new developments in pancreatic cancer · espac-4 – gem vs gem ... • well designed and executed...

New Developments in Pancreatic Cancer

Edward J. Kim, M.D., Ph.D.

EDWARD KIM, MD, PHD

PANCREATIC CANCER: EMERGING STRATEGIES

RELEVANT FINANCIAL RELATIONSHIPS IN THE PAST TWELVE MONTHS BY PRESENTER OR SPOUSE/PARTNER.

GRANT/RESEARCH SUPPORT: CELGENE, HALOZYME, MERCK, BOSTON BIOMEDICAL, EPICENTRX

CONSULTANT: ARMO, VICUS

THE SPEAKER WILL DIRECTLY DISCLOSURE THE USE OF PRODUCTS FOR WHICH ARE NOT LABELED (E.G., OFF LABEL USE) OR IF THE PRODUCT IS STILL

INVESTIGATIONAL.

14th Annual California Cancer Conference Consortium

August 10-12, 2018

Current 1st line standard of care options

Conroy et al. N Engl J Med. 2011 May 12;364(19):1817-25.

1) FOLFIRINOX

Median OS

FOLFIRINOX 11.1 months

vs

Gemcitabine 6.8 months

Current 1st line standard of care options

Von Hoff et al. N Engl J Med. 2013 Oct 31;369(18):1691-703

1a) Gemcitabine/nab-paclitaxel

Median OS

gem/nab-paclitaxel 8.5 months

vs

gemcitabine 6.7 months

Survival

1995 2000 2005 2010 2015

Media

n O

vera

ll S

urv

ival (m

on

ths)

3

6

9

12

1997 2007 2011 2013

gemcitabine

5FU gemcitabine

erlotinib

FOLFIRINOX Gemcitabine

nab-paclitaxel

Are we really doing better?

Rahib et al. Cancer Res. 2014 Jun 1;74(11):2913-21.

20

18

How can we do better?

Stage and Prognosis

Disease Stage % of cases at diagnosis % 5yr OS

Localized/Resectable 7 22

Locally Advanced/Unresectable 26 9

Metastatic 53 2

CA Cancer J Clin 2010;60:277–300

Resectable Borderline Resectable

Locally Advanced

Unresectable

Metastatic

Stage III

Stage IV

Stage I

Stage II

Stage and Treatment

Clinical Practice Staging

Localized/Resectable

Borderline Resectable

Locally advanced/Unresectable

Metastatic

Standard of Care Treatment

Surgery -> chemo+/- XRT

Chemo +/- XRT ->Surgery -> chemo?

Chemo +/- XRT ->Surgery?

Chemotherapy

Drugs that failed in clinical trials involving pancreatic adenocarcinoma: 2004-2014

Pharmacol Ther. 2015 Aug 20. pii: S0163-7258(15)00164-3

New Developments in Pancreatic Cancer

• New drugs for metastatic disease? Nothing to report yet…

• See you next year?

• New strategies with old drugs

No

Outline

• Pancreatic Cancer

– Adjuvant therapy

– Neoadjuvant therapy

– Future

– Interesting update from 2015/2017

• Evofosfamide

Conko-001

Oettle et al. JAMA 2013 Oct 9:1473-81

ESPAC-4 – gem vs gem/capecitabine

Presented By John Neoptolemos at 2016 ASCO Annual Meeting

Gr 3/4 Gem Gem-Cap

SAE’s 26% 24%

ANC 24% 38%

Hand Foot 0 7%

Diarrhea 2% 5%

Discussion

Strengths

• Well designed and

executed prospective

randomized phase III study

• Incremental but meaningful

margin of benefit

• Manageable toxicity profile

Limitations

• “Real world” tolerability

• Cost/value

Practice Changing?

• Yes, for combination therapy

PRODIGE 24/CCTG PA.6, an Unicancer GI trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected

pancreatic ductal adenocarcinomas.

Presented By Thierry Conroy at 2018 ASCO Annual Meeting


247 patients

246 patients

No bolus 5FU

Patients baseline characteristics


ESPAC-4

ECOG 0 – 42%

1 – 55%

2 – 3%

Pancreatic tumors baseline characteristics


ESPAC-4

R1 resection % was ~60% in both arms – definition of R1

Disease-Free Survival


Primary Endpoint

mDFS – 13.4m

3-yr DFS ~22%

CONKO-001

Forest plot for DFS



mOS – 22.8m

3-yr OS ~34%

CONKO-001

Safety: main nonhematologic AEs


Six-month treatment completion


Discussion

Strengths

• Well designed and

executed prospective

randomized phase III study

• Meaningful margin of

benefit

• “Manageable” toxicity

profile

Limitations

• “Real world” tolerability

• Very select patient

population

• Overall impact to

pancreatic cancer

survival

Practice Changing?

