New Agents in Pancreas Adenocarcinoma Eileen M. O’Reilly, M.D. Associate Member Memorial...

New Agents in Pancreas Adenocarcinoma

Eileen M. O’Reilly, M.D.Associate Member

Memorial Sloan-Kettering Cancer CenterAssociate Professor

Weill Medical College of Cornell University

Cytotoxic Therapies

Gemcitabine

FOLFIRINOX

FOLFIRINOX vs Gemcitabine Overall Survival

Number at riskGemcitabine

FOLFIRINOX

171 134 89 48 28 14 7 6 3 3 2 2 2

171 146 116 81 62 34 20 13 9 5 3 2 2

1 .0 0

0 .7 5

0 .5 0

0 .2 5

0 .0 0

Pro

ba

bilit

y

Mo nths0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6

Median 11.1 mo

Median 6.8 mo

HR = 0.57P < 0.0001

Conroy, T. NEJM, 2011

FOLFIRINOX Development

• FOLFIRINOX superior to gemcitabine: – OS, PFS and RR

• Investigation ongoing in locally advanced, neoadjuvant/borderline, adjuvant settings

• Relative benefit/tox for 3 vs 2 drug unknown?• Sequential vs. concurrent therapy?• Ability to combine with novel agents?

Von Hoff, D. J Clin Oncol, 2011

Ph. I-II Gemcitabine + Nab-Paclitaxel• N= 67• Phase II doses:

– Gemcitabine 1,000mg/m2 + nab-paclitaxel 125mg/m2 day 1, 8, 15, q28

• DLT’s sepsis, neutropenia• N= 44 treated at MTD

– RR 48%, med OS 12.2 months, 1-Year survival 48%

Von Hoff, D. J Clin Oncol, 2011

Gemcitabine + Nab-Paclitaxel

• Correlative results– Ca 19-9 decline associated with RR, PFS– SPARC (in stroma) correlated with OS– Mice with human pancreas xenografts:

combination of gemcitabine + nab-paclitaxel• Depleted stroma• Improved drug delivery, improved tumor response

• Phase III – data awaited

Novel Targets

New Targets, New DrugsTarget Class of Drug Example of Drug

IGF-1R Antibody to IGF-1RTyrosine kinase inhibitor

AMG 479, MK-0646, IMC-A12OSI-906

RAS/ MEK Oncolytic viral agentsMEK inhibition

ReovirusGSK1120212 (trametinib)

mTOR/ P13K/ AKT mTOR inhibitorAKT, P13K

Everolimus, temsirolimusMK-2206, XL-765, BKM-120

C-MET HGF-MET inhibitors, TKI Tivantinib (ARQ 197), Cabozantanib

Hedgehog/Stroma

Notch

Small molecule HH inhibitorStromal depletionGamma-secretase inhibitor

GDC-0449, IPI-926, LDE-225, PEGPH20R04929097, Anti-notch Ab

PSCA Antibody to PSCA AGS-1C4D4

SRC SRC, bcr-abl inhibitor Dasatinib, AZD 0530

Immunity Anti-CTLA4Vaccines

Ipilimumab, tremilumimabGVAX, telomerase, CRS-207

PARP PARP inhibitor AZD 2281, ABT-888, rucaparib

Hypoxia/Metabolism DNA cross-linking, alkylator TH-302, HIF-1α

Actionable Targets (Potentially) in Pancreas Adenocarcinoma

• Methodology– IHC biomarkers, e.g., Cox2, SPARC– Whole genome expression analysis (HT-12v4

beadchip, Illumina)– FISH analysis, e.g., C-Myc, EGFR, Her-2– Mutation analysis (Sanger sequencing), e.g., KRAS

