new developments in pancreatic cancer · espac-4 – gem vs gem ... • well designed and executed...
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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
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urv
ival (m
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ths)
3
6
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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
Slide 3
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
247 patients
246 patients
No bolus 5FU
Patients baseline characteristics
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
ESPAC-4
ECOG 0 – 42%
1 – 55%
2 – 3%
Pancreatic tumors baseline characteristics
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
ESPAC-4
R1 resection % was ~60% in both arms – definition of R1
Disease-Free Survival
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Primary Endpoint
mDFS – 13.4m
3-yr DFS ~22%
CONKO-001
Forest plot for DFS
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Slide 21
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
mOS – 22.8m
3-yr OS ~34%
CONKO-001
Safety: main nonhematologic AEs
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
Six-month treatment completion
Presented By Thierry Conroy at 2018 ASCO Annual Meeting
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
• Pancreatic Cancer
– Adjuvant therapy
– Neoadjuvant therapy
– Future
– Interesting update from 2015/2017
• 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
Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
Consensus Guideline Definitions
900 contact?
Trial design
Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
baseline characteristics
Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
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
Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting
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
• Pancreatic Cancer
– Adjuvant therapy
– Neoadjuvant therapy
– Future
– Interesting update from 2015/2017
• 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
Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium
Genomic Results
Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium
Moffitt RNA Subtypes
Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium
RNA Subtype & Chemotherapy Response
Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium
Survival by Moffitt RNA Signature
Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium
Pancreatic Cancer Organoids
Tiriac et al. Cancer Discovery. 2018 May 31 (epub ahead of print)
Outline
• Pancreatic Cancer
– Adjuvant therapy
– Neoadjuvant therapy
– Future
– Interesting update from 2015/2017
• 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?