advances in gastrointestinal malignancies edward advances...16th annual advances in oncology...

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

- 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





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


PD-1 Pathway: Pembrolizumab


Phase II Study

Melanoma: 2 mg/kg every 3 weeks


Demographics


Results: Response Rate


Results: Change in Target Lesions


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





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



Results: Best Overall Response

For comparison- ORR with:-REGARD- Ramucirumab = 3%-RAINBOW - Paclitaxel = 16%

- Ram+Ptx = 28%

Response: Change in Target Lesions


Results: PFS and OS


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





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


Phase I Study - Design


Phase I study: Eligibility Criteria


Results: Toxicity


Results: Response Rate


For comparison, ORR with:SHARP: Sorafenib = 2%

(71% SD)

Response: Change in Target Lesions


Results: Overall Survival


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

advances in gastrointestinal malignancies edward advances...16th annual advances in oncology...

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