Pathobiology and treatment of pancreatic cancer Mariacristina Di Marco Institute of Hematology end Medical Oncology “L e A Seràgnoli” Bologna University

Pathobiology and Pathobiology and treatment of pancreatic treatment of pancreatic

cancercancer

Mariacristina Di MarcoMariacristina Di MarcoInstitute of Hematology end Medical Oncology “L e A Institute of Hematology end Medical Oncology “L e A

Seràgnoli”Seràgnoli”

Bologna UniversityBologna University

Management of pancreatic cancer remains the Management of pancreatic cancer remains the most challenging work in oncology: it remains most challenging work in oncology: it remains the 4the 4th th cause of death by cancercause of death by cancer

EpidemiologyEpidemiology

EpidemiologyEpidemiology In 2009 the eximated incidence of In 2009 the eximated incidence of

pancreatic cancer in USA was 42,460 pancreatic cancer in USA was 42,460 cases, and an estimated 35,240 patients cases, and an estimated 35,240 patients died from the diseasedied from the disease

Overall 5-year survival rate among Overall 5-year survival rate among patients with pancreatic cancer in < 5%patients with pancreatic cancer in < 5%

EpidemiologyEpidemiology

Resectable disease: only 15-20% of Resectable disease: only 15-20% of patients present resectable disease at patients present resectable disease at the time of diagnosis;the time of diagnosis;

Locally advanced Locally advanced

Metastatic disease: more frequentMetastatic disease: more frequent

BiologyBiology

Accumulation of gene mutations:Accumulation of gene mutations:1.1. Activation of Activation of KRAS2 KRAS2 oncogene (90%)oncogene (90%)

2.2. Inactivation of tumor-suppressor gene Inactivation of tumor-suppressor gene CDKN2A CDKN2A (95%)(95%)

3.3. Inactivation of tumor-suppressor gene Inactivation of tumor-suppressor gene TP53 TP53 (50-(50-70%)70%)

4.4. Delated in pancreatic cancer 4 (Delated in pancreatic cancer 4 (DPC4DPC4) (50%)) (50%)

The role of angiogenesis remains The role of angiogenesis remains controversial: angiogenesis inhibitors has controversial: angiogenesis inhibitors has failed in patients with ACPfailed in patients with ACP

significant advances on the pathogenesis significant advances on the pathogenesis and molecular biology of this cancer…and molecular biology of this cancer…

……but clinical developments over the past but clinical developments over the past decade have been modest and not very decade have been modest and not very encouragingencouraging

Advanced and metastatic ACPAdvanced and metastatic ACP

Gemcitabine: the only standard of care in Gemcitabine: the only standard of care in all settings of ACP: adjuvant, locally all settings of ACP: adjuvant, locally advanced and metastatic (since 1997)advanced and metastatic (since 1997)

The research focused on the evaluation of The research focused on the evaluation of therapeutic combinations based on GEM:therapeutic combinations based on GEM:

1.1. GEM + targeted agentsGEM + targeted agents

2.2. GEM + cytotoxic drugs (doublets, triplets)GEM + cytotoxic drugs (doublets, triplets)

4years ago…4years ago…

Something has changed?Something has changed?

OS: 5.65 (GEM) vs. 4.41 (5-FU)OS: 5.65 (GEM) vs. 4.41 (5-FU) TTP: 9 week (GEM) vs. 4 week (5-FU) TTP: 9 week (GEM) vs. 4 week (5-FU)

Pz=126

Treatment ScheduleTreatment Schedule GEM

1000mg/m2/wk 5Fu 600mg/m2/wk

Hopes and failures of targeted Hopes and failures of targeted therapytherapy

ERLOTINIBERLOTINIB CETUXIMAB CETUXIMAB

BEVACIZUMABBEVACIZUMAB

AXITINIBAXITINIB

OTHER MOLECULESOTHER MOLECULES

Targeted TherapyTargeted Therapy

The only agents that, in combination with The only agents that, in combination with gemcitabine, has shown a small but gemcitabine, has shown a small but statistically significant improvement in OS: statistically significant improvement in OS: ERLOTINIBERLOTINIB

Erlotinib: orally administered small tyrosine Erlotinib: orally administered small tyrosine kinase inhibitor (TKI) of the epidermal kinase inhibitor (TKI) of the epidermal growth factor receptor growth factor receptor

