Cáncer de Páncreas: Optimización

del tratamiento sistémico

Alfredo Carrato

Hospital Universitario Ramón y Cajal, Madrid

16 de Mayo de 2015

Pancreatic cancer screening

• There is a latency period of about 10 years between the start of

pancreatic carcinogenesis and symptomatic disease

• Non-invasive precursors and early disease stages can be

identified by screening high-risk individuals:

– Several family members affected by pancreatic cancer

– An inherited predisposition harboring early curable diseases, such as

pancreatic intraepithelial neoplasms, noninvasive intraductal papillary

mucinous neoplasms and mucinous cystic neoplasms

• Endoscopic ultrasound is widely used as a screening test due to

its ability to detect small pre-invasive lesions (~1 cm)

• An ideal screening test would be a highly accurate blood marker

that could be measured non-invasively: ctDNA, CTC, etc.

Exocrine Pancreatic Adenocarcinoma

• This is a very tough disease!

• Progress in pancreatic ductal adenocarcinoma has

been very slow

• 80% of patients are diagnosed with advanced

unresectable disease

• 80% of patients who have resection and adjuvant

therapy, relapse

• “Cure” rate is only 7%

• Median survival of patients with metastases without

treatment is only about 3 months

Treatment Algorithm Overview

Adapted from: Kanji ZS, et al. CMAJ. 2013;185(14):1219-1226.

Diagnosis and stage of pancreatic cancer confirmed

Borderline resectable Resectable Advanced

Locally advanced Metastatic Distal

pancreatectomy (tail)

Total pancreatectomy

(multifocal)

Whipple procedure (head)

Adjuvant chemotherapy (usually gemcitabine or 5-FU)

Palliative chemotherapy (gemcitabine, gemcitabine/nab-paclitaxel, or FOLFIRINOX)

± Neoadjuvant chemotherapy ± radiotherapy

Surgery ± venous resection (hepatic portal or

superior mesenteric)

5-FU, 5-fluorouracil; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin.

Pancreatic Cancer Adjuvant Treatment

• 25%‐30% of patients die early

• Adjuvant therapy works

• Gemcitabine and optimally administered

5‐FU/leucovorin have similar effects

• The role of radiation is unclear

• Remember, these trials focus on highly

selected patients!

• 25% of patients do not receive adjuvant

therapy

Key Ongoing Phase III Adjuvant Trials

Trial Estimated Enrollment

Experimental Arm Comparator Arm Primary Endpoint

CONKO-0051 450 Gemcitabine + erlotinib Gemcitabine RFS

CONKO-0062 NR Gemcitabine + sorafenib Gemcitabine DFS

NEOPAC3 310 Neoadjuvant treatment with gemcitabine + oxaliplatin adjuvant treatment with gemcitabine

Adjuvant treatment with

gemcitabine PFS

PACT-154 370 Adjuvant PEXG ± neoadjuvant PEXG Gemcitabine OS

NCT010729815 722 Gemcitabine ± CRT + algenpantucel-L immunotherapy

Gemcitabine ± CRT

OS

PRODIGE 24/ ACCORD 246 490 mFOLFIRINOX Gemcitabine DFS

RTOG 0848, first rand RTOG 0848, second rand7

950

Gemcitabine + erlotinib Gemcitabine OS

Gemcitabine ± erlotinib Gemcitabine ± erlotinib + CRT

OS

APACT8 800 Gemcitabine + nab-paclitaxel Gemcitabine DFS

mFOLFIRINOX, modified regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; NEOPAC, Neoadjuvant Pancreatic Cancer; NR, not reported; PEXG, cisplatin, epirubicin, capecitabine, and gemcitabine; rand, randomization; RFS, relapse-free survival; Tx, treatment.

1. 1. World Health Organization: CONKO-005. http://apps.who.int/trialsearch/trial.aspx?trialid=DRKS00000247. 2. World Health Organization: CONKO-006. http://apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2007-000718-35-DE. 3. ClinicalTrials.gov: NCT01314027. 4. ClinicalTrials.gov: NCT01150630.

