Updates On Upper Gastrointestinal Malignancies 2015

Tanios Bekaii-Saab, MD Chief , Section of Gastrointestinal Cancers Disease Specific Research Group Leader

Professor of Medicine and Pharmacy OSUCCC- Arthur James Cancer Hospital

Gastric and Gastro-Esophageal Cancers

Advanced Gastro-esophageal Cancers

• Marginal differences between chemo doublets and triplets that perhaps do not justify the differences in toxicities.

• Trastuzumab should be considered as an option added to a platinum and 5FU in the presence of Her-2 overexpression

• Ramucirumab +/- Paclitaxel is a standard second line regimen

Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled Trial of Rilotumumab Plus Epirubicin,

Cisplatin, and Capecitabine as First-line Therapy in Patients with Advanced MET-positive Gastric or

Gastroesophageal Junction Cancer: RILOMET-1 Study

D. Cunningham,1 N. C. Tebbutt,2 I. Davidenko,3 A. M. Murad,4 S. Al-Batran,5 D. H. Ilson,6 S. Tjulandin,7 E. Gotovkin,8 B. Karaszewska,9 I. Bondarenko,10 M. A. Tejani,11 A. A.

Udrea,12 M. Tehfe,13 N. Baker,14 K. S. Oliner,15 Y. Zhang,15 T. Hoang,15 R. Sidhu,15 D. V. T. Catenacci16

1Royal Marsden Hospital, Sutton, Surrey, UK; 2Austin Health, Heidelberg, VIC, Australia; 3Krasnodar City Oncology Center, Krasnodar, Russia; 4Hospital das Clínicas da Universidade Federal e Minas Gerais, Horizonte, Brazil; 5Krankenhaus Nordwest, University Cancer Center, Frankfurt,

Germany; 6Memorial Sloan Kettering Cancer Center, New York, NY, USA; 7Russian Cancer Research Center, Moscow, Russia; 8Regional Budgetary Institution of Public Health Ivanovo Regional Oncology Dispensary, Ivanovo, Russia; 9Przychodnia Lekarska Komed Oddzial Jednego Dnia, Konin, Poland; 10Dnipropetrovsk Medical Academy, City Multifield Clinical Hospital 4, Dnipropetrovsk, Ukraine; 11University of Rochester

Medical Center, James P Wilmot Cancer Center, Rochester, NY, USA; 12SC Medisprof SRL, Cluj-Napoca, Romania; 13Centre Hospitalier de L'Universite de Montreal Notre-Dame, Montreal, QC, Canada; 14Amgen Limited, Cambridge, UK; 15Amgen Inc., Thousand Oaks, CA, USA; 16The

University of Chicago, Chicago, IL, USA

MET and Targeting in EGC • MET gene alterations in 6% gastric ca (TCGA) • MET overexpression (IHC) 40-60%+ • MET/HGF altered – poor prognostic subgroup • Early data suggests MET amplification biomarker

of response to MET-targeted agents with MET TKI

Bass. Nature, 2014. Kwak, E. J Clin Oncol, 33, 2015 Suppl 3; abst 1. Iveson, T. Lancet Oncol, 2014

Cunningham, D. J Clin Oncol 2015;33:4000 [abstr]

Phase III ECX +/- Rilotumumab (RILOMET -1)

Stratification: PS, Locally advanced vs Metastatic Primary endpoint: Overall survival (90% power, HR 0.69, N= 600)

Secondary endpoints: PFS, ORR, DCR, Safety, Immunogenicity, PK

Untreated Gastric/GE jn MET+ (≥ 25% cells tumor membrane staining IHC)

HER2- ECOG 0-1

N= 600 ECX + Placebo 15 mg/kg

q3 weeks Maintenance: placebo

ECX + Rilotumumab 15 mg/kg q3 weeks

Maintenance: Rilotumumab

R A N D O M I Z E

Overall Survival: ECX +/- Rilotumumab

More deaths in the rilotumumab arm, due to disease progression Study terminated 11/2014 (DSMC) Cunningham, D. J Clin Oncol 2015;33:4000 [abstr]

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304 209 121 66 32 15 3 1305 241 140 81 41 13 1 1

RilotumumabPlacebo

Patients at risk

Median OS months

ECX + Rilotumumab 9.6 (7.9–11.4)

ECX + Placebo 11.5 (9.7–13.1)