• N= 1,029 patients – heterogeneous population

Von Hoff, D. Proceedings ASCO, 2012 Abst #4013

Immunohistochemistry (29 Biomarkers)Biomarker Expression

RRM1 (decreased) 77%

COX2 (increased) 74%

Thymidylate synthetase (negative) 73%

TOPO1 (increased) 61%

ERCC1 (negative) 57%

PGP (negative) 47%

SPARC (increased) 44%

TOPO2A (increased) 30%

PTEN (negative) 27%

MRPI (negative) 22%

PDGFR (increased) 20%

MGMT (negative) 8%

Von Hoff, D. Proceedings ASCO, 2012 Abst #4013

FISH & Mutation AnalysesTarget % Amplified (FISH) N= 695C-Myc 33%Her-2/neu 10%EGFR 2%TOPO2A -Target % Mutated (Sanger) N= 783KRAS 73%PIK3CA 7%BRAF -C-Kit -

Von Hoff, D. Proceedings ASCO, 2012 Abst #4013

IGF-1R Targeting

Randomized Phase IIIGF-1R, TRAIL Targeting

Stratify PS 0 vs 11: 1: 1 randomizationPrimary endpoint: 6-month overall (24%↑ (45→69%) 80% p) survival

Kindler, HJ. J Clin Oncol, 2010 (abst # 4035)NCT00630552

Metastatic Pancreas Ca

N= 120

Gemcitabine + Placebo

Gemcitabine + AMG 655 10 mg/kg

RANDOMIZE

Gemcitabine + AMG 479 12 mg/kg

Results: Rand. Phase II (N= 125)Gemcitabine +

AMG 479(open-label)

Gemcitabine + AMG 655(blinded)

Gemcitabine + Placebo(blinded)

6-month OS 57% 59% 50%12-month OS 39% 20% 23%Median OS 8.7 mths 7.5 mths 5.9 mthsMedian PFS 5.1 mths 4.0 mths 2.1 mthsGd 3-4 ANC 18% 22% 13%Gd 3-4 Platelets 15% 17% 8%Gd 3-4 Fatigue 13% 12% 5%Hyperglycemia 15% 2% 35

Kindler, HJ. J Clin Oncol, 2010 (Abst #4035)

HR OS 0.67, p=0.12; HR PFS 0.65, p=0.07

NCT01231347

Phase III: Metastatic Pancreas Adenoca(GAMMA Trial)

Gemcitabine + Placebo

RANDOMIZE

Gemcitabine + AMG-479(12 mg/kg, 20 mg/kg)

UntreatedMetastatic

Pancreas CaN= 825

Primary endpoint: Overall survivalCorrelatives: IGF, IGF-BP levels and outcome

SWOG S0727Phase I- Randomized Phase II:

Value to IGF-1R + EGFR inhibition in PC?

• N= 10 dose determination of cixutumumab (IgG mAb) + gemcitabine, erlotinib

• Randomized phase II– Cixutumumab (IMC-A12) 6mg/kg, Gemcitabine

1000mg/m2, Erlotinib 100mg/daily– Gemcitabine, Erlotinib– Primary endpoint PFS

P. Philip. Proceedings ASCO, 2012 Abst #4019

SWOG S0727 ResultsGem/Erlotinib/Cixutumumab

N= 57Gem/Erlotinib

N= 59Median PFS 4 months 4 months

P= 0.96

Philip, P. Proceedings ASCO, 2012 Abst #4019

Despite strong preclinical synergy for IGF-1R and EGFR inhibition – clinical data negative

Biomarkers: Plasma [IGF], IGF mRNA predictive?

Prostate Membrane Stem Cell Antigen Targeting

Prostate Stem Cell Antigen (PSCA)

• AGS-PSCA fully human IgG1 mAb against PSCA

• PSCA: 87-100% of prostate tumors; ~60% of panc ca

• AGS-PSCA + gemcitabine inhibited tumor growth and metastases in orthotopic HPAC tumors in mice better than either alone

Gu, Z. Oncogene, 2000. Zhigang, Z. W J Surg Oncol, 2004. Kan, K-R. J Urol, 2004. Lam, J.S. Clin Can Res, 2005

Wolpin, B. J Clin Oncol, 2011 (Abst #4031). Hidalgo, M. World GI ESMO Congress, 2011