GEM GEM plus plus ErlotinibErlotinib

6.24 months (GEM+ERL) vs. 5.91 months (GEM)P=0.038

OS

vs. Gemcitabine (1000 mg/m2) + Placebo

Pz=569 (naïve advanced pancreatic cancer)

Gemcitabine (1000 mg/m2) + Erlotinib (100 or 150 mg/die)

GEM GEM plus plus ErlotinibErlotinibGrade 0(n=79)

Grade 1(n=102)

Grade ≥2(n=101)

Median survival (months)

5.3 5.8 10.5

1-year survival (%)

16 9 43

GEM GEM plus plus ErlotinibErlotinib Association between rash severity and Association between rash severity and

survival: survival: rash grade ≥ 2 rash grade ≥ 2 10.5 vs. 5.3 months in 10.5 vs. 5.3 months in

patients with no rash (p=0.037)patients with no rash (p=0.037)

K-ras status: wild-type K-ras status: wild-type increased increased benefit from erlotinib? benefit from erlotinib?

Post-hoc mutational analysis: too small Post-hoc mutational analysis: too small sample size sample size no significant gain in terms no significant gain in terms of survival related to to EGFR statusof survival related to to EGFR status

the anti-EGFR agent produced a similar the anti-EGFR agent produced a similar advantage in EGFR-positive and EGFR-advantage in EGFR-positive and EGFR-negative patients;negative patients;

In pancreatic cancer seems that EGFR In pancreatic cancer seems that EGFR mutations are infrequent, making difficult mutations are infrequent, making difficult to asses their association with to asses their association with responsiveness to anti-EGFR theraphyresponsiveness to anti-EGFR theraphy

Skin rash Skin rash has been suggested as a has been suggested as a surrogate marker of favorable response to surrogate marker of favorable response to EGFR inhibition EGFR inhibition

The mechanism of association between The mechanism of association between rash and improved outcome remains rash and improved outcome remains unclear:unclear: Marker of host immunocompetencyMarker of host immunocompetency Variability in drug absorption or metabolismVariability in drug absorption or metabolism Genetic polymorphisms in EGFRGenetic polymorphisms in EGFR

However suggests that predictive factors However suggests that predictive factors may be identified to guide appropriate may be identified to guide appropriate patient selection patient selection


ERLOTINIBERLOTINIB

CETUXIMAB CETUXIMAB BEVACIZUMABBEVACIZUMAB

AXITINIBAXITINIB


GEM GEM plus plus CetuximabCetuximab

Chimeric IgG1 monoclonal antibody that Chimeric IgG1 monoclonal antibody that specifically binds to the extracellular specifically binds to the extracellular domain of EGFR preventing downstream domain of EGFR preventing downstream signal transduction activations.signal transduction activations.

Significantly suppresses tumoral growth Significantly suppresses tumoral growth and reduces microvascular density by and reduces microvascular density by down-regulation of tumor cell-produced down-regulation of tumor cell-produced VEGF and IL-8 with inhibition induced VEGF and IL-8 with inhibition induced angiogenesisangiogenesis

GEM GEM plus plus CetuximabCetuximab

failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine.failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine.

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 25, No 18S (June 20 Supplement), 2007: LBA4509© 2007 American Society of Clinical Oncology

Abstract

Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 studyP. A. Philip, J. Benedetti, C. Fenoglio-Preiser, M. Zalupski, H. Lenz, E. O'Reilly, R. Wong, J. Atkins, J. Abruzzese and C. Blanke

G (1000 mg/m2/wk)+C (400 mg/m2 week1250 mg/m2/wk)

Vs G (1000 mg/m2/wk)

G + C G P value

OS (months) 6.5 6 0.058

PFS (months) 3.5 3 0.014

Pz=766I linea

3.4 months (cetuximab group) vs. 4.2 months (non-cetuximab group)p=0.84

7.5 months vs. 7.8 months p=0.73 PFSOS

Pz=84

GEM (1000 mg/m2/wk)+ CIS (35 mg/m2-1,8 every 21)+ Cetuximab (250 mg/m2/wk) loading dose 400 mg/m2 )

GEM (1000 mg/m2/wk)+

Vs CIS (35 mg/m2-1,8 every 21)


ERLOTINIBERLOTINIB

CETUXIMAB CETUXIMAB

BEVACIZUMABBEVACIZUMAB AXITINIBAXITINIB


Tumour Tumour characteristics and environment characteristics and environment promote VEGF expressionpromote VEGF expression

COX-2Nitric oxideOncogenes

bFGF

IL-8

EGF

Hypoxia PDGFIGF-1

VEGF release

Increased expression(MMP, tPA, uPA, uPAr,

eNOS, etc.)