Unstratified HR: 1.36 (1.05–1.75); P= 0.021

Clinical activity of AMG 337, a highly selective oral MET kinase inhibitor, in adult patients with MET-amplified

gastroesophageal junction, gastric, or esophageal cancer

Eunice L Kwak,1 Patricia LoRusso,2 Omid Hamid,3 Filip Janku,4 Muaiad Kittaneh,5 Daniel VT Catenacci,6 Emily Chan,7 Tanios S Bekaii-Saab,8 Benny Amore,9 Yuying

C Hwang,10 Rui Tang,10 Gataree Ngarmchamnanrith,10 David S Hong4

1Massachusetts General Hospital, Boston, MA; 2Yale Cancer Center, New Haven, CT; 3The Angeles Clinic and Research Institute, Los Angeles, CA; 4The University of Texas MD Anderson Cancer Center, Houston, TX; 5Karmanos Cancer Institute, Wayne State University, Detroit, MI; 6The University of Chicago, Chicago, IL; 7Vanderbilt University Medical Center, Nashville, TN; 8The Ohio State University Comprehensive Cancer Center, Columbus, OH; 9Amgen Inc., Seattle, WA; 10Amgen Inc., Thousand Oaks, CA

RECIST Responses in Patients With MET-Amplified GEJ/Gastric/Esophageal Cancer

• 13 patients with MET-amplified GEJ/gastric/ esophageal cancer treated to date; ORR = 8/13 (62%)

%∆

SO

D Fr

om B

asel

ine

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

PR per RECIST 1.1

4wk +21wk

4wk 17wk

9wk 17wk

4wk 29wk

4wk 25wk

4wk +96wk

4wk +155wk

aLocal read as of Dec 8, 2014. bLocal read as of Sept 10, 2014. Central read as of Sept 18, 2014 for all other patients. One patient not shown with non-target lesions had clinical progression.

b

4wk +9wk

a

On active treatment Off treatment

Time to response: On treatment:

Summary Anti-MET Therapies in EGC • MET targeting with rilotumumab

– No value in gastric/GE jn cancers in any MET positive subgp – Worse outcome with rilotumumab, HR 1.36 – Marked difference from phase II results; correlative analyses pending

• Substantial evidence that MET antibody targeting not of value – MetGastric*: FOLFOX +/- onartuzumab (anti-MET ab)

Negative phase III med OS 11.3 vs 11 mths, HR 0.82, p= 0.244 • Promising activity with AMG337 in MET amplified GE cancers • Focus: other strategies – angiogenesis, anti-HER2, FGFR, cancer

stem cell, immune therapies, and biomarker identification

*Shah, M. J Clin Oncol 2015;33:4012 [abstr]

Immune Therapies in EGC • PD-L1, PD-L2 associated with poor prognosis in esophago-gastric

cancers – Increased expression in certain subsets of gastric ca (EBV)

• Recognition that GI cancers may be targeted by immune system

– Higher mutation burden

• Pembrolizumab – IgG4 anti-PD-1, broad anti-tumor activity blocks PD1 interaction with

ligands PD-L1 and PD-L2

Cancer Genome Atlas Research Network, Nature, 2014. Alexandrov, Nature, 2013

Relationship Between PD-L1 Expression and Clinical Outcomes in Patients With

Advanced Gastric Cancer Treated With the Anti-PD-1 Monoclonal Antibody

Pembrolizumab (MK-3475) in KEYNOTE-012 Yung-Jue Bang,1 Hyun Cheol Chung,2 Veena Shankaran,3

Ravit Geva,4 Daniel Catenacci,5 Shilpa Gupta,6 Joseph Paul Eder,7 Raanan Berger,8 Archana Ray,9 Marisa Dolled-Filhart,9

Kenneth Emancipator,9 Kumudu Pathiraja,9 Jared Lunceford,9 Jonathan Cheng,9 Minori Koshiji,9 Kei Muro10

1Seoul National University Hospital, Seoul, South Korea; 2Yonsei Cancer Center, Yonsei University College of Medicine, Seoul,

Korea;3University of Washington, Seattle, WA; 4Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 5University of Chicago, Chicago, IL, USA; 6H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;

7Yale University, New Haven, CT, USA; 8Sheba Medical Center, Tel Hashomer, Israel; 9Merck & Co, Inc, Kenilworth, NJ, USA; 1Aichi Cancer Center Hospital, Nagoya, Japan

KEYNOTE-012: Gastric Cancer Cohort

65/162 = 40% PD-L1+ (+ in immune cells or ≥ 1% tumor cells by 22C3 ab) Primary Endpoint: Overall Response Rate q 8 wks central review Median age 63 yrs; 56% ECOG 1; 66% ≥ 2 lines therapy; 19 Asia, 20 ROW

Previously treated Gastric/GE jn

ECOG 0-1 PD-L1 Positive

N= 39

Pembrolizumab 10 mg/kg q 2 wks

Bang, Y-J. J Clin Oncol 2015;33:4001 [abstr]

Pembrolizumab in Gastric Ca: Maximum Percentage Change From Baseline in Tumor Size, N= 32

aOnly patients with measurable disease per RECIST v1.1 by central review at baseline and at least 1 post-baseline tumor assessment were included (n = 32). Analysis cut-off date: March 23, 2015.