• Yes, confirms role of combination adjuvant therapy

• Yes, for super-fit patients

Key Unanswered Questions

• Impact of dose intensity

• Subsequent treatment at recurrence

• Other combination therapies

– Gem/nab-paclitaxel: APACT study

– Multiple options, no head-to-head, same problem as

metastatic

• Role for radiation

– RTOG 8048

• Neoadjuvant vs adjuvant

Outline




– Future


• Evofosfamide

Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC) : <br />A randomized, controlled, multicenter

phase III trial of the<br /> Dutch Pancreatic Cancer Group

Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting

Trial design


Consensus Guideline Definitions

900 contact?

Trial design


baseline characteristics


Resection Rate

Presented By Colin Weekes at 2018 ASCO Annual Meeting

Overall Survival Analyses

Presented By Colin Weekes at 2018 ASCO Annual Meeting

Disease free survival


Discussion

Strengths

• Randomized controlled

study

• Supports trend towards

systemic therapy in earlier

stage disease

Limitations

• Need separate trials for

Resectable and

Borderline Resectable

• Borderline resectable

should not be treated with

surgery as first-line

therapy

Practice Changing?

• No

Key Unanswered Questions

• Neoadjuvant vs adjuvant

– SWOG 1505 – resectable

• perioperative FOLFIRINOX or Gem/nab-paclitaxel

– Alliance A021501 – borderline resectable

• FOLFIRINOX +/- RT -> surgery -> FOLFOX

Outline




– Future


• Evofosfamide

Future

• New ways to categorize patients – DNA Repair

• BRCA-ness

– MSI-high

• Tumor Microenvironment – eg Stromal targeting

• Immunotherapy - numerous trials*

• COMPASS trial

• Organoids – chemotherapy sensitivity profiles

Genomics-Driven Precision Medicine for Advanced Pancreatic Ductal Carcinoma (PDAC) - Early Results from the COMPASS Trial (NCT02750657)

Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

Study Design


Genomic Results


Moffitt RNA Subtypes


RNA Subtype & Chemotherapy Response


Survival by Moffitt RNA Signature


Pancreatic Cancer Organoids

Tiriac et al. Cancer Discovery. 2018 May 31 (epub ahead of print)

Outline




– Future


• Evofosfamide

Evofosfamide (TH-302) – hypoxia-activated cytotoxic alkylator

Weiss et al. Clin Cancer Res. 2011 May 1;:2997-3004

Evofosfamide (TH-302) – Phase II randomized

Median OS (m)

6.9 vs (8.7-9.2)

p = NS

Gem Gem

TH-302 240

Gem

TH-302 340

Overall Response Rate 12% 17% 26%

Ca 19-9 decline >50% 52% 51% 70%

Borad et al. J Clin Oncol. 2015 May 1:1475-81

Metastatic/Locally Advanced

Pancreatic Cancer

N= 693

Primary Endpoint = Overall Survival

Gemcitabine

1000mg/m2

Weekly x3 of 4

Gemcitabine

1000mg/m2

+

TH-302

340mg/m2 IV

Weekly x3 of 4

Evofosfamide: MAESTRO Phase III trial

Phase III trial Gem/placebo Gem

TH-302 340 p

mOS 7.6 8.7 .059

mPFS 3.7 5.5 .004

Confirmed ORR 9% 15% .009

Phase II trial Gem Gem TH-302 240

Gem TH-302 340

ORR 12% 17% 26%

Details…

• new ethanol-based formulation to improve drug product solubility was introduced after the Ph 2 study and before the start of the Ph 3 study

PK Parameters

Ph 2 Evo + Gem

Evo 240 mg/m2 + Gem Evo 340 mg/m2 + Gem

N Geometric

Mean Mean (SD) N

Geometric Mean Mean

Cmax(µg/mL) 47 5.32 6.09

(3.11) 51 9.27

10.17 (4.92)

AUC (µg-h/mL)

44 5.33 5.90

(2.81) 47 8.94

9.76 (4.54)

Ph 3 Evo + Gem

Evo 340 mg/m2 + Gem

N Geometric

Mean Mean (SD)

317 6.34 7.54

(5.49)

302 6.02 6.61

(3.03)

Ph 3 Evo + Gem

Evo 340 mg/m2 + Gem

N Geometric

Mean Mean (SD)

317 6.34 7.54

(5.49)

302 6.02 6.61

(3.03)

Thank You

Questions?

new developments in pancreatic cancer · espac-4 – gem vs gem ... • well designed and executed...

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