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Advances in Gastrointestinal Malignancies
Edward J. Kim MD, PhDSeptember 26, 2015
16th Annual Advances in OncologySeptember 25-26, 2015
Edward J KimAdvances in Gastrointestinal Malignancies
Relevant financial relationships in the past twelve months by presenter or spouse/partner:Grant/Research Support: Celgene, OncoMedConsultant: Bayer, Momenta, Pharmacyclics, Guardant HealthSpeakers Bureau: Guardant Health
The speaker will directly disclose the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.
Topics
• Pancreatic Cancer– GVAX/CRS-207
• Colorectal Cancer– Pembrolizumab
• Gastric Cancer– Pembrolizumab
• Hepatocellular Carcinoma– Nivolumab
Topics
• Pancreatic Cancer– GVAX/CRS-207
• Colorectal Cancer– Pembrolizumab
• Gastric Cancer– Pembrolizumab
• Hepatocellular Carcinoma– Nivolumab
- 2 virulence genes are deleted- Stimulates robust innate and adaptive T-cell immunity to mesothelin
Le et al. ASCO GI 2014
GVAX/CRS-207
Full analysis set patients who received > 1 dose
Per protocol setpatients who received > 3 doses
GVAX/CRS-207: Phase II Trial
Le et al. J Clin Oncol. 2015 Apr 20:1325-33
Metastatic Pancreatic Adenocarcinoma2nd or 3rd+ line of therapy
N = 240
Primary endpoint = Overall SurvivalArm C – single agent chemotherapy
GVAX/CRS-207: Ongoing Phase II Trial
Topics
• Pancreatic Cancer– GVAX/CRS-207
• Colorectal Cancer– Pembrolizumab
• Gastric Cancer– Pembrolizumab
• Hepatocellular Carcinoma– Nivolumab
Presented By Dung Le
Mismatch Repair Deficiency
• Deficiency in DNA mismatch repair genes leads to microsatellite instability (MLH1, MSH2, MSH6, PMS2)
• Germline mutation– Lynch syndrome
• Sporadic mutation – 15% of sporadic CRC -> 3-5% of advanced disease
• Epigenetic– MLH1 hypermethylation
• In addition to colorectal cancer, also seen in:– Gastric, cholangiocarcinoma, ampullary, small bowel,
pancreatic, endometrial, sarcoma, prostate
Mutations per tumor class
Presented By Dung Le
PD-1 Pathway: Pembrolizumab
Presented By Dung Le
Phase II Study
Melanoma: 2 mg/kg every 3 weeks
Presented By Dung Le
Demographics
Presented By Dung Le
Results: Response Rate
Presented By Dung Le
Results: Change in Target Lesions
Presented By Dung Le
Results: Progression-Free Survival
Presented By Dung Le 2015 ASCO Annual Meeting
Results: Overall Survival
Presented By Dung Le 2015 ASCO Annual Meeting
Mutation Burden is associated with Efficacy
Presented By Dung Le at 2015 ASCO Annual Meeting
Summary
• Mismatch repair deficient tumors are highly responsive to checkpoint blockade with anti-PD-1.– Treatment approach associated with benefit
based on genetic status – not tumor type
• Mismatch repair proficient tumors are not responsive to checkpoint blockade with anti-PD-1
Followup Study: KEYNOTE-164
Topics
• Pancreatic Cancer– GVAX/CRS-207
• Colorectal Cancer– Pembrolizumab
• Gastric Cancer– Pembrolizumab
• Hepatocellular Carcinoma– Nivolumab
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
Presented By Yung-Jue Bang
Presented By Yung-Jue Bang2015 ASCO Annual Meeting
Phase I: KEYNOTE-012 – gastric cohort
Demographics
Presented By Yung-Jue Bang2015 ASCO Annual Meeting
Presented By Yung-Jue Bang2015 ASCO Annual Meeting
Results: Best Overall Response
For comparison- ORR with:-REGARD- Ramucirumab = 3%-RAINBOW - Paclitaxel = 16%
- Ram+Ptx = 28%
Response: Change in Target Lesions
Presented By Yung-Jue Bang2015 ASCO Annual Meeting
Results: PFS and OS
Presented By Yung-Jue Bang2015 ASCO Annual Meeting
For comparison- median OS with-REGARD- Ramucirumab = 5.2 months-RAINBOW - Paclitaxel = 9.6 months
- Ram+Ptx = 7.4 months
• Gastric cancer exhibits response to checkpoint blockade by anti-PD-1– Heavily pre-treated population– PD-L1 positive patients
• Need for further refinement of optimal patient population – Durable benefit = 11 month median OS
• Manageable toxicity profile• Future Studies :
– KEYNOTE-059 Ph II - pembrolizumab vs chemotherapy– KEYNOTE-061 Ph III - 2nd line pembrolizumab vs paclitaxel
Summary
Topics
• Pancreatic Cancer– GVAX/CRS-207
• Colorectal Cancer– Pembrolizumab
• Gastric Cancer– Pembrolizumab
• Hepatocellular Carcinoma– Nivolumab
Phase 1/2 Safety and Antitumor Activity of Nivolumab in Patients
With Advanced Hepatocellular Carcinoma (HCC): CA209-040
Presented By Anthony El-Khoueiry
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
PD-1 Pathway: Nivolumab
Phase I study
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
Phase I Study - Design
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
Phase I study: Eligibility Criteria
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
Results: Toxicity
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
Results: Response Rate
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
For comparison, ORR with:SHARP: Sorafenib = 2%
(71% SD)
Response: Change in Target Lesions
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
Results: Overall Survival
Presented By Anthony El-Khoueiry2015 ASCO Annual Meeting
For comparison: with Sorafenib- 12 month Survival Rate = 44%- Median OS 10.7 months
Summary
• Hepatocellular Carcinoma responds to checkpoint blockade by anti-PD-1– Durable response – Encouraging response rate and overall survival
• Nivolumab has manageable toxicity profile in patients with HCC including those with HBV or HCV infection
• Ongoing dose expansion phase
Questions?
Advances in Gastrointestinal Malignancies16th Annual Advances in
Oncology�September 25-26, 2015���Edward J Kim� Advances in
Gastrointestinal Malignancies��Relevant financial relationships in
the past twelve months by presenter or
spouse/partner:�Grant/Research Support: Celgene,
OncoMed�Consultant: Bayer, Momenta, Pharmacyclics, Guardant
Health�Speakers Bureau: Guardant Health��The speaker will directly
disclose the use of products for which are not labeled (e.g., off
label use) or if the product is still
investigational.TopicsTopicsSlide Number 5Slide Number 6Slide
Number 7TopicsSlide Number 9Mismatch Repair DeficiencyMutations per
tumor classPD-1 Pathway: Pembrolizumab Phase II Study
DemographicsResults: Response RateResults: Change in Target
LesionsResults: Progression-Free SurvivalResults: Overall
SurvivalMutation Burden is associated with Efficacy SummaryFollowup
Study: KEYNOTE-164TopicsRelationship 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-012Phase I: KEYNOTE-012 –
gastric cohortDemographics Results: Best Overall ResponseResponse:
Change in Target LesionsResults: PFS and OSSummaryTopicsPhase 1/2
Safety and Antitumor Activity of Nivolumab in Patients With
Advanced Hepatocellular Carcinoma (HCC): CA209-040
PD-1 Pathway: NivolumabPhase I studyPhase I Study - DesignPhase I
study: Eligibility CriteriaResults: ToxicityResults: Response
RateResponse: Change in Target LesionsResults: Overall
SurvivalSummarySlide Number 43