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53.1% decrease in target lesions

Overall RR 22%

Conclusions : PD1 in GCA • Significant activity of pembrolizumab in advanced gastric cancer

– 22% RR (central), 40 week duration of response, 66% OS at 6 mths, median OS 11.4 mths

– PD L1 expression – preliminary correlation with outcome – MSI-H? – Supporting data from KEYNOTE-028 in esophageal ca*

• 41% PD-L1+; N= 23; ORR 23% (N= 5)

• Ongoing trials in gastric/GE junction – Phase II pembrolizumab +/- cisplatin/5-FU (KEYNOTE-059): PD-L1 + or - – Phase III pembrolizumab vs paclitaxel 2nd-line (KEYNOTE-061) – Phase III nivolumab vs placebo in previously treated (Japan) – Phase IB/II MEDI4736 + tremilumumab, MEDI4736 or tremi. (2nd-line)

*Doi, T. J Clin Oncol 2015;33:4010 [abstr]. NCT02335411. NCT02267343

Pancreas Neuroendocrine Tumors

Pancreas Neuroendocine Tumors • Several treatment options

– Observation – Regional therapies e.g., embolization, SIRT, surgery – Somatostatin analogs

• Octreotide, lanreotide • Peptide Receptor Radionuclide Therapy

– Cytotoxic therapies • Temozolomide, streptozocin, fluoropyrimidines

– Pathway directed agents • mTOR: Everolimus • VEGF: Sunitinib

Randomized Phase II Study of Everolimus vs. Everolimus plus Bevacizumab in Patients with Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

CALGB 80701 (Alliance)

Matthew H. Kulke,1 Donna Niedzwiecki,2 Nathan R. Foster,3 Briant Fruth,3 Pamela L. Kunz,4 Hagen Kennecke,5 Edward M

Wolin,6 Alan P. Venook7 1. Dana-Farber Cancer Institute, Boston, MA; 2. Alliance Statistics and Data Center and Department of Biostatistics and

Bioinformatics, Duke University, Durham, NC; 3. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN 4. Stanford Cancer Institute, Palo Alto, CA 5. Vancouver Center: BC Cancer Agency, Vancouver, CA 6. University of Kentucky,

Lexington, KY; 7. University of California San Francisco, San Francisco, CA

Kulke, M. J Clin Oncol 2015;33:4005 [abstr]

Randomized Phase II CALGB 80701

Stratification: Prior SSA, Prior cytotoxic therapy, Prior sunitinib Primary endpoint: Progression-free survival (9 14 mths, 90% power, 1-sided alpha 0.15)

Advanced PNET POD within 12 mths

No prior mTOR/ bevazicumab therapy

N= 150 Everolimus 10 mg daily +

Bevacizumab 10 mg/kg q 2 wks + Octreotide LAR

Everolimus 10 mg daily + Octreotide LAR

R A N D O M I Z E

CALGB 80701: PFS by Treatment Arm

Summary CALGB 80701, PNET’s • Important trial evaluating VEGF and mTOR pathway

inhibitors – Higher RR, PFS, but more AE’s for everolimus and bevacizumab

• Data do not support use of everolimus and bevacizumab outside of a trial, but continued focus on these pathways important – Sequential vs concurrent? – Patient selection – Newer agents, different disease settings – Sequencing of treatment modalities

Pancreas Adenocarcinoma

• Gemcitabine and Nab-Paclitaxel (GA) is a preferred standard • FOLF + MM-398 , once approved will become a standard for second line treatment following

failure with GA • FOLFIRINOX can be considered in patients < 70 y.o. , with PS 0-1 , normal bilirubin and no

significant comorbidities • Kitchen sink approach vs. Sequential approach • Perhaps a better choice for patients with borderline or locally advanced pancreas

cancer. • mOS has not reached the 1 year despite all these agents • Ruxolitinib, a JAK1/JAK2 inhibitor, in combination with capecitabine exhibited clinical activity

relative to capecitabine alone in second-line metastatic pancreatic cancer in select patients with CRP levels > 13