ANGIOGENESIS

Survival Proliferation Migration

Permeability

Binding and activationof VEGF receptor

GEM GEM plus plus BevacizumabBevacizumab

A phase II trial of G + anti-VEGF antibody A phase II trial of G + anti-VEGF antibody B reported a 21% response rate and a B reported a 21% response rate and a median survival of 8.8 months (mo) in 52 median survival of 8.8 months (mo) in 52 PC pts (Kindler, JCO 2005). PC pts (Kindler, JCO 2005).

These data led CALGB to conduct a These data led CALGB to conduct a phase III trial of GB vs. GP in pts with phase III trial of GB vs. GP in pts with advanced PC.advanced PC.

GEM GEM plus plus BevacizumabBevacizumab Humanized monoclonal immunoglobulin G antibody Humanized monoclonal immunoglobulin G antibody

inhibitor of VEGFinhibitor of VEGF

Pz=602, Advanced pancreatic cancerPz=602, Advanced pancreatic cancer

G (1000 mg/mG (1000 mg/m22/wk)+ B (10 mg/m/wk)+ B (10 mg/m22) Vs. G (1000 mg/m) Vs. G (1000 mg/m22/wk)+ Placebo/wk)+ Placebo

OS: 5.8 months for combination vs. 6.1 months for GEMOS: 5.8 months for combination vs. 6.1 months for GEM

tha addition of Bevacizumab to Gemcitabine does not improve tha addition of Bevacizumab to Gemcitabine does not improve survival in advanced pancreatic cancersurvival in advanced pancreatic cancer

A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis od Cancer and Leukemia Group B (CALGB) 80303.Kindler HL, Niedzwiecki D, Hollis D, Oraefo E, Schrag D, Hurwitz H, et alASCO Gastrointestinal Cancer Symposium 2007. Abstract No: 108

Rationale for combining Rationale for combining bevacizumab and erlotinibbevacizumab and erlotinib

Both HER1/EGFR and VEGF are overexpressed in many Both HER1/EGFR and VEGF are overexpressed in many tumourstumours11

VEGF has been implicated in resistance to anti-HER1/EGFR VEGF has been implicated in resistance to anti-HER1/EGFR therapytherapy

Treatment with two agents targeted against critical pathways Treatment with two agents targeted against critical pathways may be more effective than a single pathwaymay be more effective than a single pathway22

Preclinical studies have shown that anti-VEGF and anti-Preclinical studies have shown that anti-VEGF and anti-HER1/EGFR therapies have at least additive effectsHER1/EGFR therapies have at least additive effects33

Clinical trials in various indications (renal cell cancer,Clinical trials in various indications (renal cell cancer,44 non- non-small cell lung cancer,small cell lung cancer,55 head and neck squamous cell head and neck squamous cell carcinomacarcinoma66) have shown that the combination of bevacizumab ) have shown that the combination of bevacizumab and erlotinib is activeand erlotinib is active

AVITA studyAVITA study The first trial to combine an anti-angiogenic and an anti-The first trial to combine an anti-angiogenic and an anti-

EGFREGFR

Pz=301, phase III study in patients with metastatic Pz=301, phase III study in patients with metastatic pancreatic cancer and ECOG 0-1pancreatic cancer and ECOG 0-1

GEM (1000 mg/mGEM (1000 mg/m22/wk) + Erlotinib (100 mg/day) + /wk) + Erlotinib (100 mg/day) + Bevacizumab(5 mg/kg every 2 wk) Bevacizumab(5 mg/kg every 2 wk) Vs.Vs. GEM (1000 GEM (1000 mg/mmg/m22/wk) + Erlotinib (100 mg/day) + Placebo/wk) + Erlotinib (100 mg/day) + Placebo

OS7.1 months (bev. arm) vs. 6 months (p=0.208)

PFS3.6 months vs. 4.6 months with bevacizumab (p=0.0002)