2. 5. ClinicalTrials.gov: NCT01072981. 6. ClinicalTrials.gov: NCT01526135. 7. ClinicalTrials.gov: NCT01013649. 8. ClinicalTrials.gov: NCT01964430.

A Pilot Study of Neoadjuvant Chemo and ChemoRT

followed by Surgical Resection and Adjuvant Chemo

for Borderline Resectable Pancreatic Cancer

• A02101 Single-arm Phase II study schema

FOLFIRINOX x 2 months

CAPECITABINE XRT 50.4 GY

SURGERY GEMCITABINE

x 2 months

RESTAGING

Hypothesis: The time required for pre-op therapy allows aggressive disease to

declare itself and patients who will not benefit from surgery can receive

alternate treatment

Patients who are not resected seem to fare better if systemic therapy was given

Definition of Borderline Resectable Disease

SMV/portal vein Tumour abutment, encasement, or short segment of venous occlusion

SMA Tumour abutment <180 degrees

Hepatic artery Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement, or direct abutment of the hepatic artery, without extension to the celiac axis

Involved lymph nodes outside areas of resection or presence of distant metastasis

No (Image modified from http://visualsonline.cancer.gov/)

Vauthey JN, et al. Ann Surg Oncol. 2009 Jul;16(7):1725-1726. Callery MP, et al. Ann Surg Oncol. 2009;16:1727-1733.

NCCN Clinical Practice Guidelines in Oncology, Pancreatic Adenocarcinoma, v 1, 2013.

Defined by the 2008 AHPBA/SSO/SSAT consensus guidelines Adopted by the National Comprehensive Cancer Network guidelines

AHPBA, American Hepato-Pancreato-Biliary Association; SSAT, Society for Surgery of the Alimentary Tract; SSO, Society of Surgical Oncology.

Treatment Overview:

Borderline Resectable Disease

Borderline resectable

± Neoadjuvant chemotherapy ± radiotherapy

Surgery ± venous resection

(hepatic portal or superior mesenteric)

Adapted from: Kanji ZS, et al. CMAJ. 2013;185(14):1219-1226.

Treatment Overview: Advanced Disease

Kanji ZS, et al. CMAJ. 2013;185(14):1219-1226.

Advanced

Locally advanced Metastatic

Palliative chemotherapy (gemcitabine, gemcitabine/nab-paclitaxel, or

FOLFIRINOX)

Treating advanced pancreatic cancer: the story so far

• Pre-1997: 5-fluorouracil monotherapy

• 1997: GEM monotherapy shown to improve survival,1

becomes standard of care for advanced PC

• 2000s: Various GEM-based combinations fail to demonstrate

clinically significant survival benefit

• 2007: Erlotinib/GEM shows significant survival benefit vs

GEM,2 approved in Europe

• 2011: FOLFIRINOX shows significantly improved survival

and response rates vs GEM,3 but is associated with greater toxicity

• 2013: MPACT Trial of ABX-GEM as a backbone therapy of

metastatic Pancreatic Cancer

1. Burris HA, et al. J Clin Oncol. 1997;15:2403‒2413; 2. Moore MJ, et al. J Clin Oncol. 2007;25:1960‒1966; 3. Conroy T, et al. N Engl J Med. 2011;364:1817‒1825.

GEM, gemcitabine; FOLFIRINOX, oxaliplatin, irinotecan, fluorouracil, leucovorin; PC, pancreatic cancer

The FOLFIRINOX regimen has not been approved by the EMA for treatment of pancreatic cancer.

Prodige 4 - ACCORD 11 trial design and overall survival

Conroy T, et al. N Eng J Med.

2011;364:1817-1825

Making FOLFIRINOX Tolerable

(Tempero MA):

1) omit bolus 5FU; 2)reduce doses; 3)

chemotherapy holidays

Most common grade 3 or 4 adverse events occurring in more than 5% of patients in the safety population

FOLFIRINOX vs gemcitabine: Safety

Conroy T, et al. N Engl J Med 2011; 364:1817-25.

