjuvant patients

CONCLUSIONS: FOR THE PRACTICE

Resectable: adjuvant FOLFIRINOX in fit patients, Gem+capecitabine or Gem in the others

Metastatic:

◆ First line FOLFIRINOX for fit patients or Gem+Nab-paclitaxel or Gem in the others

◆ Second line: 5FU+ Nal-IRI or FOLFOX or gem-based if FOLFIRINOX 1st line

New approaches:

◆ BRCAness: olaparib in the near future for germline mutated mPC after platinum containing induction

chemotherapy (FOLFIRINOX)

◆ IO agents in MSI high pancreatic cancer patients (<1%)

Clinical trials: always try to enrol your mPC patients in clinical trials +++

THANK YOU!

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ESMO E-Learning Advanced Pancreatic Cancer and … · 2020. 1. 27. · PANCREATIC CANCER SURGERY General considerations Surgery is the only potential curative treatment for pancreatic