ERLOTINIBERLOTINIB

CETUXIMAB CETUXIMAB


AXITINIBAXITINIB OTHER MOLECULESOTHER MOLECULES

GEM GEM plus plus Axitinib-1Axitinib-1

Oral vascular endothelial growth factor Oral vascular endothelial growth factor (VEGF) inhibitor(VEGF) inhibitor

Demonstrated promise in a small Demonstrated promise in a small randomized phase II study, Spano et al. randomized phase II study, Spano et al. 20082008

OS

6.9 months (GEM+Axitinib) vs. 5.6 months (GEM)

HR= 0.71

Pz=103

GEM (1000 mg/m2/wk)+Axitinib (5mg x 2/d)

Vs GEM (1000 mg/m2/wk)

GEM GEM plus plus Axitinib-2Axitinib-2

Phase III study was interrupt Phase III study was interrupt

January 30, 2009 - Pfizer Discontinues Global Phase III Trial of Axitinib for Futility in Advanced Pancreatic CancerNEW YORK--(BUSINESS WIRE)--Pfizer Inc announced today the discontinuation of a Phase III study of its investigational agent axitinib for the treatment of advanced pancreatic cancer. Based on an interim analysis…


ERLOTINIBERLOTINIB

CETUXIMAB CETUXIMAB


AXITINIBAXITINIB


Other moleculesOther molecules

Sorafenib Sorafenib oral multikinase inhibitor oral multikinase inhibitor able to inhibit the tumor growth able to inhibit the tumor growth targeting MAPK pathway by Raf-targeting MAPK pathway by Raf-kinase, VEGF-R2, -R3, PDGFR-kinase, VEGF-R2, -R3, PDGFR-ββ

Other moleculesOther molecules

Sorafenib + Gem Sorafenib + Gem was tested in two small was tested in two small clinical trials clinical trials no efficacy no efficacy

OS: 4 monthsOS: 4 months

PFS: 3,2 monthsPFS: 3,2 months

Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II ConsortiumJ. A. Wallace, G. Locker, S. Nattam, K. Kasza, K. Wade-Oliver, W. M. Stadler, E. E. Vokes and H. L. Kindler

SG is inactive

Pz=17

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings

Future directions in targeted Future directions in targeted therapytherapy

MasatinibMasatinib

Insulin-like growth factor-1 receptor Insulin-like growth factor-1 receptor (IGF-1R) inhibitor(IGF-1R) inhibitor

MasatinibMasatinib

Tyrosine kinase inhibitor targeting c-kit, Tyrosine kinase inhibitor targeting c-kit, PDGFR, FGFR3 and FAK pathwayPDGFR, FGFR3 and FAK pathway

Masatinib was found to enhance the Masatinib was found to enhance the antiproliferative effects of gemcitabine in antiproliferative effects of gemcitabine in preclinical studiespreclinical studies

Study DesignStudy Design 22 non-randomized,

chemotherapy-naïve patients

Primary endpoint: TTP

Treatment ScheduleTreatment Schedule GEM 1000mg/m2/wk

Masatinib 9 mg/kg/day

TOT Locally advanced

Metastatic

# Pts. 22 9 13

TTP (mo)

6.4 8.3 2.7

OS (mo) 7.1 8.4 6.8

18 mo-S (%)

- 22 23

The efficacy and safety of Masatinib The efficacy and safety of Masatinib combined with Gemcitabine are combined with Gemcitabine are encouraging, with extended survival encouraging, with extended survival and median TTP that support and median TTP that support initiation of phase III trialinitiation of phase III trial

GEM-based chemotherapyGEM-based chemotherapy

Various combination using Gem: none of Various combination using Gem: none of them is proved to be superior to Gem them is proved to be superior to Gem monotherapymonotherapy

Some success has been observed by Some success has been observed by combining:combining:

1.1. GEM + platinum compounds GEM + platinum compounds

2.2. GEM + fluoropyrimidines(e.i. capecitabine)GEM + fluoropyrimidines(e.i. capecitabine)

3.3. GEM + novel agentsGEM + novel agents

This meta-analysis evaluated 6026 patients in 33 randomized trials

Cisplatin (40 mg/m2 day 1)+ Epirubicin (40 mg/m2 day 1) +Gemcitabine (600 mg/m2 day 1,8) +5-FU (200 mg/m2 day 1-28)

Gemcitabine (1000 mg/m2 /wk) Vs.