No. of patients/total no. (%)

Event FOLFIRINOX (n=171) Gemcitabine (n=171) p-value

Hematologic

Neutropenia 75/164 (45.7) 35/167 (21.0) <0.001

Febrile neutropenia 9/166 (5.4) 2/169 (1.2) 0.03

Thrombocytopenia 15/165 (9.1) 6/168 (3.6) 0.04

Anemia 13/166 (7.8) 10/168 (6.0) NS

Non-hematologic

Fatigue 39/165 (23.6) 30/169(17.8) NS

Vomiting 24/166 (14.5) 14/169(8.3) NS

Diarrhea 21/165 (12.7) 3/169(1.8) <0.001

Sensory neuropathy 15/166 (9.0) 0/169 <0.001

Elevated level of alanine aminotransferase

12/165 (7.3)

35/168 (20.8)

<0.001

Thromboembolism 11/166 (6.6) 7/169(4.1) NS

MPACT Study Design and overall survival

Von Hoff DD, et al. N Engl J Med. 2013:369(18):1691-703.

Survival parameter

nab-paclitaxel + gemcitabine (n=431) Gemcitabine (n=430)

Original data cut-off

(Sep ‘12)

Updated cut-off

(May ‘13)

Original data cut-off

(Sep ‘12)

Updated cut-off

(May ‘13)

Median OS, months 8.5 8.7 6.7 6.6

Survival rates

6 months 67% 66% 55% 55%

12 months 35% 35% 22% 22%

24 months 9% 10% 4% 5%

36 months — 4% — 0

40 months — 3% — 0

42 months — 3% — 0

Goldstein D, et al. Oral presentation at: ASCO GI 2014 (abs 178)

Date of preparation September 2014 INT-ABR140149

MPACT long-term survivors (post hoc analysis)

MPACT benefit in patient subgroups (post hoc analysis)

nab-P + Gem Gem

HR P Value Events/n

Median

OS, mo Events/n

Median

OS, mo

380/431 8.7 394/430 6.6 0.72 <0.0001

220/254 9.6 222/242 6.8 0.65 <0.0001

160/177 7.7 172/188 6.5 0.80 0.0484

157/186 9.7 156/173 7.1 0.71 0.0039

223/245 8.1 238/257 6.2 0.74 0.0016

156/179 7.6 153/161 4.3 0.59 <0.0001

220/248 9.7 240/268 7.9 0.77 0.0053

167/191 9.5 170/180 6.4 0.59 <0.0001

210/237 8.1 221/246 6.9 0.79 0.0171

331/365 8.3 331/360 5.9 0.71 <0.0001

49/66 11.1 63/70 10.2 0.73 0.1109

25/33 12.9 20/21 9.0 0.47 0.0384

184/202 8.6 185/206 6.9 0.77 0.0164

117/136 7.9 129/140 5.9 0.79 0.0688

54/60 8.7 60/63 5.0 0.51 0.0012

50/60 9.3 49/56 7.0 0.90 0.6401

108/122 8.8 109/120 7.3 0.80 0.1114

177/197 8.4 184/195 5.7 0.61 <0.0001

52/61 9.4 57/59 6.7 0.59 0.0104

63/64 7.7 60/62 5.9 0.84 0.3715

28/38 10.7 27/38 6.9 0.82 0.4705

237/268 8.8 250/271 6.6 0.69 <0.0001

Goldstein D, et al. Oral presentation at: ASCO GI 2014 (abstract 178)