Randomized Phase II Gemcitabine +/- AGS-1C4D4

Stage IV Panc CaECOG 0-12: 1 RandomizationN= 165

Primary Endpoint6-month Survival Rate45% → 65%

Secondary EndpointsOS, PFS, RR, ToxicityEffect of PSCA on OS, PFS, RR

GemcitabineN= 68

RANDOMIZE

Gem + AGS-1C4D4N= 137

Randomized Phase II Gemcitabine +/- AGS-1C4D4

Gemcitabine(N= 63)

Gem + AGS(N= 133) P-Val

6-month Survival 44.4% 60.9% 0.016Median OS 5.53 mths 7.9 mths 0.06PSCA + (N= 66)6-month Survival

8.5 mths57%

10.3 mths79%

0.260.03

PSCA - (N= 57) 4.6 mths 4.5 mths 0.27

Wolpin, B. J Clin Oncol, 2011 (Abst #4031); Hidalgo, M. World GI ESMO Congress, 2011

Embryonic Pathway TargetingStromal Depletion

Hedgehog Pathway and PC

• Developmental pathway – neural, teeth, GI tract, lungs, etc

• Expressed abnormally in 70-80% pancreas adenoca• Activation of pathway important in carcinogenesis,

progression of panc ca• Hh pathway: stroma/desmoplasia, stem cells• SMO inhibitors

– Cyclopamine, GDC-0449, IPI-926, LDE225

Von Hoff, D. NEJM, 2009. Thayer, S. Nature, 2003. Feldmann, G. Gut, 2008. Jimeno, A. Mol Can Ther, 2009. Oliver, K. Science, 2009

Trials Evaluating Hh Pathway Inhibition in Pancreas Adenocarcinoma

Phase N Regimen Stage NCTII ~80 Gem, Nab-Paclitaxel + GDC-0449 IV 01088815

IB-Rand. II 105 Gemcitabine + GDC-0449/ P IV 01064622IB- Rand II 122 Gemcitabine + IPI-926/ P IV 01130142IB- Rand II FOLFIRINOX + IPI-926 III-IV 01383538II (pre-op) 20 GDC-0449 I-II 01096732IB- Rand II 30+ Gemcitabine + LDE225/ P III-IV 01487785

P= Placebo. GDC-0449= Vismodegib. IPI-926= Saridegib

Preliminary data Gemcitabine +/- IPI-926 – Survival favors control arm

Rand. Phase II: Gem + Vismodegib/PInterim Analysis after 50% PFS Events

Gem/ Vismodegib (N= 53)

Gem/ Placebo (N= 56)

CR/ PR - / - 3%/ 11%Stable Disease 49% 31%Med. PFS (95% CI) 3.7 months (2.4- 4.6) 2.4 months (1.9- 3.2)

Adjusted HR 0.92 (0.52- 1.63)Med. OS (95% CI) 6.3 months (4.9- 7.8) 5.4 months (4.2- 8.0)

Adjusted HR 0.97 (0.47- 2.01)One- Year survival 24% 24%

Catennaci, D. Proceedings ASCO, 2012 Abst # 4022

Correlatives: [Shh], CT perfusion

Phase IB, Randomized Phase IIGemcitabine + PEGPH20

• Pancreas cancers – high level of hyaluronan• Preclinical activity for PEGHP20

– Degrades hyaluronan– Facilitates drug delivery– Reduces interstitial fluid pressure– Improved effect with cytotoxics

• Ongoing dose-finding phase IB

Jacobeth, M. Gut, 2012. Hingorani, S. Cancer Cell, 2012. NCT01453153

Biomarker Driven Therapies

Biomarker Classification

• Prognostic– Classify patients into clinical subgroups with expected

distinct clinical outcomes

• Predictive– Identify patients who are likely to be sensitive and/ or

resistant to a specific agent

Biomarkers in Pancreas Adenoca

• Few and none validated…yet• Ca 19-9 most studied

– Tumor-associated antigen

• Candidate biomarkers include– Therapy: hENT-1, dCK, ERCC1, Topo-1, TS,

gemcitabine SNP’s– Tumor: Kras, SPARC, BRCA, SMAD4, S100A2, CXCR4

Gemcitabine Uptake & Metabolism

Adapted. Ko A, et al. Gastroenterol, 2009

ENT1: equilibrative nucleoside transporter

CNT: concentrative nucleotide transporters

DCK: deoxycytidine kinase (rate-limiting)