• JANUS 1 and 2 underway

Advanced Pancreas Cancer

A modified regimen of gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer

Chemotherapy Dose Administration Frequency Gemcitabine 1000 mg/m2 IVPB over 30 min given q2weeks Nab-paclitaxel 125 mg/m2 IVPB over 30 min

Survival analyses N Median (months) 95% CI (months) Progression free survival 57 5.4 4.1; 7.4

Overall survival 57 10 5.9; 13

Toxicities N(%) Grades All grades 3 / 4

Neutropenia 12 (25) 5 (10) Febrile neutropenia 1 (2.1) -- Thrombocytopenia 9 (15) 3 (2) Neuropathy 13 (27) 1 (2) Fatigue -- 3 (6)

Krishna K et al. Abstract 366 – ASCO GI 2015

High Response Rate and PFS with PEGPH20 Added to Nab-Paclitaxel/Gemcitabine in Stage IV Previously Untreated Pancreatic Cancer Patients with High-HA

Tumors: Interim Results of a Randomized Phase 2 Study

Sunil Hingorani, MD, PhD1, William Harris, MD2, Andrew Hendifar, MD, MPH3, Andrea Bullock, MD4, Wilson Wu, PhD5, Ya Huang5, Ping Jiang, MD5

1Fred Hutchinson Cancer Research Center, Seattle, WA 2University of Washington School of Medicine, Seattle, WA

3Cedars Sinai Medical Center, Los Angeles, CA 4Beth Israel Deaconess Medical Center, Boston, MA

5Halozyme Therapeutics, Inc., San Diego, CA

Microenvironment in Pancreas Adenocarcinoma

• Hypovascular, hypoxic

• Physical stromal barrier – Hyaluronan (HA)

glycosaminoglycans – Increased EMT, chemoresistance

• PEGPH20 rhuman hyaluronidase

– Depletes HA in stroma – Improves drug delivery

Jaocobetz, et al. Gut, 2013. Courtesy: J. Shia (MSKCC)

Hingorani, S. J Clin Oncol 2015;33:4006 [abstr]

Randomized Phase II Gemcitabine + nab-Paclitaxel +/- PEGHPH20

Primary endpoint: Progression-free survival Secondary endpoints: PFS by Hyaluronan, ORR, OS, Safety, Correlatives

Untreated Met Panc Adenoca

KPS 70-100% N= 260 planned

nab-Paclitaxel + Gemcitabine

nab-Paclitaxel + Gemcitabine + PEGPH20

3ug/kg SQ x 2 wk (C1)wkly

R A N D O M I Z E

Study Conduct • Hold April 2014

– DSMC/ FDA – increased thromboembolic (TE) events

– Re-opened later 2014 • Rigorous screening for TE’s • Primary prophylaxis: enoxaparin

• Data presented is early

0 2 4 6 8 1 0 1 2 1 40

5 0

1 0 0

S tu d y D u ra tio n (m o n th s )

K-M

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e of

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e S

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val (

%)

A G

P A G

Rand Phase II: PFS In HA-High Pts Treated with PEGPH20 + nab-P+Gem (PAG) vs AG

AG 4.3 months

PAG 9.2 months

HR 0.39 (0.15, 1.04)

Summary PEGPH20 + nab-P+Gem • Interesting early data in HA high patients

– Improved PFS (HR 0.39), improved response rate, trend OS – Phase III planned in HA high patients – needs validation

• Value to primary prophylaxis with enoxaparin, supports CONKO-004

• Key theme of randomized phase II trials, biomarker exploration

• Maturation of series of randomized phase II’s with gemcitabine + nab-paclitaxel

backbone over next 1-2 yrs – Many promising agents/targets: PEGPH20, Notch, stem cell, wnt-β-catenin, JAK/STAT,

immunotherapy, etc. – Treatment selection – CRP, homologous repair deficient, Hyaluronan-high?

Pelzer, U. J Clin Oncol, 2015

Novel Therapy Approaches Panc Adenoca

Garrido-Laguna, I, Hildalgo, M. Nat Cancer Reviews, 2015

Resectable Disease : The role of Adjuvant Therapy

• Pancreas cancer is a systemic disease

• The role of adjuvant therapy following resection of pancreas cancer is well established

• Patients spend 25-30% of their average lifetime on adjuvant therapy.

• What type of adjuvant therapy? • Gemcitabine or b5FU are standard for treating patients with resected

pancreas cancer ( R0 and R1) based on best Level 1 evidence. • Favor Gemcitabine Better toxicity profile

• Many questions about the role of radiation remain unresolved, with toxicity and

cost concerns, and a lack of proven added survival benefit to chemotherapy alone.