Group

0.125 0.25 0.5 1.0 2.0

HR

All patients

Age < 65 years

Age ≥ 65 years Female

Male

KPS 70 - 80 KPS 90 - 100

Australia

Western Europe North America

Eastern Europe

Primary tumor location: head Primary tumor location: other

No liver metastases Liver metastases

Normal CA 19-9

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

>3 metastatic sites

1 metastatic site

3 metastatic sites

2 metastatic sites

Favours Gem Favours nab-P + Gem

Abraxane-gem vs Folfirinox

Abraxane - Gemcitabina FOLFIRINOX

Diseño Regulatorio Fase III

No regulatorio Fase II/III

Promotor Celgene PRODIGE

Geografía Internacional 3 continentes

Francia

Tamaño muestral 861 pacientes 342 pacientes

Periodo de inclusión Mayo 2009 a abril 2012 3 años

Dic 2005 a oct 2009 4 años

Número de centros 151 48

Elegibilidad Sin límite de edad (10% de pacientes >75 años) KPS 100 (16%) – KPS 90-80 (77%) - KPS 70 (7%)

< 75 años ECOG 0 (37.4%) – ECOG 1 (62%) – ECOG 2 (0.6%)

• A network meta-analysis is not justified in advanced pancreatic

cancer since only 2 regimens – FOLFIRINOX and nab-paclitaxel +

gemcitabine –have demonstrated a significant improvement in OS

compared with the former standard of care, gemcitabine

• Differences between the MPACT and ACCORD trials limit the

validity of any cross-trial comparisons for these 2 regimens

• Both network analyses indicate that there is no significant difference

in efficacy between FOLFIRINOX and nab-paclitaxel + gemcitabine

• The large CIs/credible regions observed for many indirect

comparisons limit any robust interpretation of these efficacy results

• Despite the limitations of Bayesian network meta-analyses, both

groups indicate that nab-paclitaxel + gemcitabine and FOLFIRINOX

are the most likely to provide the best OS benefit among available

regimens, given the magnitude of benefit seen with both regimens in

the Phase III trials

Bayesian network meta-analyses

Gresham et al, BMC Cancer 2014;14:471

Chan et al, PLoS ONE 2014;9:e108749

Cartwright TH et al. J Clin Oncol 2014:32(15s):287s (Abs 4132)

Eligibility of metastatic pancreatic adenocarcinoma

(MPA) patients for first-line palliative intent nab-

Paclitaxel plus gemcitabine (NG) versus FOLFIRINOX

Peixoto RD, Renouf DJ, Lim HJ, Cheung WY - Department of Medical Oncology,

British Columbia Cancer Agency & University of British Columbia, Vancouver,

BC, Canada

Conclusion

In our population-based analysis, almost twice as many

pts would be eligible for NG (45.2%) when compared to

FOLFIRINOX (24.7%), mostly due to ECOG PS.

The longer mOS observed in the FOLFIRINOX-eligible

population likely reflects the exclusion of ECOG PS 2

patients (8.6 months vs 6.7 months).

ASCO 2014

Suggested treatment algorithm for mPC by PS

KPS 50-60% Disease control

KPS >60%

Bilirubin <5ULN

High pressure

for rapid remission

KPS 90-100%

Bilirubin <2 ULN

Poor PS

Reduced PS Good PS

Gemcitabine nab-paclitaxel + gemcitabine

nab-paclitaxel + gemcitabine

Gemcitabine ± erlotinib FOLFIRINOX

OR OR

BSC

OR

Adapted from Oettle. Cancer Treatment Reviews, 2014

Metastatic disease treatment options

• Several treatment options based on phase III trials are available

for patients with metastatic pancreatic cancer

– FOLFIRINOX is an effective treatment option in fit patients

– Nab-paclitaxel is the only cytotoxic agent that, when

combined with gemcitabine, significantly improved OS, PFS,

and ORR vs. gemcitabine

– Gemcitabine plus platinum derivatives or fluoropyrimidines

represent options in fit patients, who are not considered

candidates for FOLFIRINOX or nab-paclitaxel-gemcitabine

– Gemcitabine monotherapy may be reserved for patients with

poor performance status and the elderly

• “Targeted” therapeutic agents have been disappointing for a

variety of clinical and biologic reasons, but promising new drugs

are on the horizon (next talk)

¡Muchas gracias!

acarrato@telefonica.net