RRM 1/2: ribonucleotide reductase

DCTD: deoxycytidine monophosphate deaminase

CDA: cytidine deaminase

hENT1 – Preclinical Data

• Cell line data in PC indicate hENT1 major transporter of gemcitabine

• Pharmacologic inhibition of hENT1 renders cells gemcitabine resistant

• Correlation [hENT1] and chemosensitivity

Garcia-Manteiga J, et al. Clin Can Res, 2003. Mackey JR, et al. Can Res, 1998. Mori, R. Onc Rep 2007. Nakano Y. Br J Can, 2007. Achiwa H. Cancer Sci, 2004. Galmarini CM, Haematologica, 2006

hENT1 – Clinical Data

• Surgical series– hENT1 (+) PC had significantly longer survival compared to

hENT (–): 13 vs 4 months

• Retrospective (N= 83)– hENT1 mRNA in resected PC associated with ↑OS– hENT1 low vs high: 9.3 vs 25.7 mths, p<0.001

• Retrospective (N= 434)– High hENT1, dCK predicts benefit from gemcitabine

Spratlin J, et al. Clin Can Res, 2004. Giovannetti E, et al. Can Res, 2006. Marechal, R. World GI ESMO, 2011 (Abst # O-00008)

hENT1 is Predictive for Outcome after Gemcitabine; Not Prognostic

Farrell, J. Gastroenterol, 2009

N= 198 Adjuvant Gemcitabine or 5-FU + 5-FU/RT (RTOG 97-04)Overall Survival: Categorized by hENT1 level

NCT01124786; NCT01233375

CO-1.01 (CP-4126)

• Gemcitabine-5’-elaidate, hENT1 independent• Xenografts – Improved activity over gemcitabine• Randomized Ph II untreated metastatic PC (LEAP):

Gemcitabine vs CO-1.01– Primary: OS in hENT1 (low); all; hENT1 (high)– N= 360

• Single-arm 2nd-line: Gemcitabine-refractory disease (no hENT1)

Pancreas Cancer & BRCA Mutations

• Rare in general population– Increased prevalence in Ashkenazi population– Founder mutations

• BRCA 1 185delAG, 5832insC• BRCA 2 6174delT

• MSKCC data– Resected pancreas ca 5.5% BRCA mutation (selected on

basis of Ashkenazi heritage)– Ashkenazi breast-pancreas families 14.2% BRCA positive

Ferrone, C. J Clin Oncol, 2009. Stadler, ZK. Cancer, 2012

PC, BRCA & PARP Inhibition• BRCA 1, 2 function integral to DS DNA repair• PARP inhibition established value in ovary,

breast cancer with BRCA-related mutations• Preclinical data in PC – Capan-1

– Very susceptible to KU-0058684– Susceptible to alkylating agents

• Anecdotal clinical data in PC

Friedensen. Med Gen Med, 2005. Couch. Can Epid Biom Prev, 2007. McCabe. Cancer Biol Therapeut, 2005. Goggins, M. Cancer Res, 1996

Poly (ADP-Ribose) Polymerase (PARP)DNA damage –endogenous, cytotoxics,radiation, etc.

If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks

Loss of Functional BRCA-1 or 2 Affects DNA Double-Strand Break Repair Pathway

Ashworth, et al. J Clin Oncol, 2008

Pt # StageBRCA

Mutation1st line Response 2nd line Response 3rd line Response

OS(mo)