Study DesignStudy Design 99 chemotherapy-naïve patients Primary endpoint: 4-months PFS

38.5% (PEFG) vs. 21.3% (GEM)p=0.11

60% (PEFG) vs. 28% (GEM) p=0.003

PFS

1 year survival rate:

GEM GEM plusplus Oxaliplatin Oxaliplatin

Pz=313Pz=313

GemcitabineGemcitabine ( (1000 mg/m1000 mg/m22-100 min infusion-100 min infusion) + ) + OxaliplatinOxaliplatin (100 mg/m (100 mg/m22) ) vs. vs. Gemcitabine (1000 Gemcitabine (1000 mg/mmg/m22- 30 min infusion) - 30 min infusion)

Locally advanced (30%) or metastatic pancreatic Locally advanced (30%) or metastatic pancreatic adenocarcinoma adenocarcinoma

PFS: 5.8 vs. 3.7 months, p=0.04Superiority of Gemox was observed in both locally advanced (B) and metastatic (C)

OS: 9.0 vs. 7.1 months, p=0.13

GEM GEM plusplus Capecitabine Capecitabine

Capecitabine is an orally administered Capecitabine is an orally administered fluorouracil pro-drug, which is activated by fluorouracil pro-drug, which is activated by a three-step targeted process a three-step targeted process (carboxylesterases, cytidine deaminase (carboxylesterases, cytidine deaminase and thymidine phosphorylase respectively.and thymidine phosphorylase respectively.

This drug mimics continuous infusion of 5-This drug mimics continuous infusion of 5-FU andits intratumoral activation improved FU andits intratumoral activation improved the therapeutic index and reduced toxicity the therapeutic index and reduced toxicity in normal tissuein normal tissue


Study DesignStudy Design 533 chemotherapy-naïve patients Primary endpoint: OS

Treatment ScheduleTreatment Schedule GEM 1000 mg/m2 1,8,15 every 4 wk +

CAP 830 mg/m2/bid, d 1-14

Vs

GEM 1000 mg/m2

GEMCAPE GEM P value

# Pts. 267 266

RR (%) 19,1 12,4 0.034

OS (mo) 7,1 6,2 0.08

PFS (mo) 5,3 3,8 0.004


7.1 (GemCape) vs. 6.2 (Gem)p=0.08

This survival advantage in the capecitabine group was greater in metastatic desease

5.3 (GemCape) vs. 3.8 (Gem)p=0.004

PFS

OS


Study DesignStudy Design 319 chemotherapy-naïve patients Primary endpoint: OS

Treatment ScheduleTreatment Schedule GEM 1000 mg/m2 1,8 every 3 wk +

CAP 650 mg/m2/bid, d 1-14

Vs

GEM 1000 mg/m2

GEMCAPE GEM

# Pts. 160 159

RR (%) 10,0 7,8

OS (mo) 8,4 7,2

1YrS (%)

32 30

p=0.23


Subgroup analysis advantage in terms of survival was Subgroup analysis advantage in terms of survival was statistically significant when the analysis was restricted statistically significant when the analysis was restricted to those patients with good Performance status revealing to those patients with good Performance status revealing OS = 10.1 months vs. 7.4 months, OS = 10.1 months vs. 7.4 months, pp = 0.014 = 0.014

Gemcitabine and Cisplatin-based Gemcitabine and Cisplatin-based chemotherapychemotherapy

GEM GEM plusplus Cisplatin Cisplatin

Pz=400Pz=400

Gemcitabine (1000 mg/mGemcitabine (1000 mg/m22) + Cisplatin (25 ) + Cisplatin (25 mg/mmg/m22) ) vs.vs. Gemcitabine (1000 mg/m Gemcitabine (1000 mg/m22) )

Locally advanced or metastatic ACP, Karnofsky Locally advanced or metastatic ACP, Karnofsky Performance Status (KPS) ≥ 50Performance Status (KPS) ≥ 50

GEM GEM plusplus Cisplatin Cisplatin

8.3 months (Gem) vs. 8.3 months (Gem) vs. 7.2 months (GemCis)7.2 months (GemCis)pp=0.38 =0.38

3.9 months (Gem) vs. 3.9 months (Gem) vs. 3.8 months (GemCis)3.8 months (GemCis)pp=0.80 =0.80

OS

PFS

Surprisingly, this large trial did not Surprisingly, this large trial did not demonstrate any survival benefit by demonstrate any survival benefit by adding cisplatin to gemcitabine. adding cisplatin to gemcitabine.