Adjuvant Therapy • Current investigational adjuvant questions

– Value of multi-drug cytotoxic combinations? • FOLFIRINOX vs gemcitabine (PRODIGE) • Gemcitabine + nab-paclitaxel vs gemcitabine (APACT) • Gemcitabine + capecitabine vs gemcitabine (ESPAC-04)

– Role of adjuvant fluoropryimidine-based RT (RTOG 0848)?

– Value of addition of EGFR-TKI erlotinib (CONKO-005)?

Sinn M, Liersch T, Gellert K, Messmann H, Bechstein W, Waldschmidt D, Jacobasch L, Wilhelm M, Rau BM, Grützmann R, Weinmann A,

Maschmeyer G, Pelzer U, Stieler JM, Striefler JK, Ghadimi BM, Bahra M, Oettle H, Dörken B, Riess H

Charité – Universitätsmedizin Berlin, Germany In cooperation with AIO Germany (Arbeitsgruppe Internistische Onkologie)

CONKO-005 Adjuvant therapy in

R0 resected pancreatic cancer patients with Gemcitabine plus Erlotinib vs Gemcitabine for 24 weeks

Sinn, M. J Clin Oncol 2015;33:4007 [abstr]

Phase III Open-Label Trial (CONKO-005)

Stratify: Nodal status N0 vs N1, Surgery, T stage, KPS Primary Endpoints: DFS 14 18 mths, power 80%, 0.05 Secondary endpoints: OS, Safety

R0 Resected Panc Adenoca

KPS 70-100% N= 436 Gemcitabine

N= 217

Gemcitabine + Erlotinib 100mg PO daily

N= 219

R A N D O M I Z E

Overall Survival CONKO-005

Sinn, M. J Clin Oncol 2015;33:4007 [abstr]

Gem + E N= 219

Gemcitabine N= 217

DFS 11.6 mths 11.6 mths HR 0.89 (95% CI 0.72- 1.1)

Med OS 24.6 mths 26.5 mths

HR 0.90 (95% CI 0.71-1.15)

Estimated Survival

2 years 54% 53%

5 years 28% 19%

Conclusions Adjuvant Therapy • Addition of erlotinib – not meaningful

– CONKO-005 first mature erlotinib data set in adjuvant setting

• No improvement in DFS, OS, no relationship between rash grade and improved DFS

• Correlative analyses pending – LAP-07* (locally advanced): no benefit to erlotinib – RTOG 0848 (adjuvant) revised 2014: removed erlotinib

randomization *Hammel, P. J Clin Oncol 2013;31:LBA4003 [abstr]

HCC

38

HCC

• Sorafenib in Child’s Pugh A patients is SOC in advanced disease

• Sorafenib may be SELECTIVELY used in select patients with Child’s Pugh B

• Sorafenib MAY NOT be used following locoregional procedures , including curative ones.

Phase 1/2 Safety and Antitumor Activity of Nivolumab in Patients With Advanced

Hepatocellular Carcinoma (HCC): CA209-040

Anthony B. El-Khoueiry,1 Ignacio Melero,2 Todd S. Crocenzi,3 Theodore H. Welling III,4 Thomas Yau,5 Winnie Yeo,5 Akhil Chopra,6

Joseph F. Grosso,7 Lixin Lang,7 Jeffrey Anderson,7 Christine dela Cruz,7 Bruno Sangro2

1University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 2Clinica Universidad de Navarra and CIBERehd, Pamplona, Spain; 3Providence Cancer Center, Portland, OR, USA; 4University of Michigan, Ann Arbor, MI, USA; 5University of Hong Kong, China; 6Johns Hopkins Singapore International Medical Centre, Singapore; 7Bristol-Myers

Squibb, Princeton, NJ, USA

Abstract LBA 101

Maximal Change in Target Lesions From Baseline

120

100

80

60

40

20

0

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Patients (N = 40)†

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ge in

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e, %

Uninfected

HCV

HBV

Confirmed response *

* * * * * *

* * †2 uninfected patients not shown: 1 had disease progression before the first assessment; 1 had a maximal change of +23% ‡Patient with resolved HCV infection

‡

41

Take Home Messages: Non-CRC GI • Few practice changes in 2015, however:

– Highlights • Emering role of immune-based therapies in EGC and HCC • Emerging potential for biomarker selection in pancreas

adenocarcinoma: Hyaluronan-High – needs validation

– Lowlights • End of MET ab targeting in EG cancers • End of erlotinib era in pancreas adenocarcinoma

Courtesy Eileen O’Reillye ,MD. MSKCC