1 T2N0M0 BRCA1Surgery & Adjuvant Gemcitabine

Relapse16.3 mo

AZD 2281/ GemPR 2 moPOD 4.5 mo

FOLFIRINOXAssessment pending

24.7, AWD

2 T3N0M0 BRCA2Surgery & Adjuvant GTX

Relapse 12.8 mo Pending 13.4, AWD

3 T3,N0, II BRCA 2*7535delA

Surgery & Adjuvant Gemcitabine

Relapse 11 moFOLFIRINOX – FOLFOX

CR 3 moRx d/c for toxicityLR 8mo

Cisplatin/5FU -CapecitabineRT

PR 38.4, AWD

4T3,N1,

IIBBRCA2

*4075DGT

Surgery & Adjuvant Gem/ Cisplatin

Relapse at 14 mo 14.7, AWD

5T3, N1

IIB BRCA2Surgery & Adjuvant Gem, 5FU/RT

Relapse at 13 mo Gem/oxaliplatinPRPOD 6 mo

AZD-2281 SD 6 mo 34.3, AWD

6 T4, III BRCA2Y1894X

GTX POD at 5 mo FOLFOX Response at 3 mo 8.8, AWD

7 T4, III BRCA2Gem/ Cisplatin→ Gem /RT→ gem

SD /minor responsePOD 11 mo

FOLFOX POD 2 mo 20.4,DOD

8 IV BRCA2*6174delT

Unknown POD at 7 mo 9.1, DOD

9 IV BRCA1*4603G->T

Gem/ Capecitabine

PR 3 mo FOLFOX POD 14 moFlavopiridol/ Docetaxel

POD 2 mo 27.6, DOD

10 IV BRCA1*187delAG

Gem + AZD2281PR 2 mo, POD 6 m

FOLFOX→ CPT-11/ Gem(Oxali d/c reaction)

POD 2.5 moABT-888 & Temozolomide (1 cycle)

POD 6 weeks13.7, DOD

11 IV BRCA2 No treatment 1.0, DOD

12 IV BRCA1*IVS8+7G>A

Gem & AZD 2281PRPOD 7 mo

Gem/ Capecitabine

POD 2 mo FOLFOX POD 11.5 ,DOD

13 IV BRCA2 Gem/ CisplatinPRPOD 9 mo

FOLFOX POD 2 mo MK 2206 POD 2 mo 15.2, AWD

14 IVBRCA2

IVS13 -2A>T, V211I (859 G>A)

Gem/ OxaliplatinPRSD 7 mo

9.2, AWD

15 IV BRCA2 Gem/ Oxaliplatin Pending 1.5, AWD

MSKCC: BRCA Mutation Carriers with Panc Adenoca

AWD: Alive with disease, DOD: Dead of disease, NED: No evidence of disease POD: Progression of disease, PR: Partial response, SD: Stable disease GTX: Gemcitabine, docetaxel, capecitabine

Key Observations:Activity to platinum-agentsActivity to PARP inhibitors

(Lowery, MA, O’Reilly, EM, The Oncologist, 2011)

Randomized Phase II Cisplatin + Gem +/- Veliparib in BRCA/ PALB2 mutated PC

• Eligibility Untreated LA or metastatic PC with BRCA 1-2, PALB2 m ECOG 0-1

Randomized phase II (N= 50)Arm A: Cisplatin + gemcitabine + veliparibArm B: Cisplatin + gemcitabine

Gemcitabine + cisplatin d3+10, q 21Veliparib dosing day 1-12, BID, PO

Dosing veliparib from ongoing phase I (NCT01282333)

PI: E.M. O'Reilly (CTEP, Lustgarten Foundation)

Emerging Therapies in PC

• FOLFIRINOX– Active, increasingly integrated into practice– Feasibility of adding novel agents?

• New cytotoxic agents− Nab-paclitaxel/ gemcitabine; C0-1.01

• IGF-1Ri, Hh pathway inhibitors? • TH-302, PEGPH20, PARPi – early

• Increasing pre-clinical support• Randomized phase II trials – platform

The Future in Pancreas Cancer Therapeutics …

• Cytotoxics are here to stay• Improved molecular classification• Incremental therapeutic improvements• Profiling tumors e.g., BRCA/ PALB2, wild-type

ras, SMAD4 retained, ERCC1, hENT1?• Ongoing goals: enhanced understanding

tumor biology, preclinical models, biomarker development, validation and collaboration