The results not only confirmed a The results not only confirmed a previously published negative phase III previously published negative phase III trial, but also warned all clinicians to trial, but also warned all clinicians to carefully interpret pooled or meta-carefully interpret pooled or meta-analyses.analyses.

Novel agents in the treatment of Novel agents in the treatment of advanced pancreatic canceradvanced pancreatic cancer

A number of studies are exploring further A number of studies are exploring further first line optionsfirst line options

Future directions in Future directions in chemotherapic agents chemotherapic agents

S-1S-1

EndoTAG-1EndoTAG-1

Nab-paclitaxelNab-paclitaxel

S-1S-1 S-1 is a new oral fluorinated pyrimidine S-1 is a new oral fluorinated pyrimidine

that includes tegafur (FT), a prodrug of 5-that includes tegafur (FT), a prodrug of 5-FU and two 5-FU- modulating substances, FU and two 5-FU- modulating substances, 5-chloro-2,4-dihydroxypyridine (gimeracil- 5-chloro-2,4-dihydroxypyridine (gimeracil- competitive inhibitor of dihydropyrimidine competitive inhibitor of dihydropyrimidine dehydrogenase) and potassium oxonate dehydrogenase) and potassium oxonate (oteracil-inhibits phosphorylation of 5-FU (oteracil-inhibits phosphorylation of 5-FU in G.I. tract in G.I. tract reduces G.I. toxicity) reduces G.I. toxicity)

S-1S-1

Study DesignStudy Design 32 chemotherapy-naïve patients32 chemotherapy-naïve patients

Treatment ScheduleTreatment Schedule GEM 1250 mg/m2/wk + S-1 40 mg/m2/bid, d 1-14

TTP: 4.92 monthsTTP: 4.92 months OS: 7.89 monthsOS: 7.89 months

Survival duration was significantly longer for patient with good performance status (ECOG 0-1)

Combination S-1 and Gem showed promising antitumor activity, expecially for the good performance status patients with unresectable pancreatic cancer

11.42 months-ECOG 0-1

3.40 months-ECOG 2:

OS

S-1S-1

TTP: 5.4 months OS: 8.4 months

Study DesignStudy Design 38 chemotherapy-38 chemotherapy-

naïve patientsnaïve patients

Treatment ScheduleTreatment Schedule GEM 1000 mg/m2/wk + S-1 40 mg/m2/bid, d 1-14

EndoTAG-1EndoTAG-1 Cationic lipidic complexed paclitaxel is a novel Cationic lipidic complexed paclitaxel is a novel

vascular targeting agentvascular targeting agent A randomized phase II trial has explored several A randomized phase II trial has explored several

dosing schedules in untreated patients.dosing schedules in untreated patients.

Combination treatment with GEM+E was well tolerated and led to Combination treatment with GEM+E was well tolerated and led to substantially substantially prolonged PFS and OS prolonged PFS and OS compared to standard therapy compared to standard therapy in this phase II trial. Further studies are warranted to demonstrate a in this phase II trial. Further studies are warranted to demonstrate a statistically significant survival benefit associated with GEM+E in statistically significant survival benefit associated with GEM+E in advanced PC.advanced PC.

A phase II trial of cationic liposomal paclitaxel in A phase II trial of cationic liposomal paclitaxel in combination with gemcitabine in patients with combination with gemcitabine in patients with unresectable pancreatic cancer.unresectable pancreatic cancer.

M. Löhr, S. Haas, W. Bechstein, G. Bodoky, A. Maerten, W. Fischbach, C. Lilla, A. Mescheder, A. Pap, U. R. Fölsch

ASCO 2009

Nab-paclitaxelNab-paclitaxel

A nanoparticle albumin-bound paclitaxelA nanoparticle albumin-bound paclitaxel Phase I trial GEM+Nab-paclitaxel: interisting activity with Phase I trial GEM+Nab-paclitaxel: interisting activity with

partial responce and Ca19-9 declinepartial responce and Ca19-9 decline

SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: A phase I/II study.

The combination of Nab-P and G was generally well tolerated and had substantial enough antitumor activity in patients with pancreatic cancer (OS: 9 months). SPARC+ status in these patients was associated with higher response rate and longer PFS.

Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings

3. FUTURE DIRECTIONS3. FUTURE DIRECTIONS

Additional areas of development of new Additional areas of development of new therapeutics include:therapeutics include: IGF-1R signaling inhibitors (combined with IGF-1R signaling inhibitors (combined with

Gem/erlotinib)- phase I trials:Gem/erlotinib)- phase I trials:• MK-0646 (humanized IgG1 monoclonal antibody that MK-0646 (humanized IgG1 monoclonal antibody that

binds IGF-1R)binds IGF-1R)

• IMC-A12 (fully human IGF-1R monoclonal antibody)IMC-A12 (fully human IGF-1R monoclonal antibody) PI3/Akt signaling inhibitionPI3/Akt signaling inhibition PARP inibitionPARP inibition c-Met inibitionc-Met inibition

3. FUTURE DIRECTIONS3. FUTURE DIRECTIONS

Over the last 12 years, we have extensively Over the last 12 years, we have extensively explored all possible agents to combine explored all possible agents to combine with GEMwith GEM

It is time to think out of the gemcitabine box It is time to think out of the gemcitabine box and put more effort on novel agents, such and put more effort on novel agents, such as Nab-paclitaxel, S-1, IGFR inhibitorsas Nab-paclitaxel, S-1, IGFR inhibitors

PharmacogenomicsPharmacogenomics

Genetic polymorphisms and tumor-specific Genetic polymorphisms and tumor-specific expression of mRNA and proteins, may affect expression of mRNA and proteins, may affect both the efficacy and toxicity of GEMboth the efficacy and toxicity of GEM

hENT1 (human equilibrative nucleoside hENT1 (human equilibrative nucleoside transporter) may have a prognostic role transporter) may have a prognostic role

Preclinical studies: Preclinical studies: positive correlation between positive correlation between hENT1 gene expression and hENT1 gene expression and chemosensitivity chemosensitivity

hENT1 protein expression was associated with hENT1 protein expression was associated with increased OS and DFS in ACP who receive increased OS and DFS in ACP who receive gemcitabine in adjuvant setting (RTOG 9704)gemcitabine in adjuvant setting (RTOG 9704)

hENT1 deficiency hENT1 deficiency poor response rate to GEM poor response rate to GEM

Interesting new trials are moving to the study of Interesting new trials are moving to the study of new molecules (independent of such new molecules (independent of such transporters). transporters).

ConclusionsConclusions

Gemcitabine remains the standard of care Gemcitabine remains the standard of care for pancreatic cancerfor pancreatic cancer

Need of trial designed to separate locally Need of trial designed to separate locally advanced from metastatic pancreatic advanced from metastatic pancreatic cancercancer

Need for better knowledge of Need for better knowledge of pharmacogenomicspharmacogenomics

Predictive tests for therapeutic responsePredictive tests for therapeutic response

Given the short life expectancy with advanced Given the short life expectancy with advanced pancreatic cancer, many patients deteriorate pancreatic cancer, many patients deteriorate quickly after DP, rendering further active quickly after DP, rendering further active treatment inappropriate. treatment inappropriate.

Perhaps as many as 1 in 3 patients are fit Perhaps as many as 1 in 3 patients are fit enough for consideration of a second line option: enough for consideration of a second line option: patients with good performance status (WHO 0-1)patients with good performance status (WHO 0-1) adequate haematological, renal and hepatic functionadequate haematological, renal and hepatic function

The earlier detection of disease progression or The earlier detection of disease progression or relapse with the use of advanced imaging relapse with the use of advanced imaging technologies and serum tumour markers is likely technologies and serum tumour markers is likely to expand the pool of suitable patients.to expand the pool of suitable patients.

Advanced pancreatic cancer: is it Advanced pancreatic cancer: is it possible a second line treatment?possible a second line treatment?

Palliative chemotherapy is usually administered Palliative chemotherapy is usually administered in an attempt of prolonging survival potentially in an attempt of prolonging survival potentially and providing quality of lifeand providing quality of life

How to treat a patient with advanced pancreatic How to treat a patient with advanced pancreatic cancer after gemcitabine failure?cancer after gemcitabine failure?

There is growing evidence supporting some There is growing evidence supporting some benefit of chemotherapy after gemcitabine in benefit of chemotherapy after gemcitabine in selected patients.selected patients.

Documents

Pathobiology and treatment of pancreatic cancer Mariacristina Di Marco Institute of Hematology end Medical Oncology “L e A Seràgnoli” Bologna University