Audrey H Choi, MD1, Joseph Kim, MD1, James R Bading, MD2, David M Colcher, PhD2, Sangjun Lee, PhD1, Vincent Chung, MD3, Jinha Park, MD, PhD4

Departments of 1Surgery, 2Cancer Immunotherapeutics and Tumor Immunology, 3Medical Oncology and 4Radiology

City of Hope National Medical Center, Duarte, CA USA

Evaluation of a Novel Trastuzumab-Linked Radioimmunoconjugate for In Vivo Assessment

of HER2 Expression in Gastric Cancer

Disclosures

• The authors have no relevant disclosures

Introduction

• Gastric cancer is the 2nd most common cause of cancer-related death worldwide1

• Poor prognosis for patients with advanced disease (median 7 months)• Lack of effective systemic therapies

• Advances in targeted therapies have improved gastric cancer outcomes and extended overall survival beyond 1 year• Trastuzumab for Gastric Cancer (ToGA) trial: phase III

RCT comparing trastuzumab plus chemotherapy (median OS 13.8 mo) versus chemotherapy alone (median OS 11.1 mo, p=0.005)2

1Kamangar et al, J Clin Oncol 20062Bang et al, Lancet 2010.

The challenge of accurately quantifying HER2

• Trastuzumab is a humanized monoclonal antibody against the HER2 receptor– Known to be an effective treatment in

cancers with HER2 overexpression

• However, HER2 expression has been difficult to assess and quantify– ToGA: only eligible to receive

trastuzumab if HER2 overexpression by immunohistochemical staining (IHC) or HER2 gene amplication by fluorescence in situ hybridization (FISH)• 22% screened patients met the HER2

criteria– City of Hope: 10% of advanced gastric

cancer patients meet criteria

Current methods of HER2 assessment may underestimate trastuzumab-eligible patients

• Tumor-level heterogeneity of HER2 has been linked to discordant pathology scoring1,2

• Additionally, trastuzumab has been reported to benefit patients who are HER2-negative by IHC and FISH3

• These findings have several important implications:• Accuracy of IHC and FISH to identify HER2-

overexpressing tumors may be limited by tumor heterogeneity and/or limitations of the tests themselves

• Alternatively, there may be additional unidentified molecular markers that predict response to trastuzumab better than HER2 assessment by IHC or FISH

1Potts et al, Laboratory Investigation 20122Lewis et al, Am J Clin Path 20053Paik et al, J Clin Oncol 2007

A Novel Radioimmunoconjugate

• 64Cu-DOTA-Trastuzumab– Clinical grade trastuzumab

conjugated to the chelating agent DOTA (tetra-azacyclododecanetetra-acetic acid) and labeled with 64Cu radioisotope

• This compound has been shown to accurately detect HER2-positive breast cancer tissue by positron emission tomography (PET) in patients with metastatic breast cancer at our institution1

Figure 1. 64Cu-DOTA-Trastuzumab PET of a breast cancer patient classified as HER2-negative by biopsy and IHC/FISH

1Mortimer et al, J Nucl Med 2014

Hypothesis

• 64Cu-DOTA-Trastuzumab PET may better localize HER2-overexpressing gastric cancer– Potentially overcoming the problem of tumor

heterogeneity– Non-invasive radiographic “biopsy”

• 64Cu-DOTA-Trastuzumab PET can more accurately measure functional HER2 expression than IHC/FISH

Objective

• Clinical trial (NCT01939275) to evaluate 64Cu-DOTA-Trastuzumab for assessing in vivo HER2 expression with modified PET/CT imaging of gastric cancer patients.

Study Design – Imaging phase

Gastric cancer patients identified in medical oncology,

surgery clinics

Surgical candidates1. Biopsy-proven gastric CA, ≥18 yo

2. Early stage: curative-intent procedure3. Locally-advance, metastatic: palliative

procedure

CT for staging

Non-surgical candidates

15 mCi 64Cu-DOTA-Trastuzumab IV injection

given 48 hrs prior to PET/CT

64Cu uptake (SUV) measured in tumor and

adjacent non-tumor tissues

Study Design – Surgical pathology phase

Surgical candidates to operating room: areas corresponding to 64Cu uptake on

PET marked with suture in OR

Marked specimen to pathology

IHCParaffin-embedded tissue into 4

µm sections, stained by anti-HER2 antibody

FISHParaffin-embedded tissue,

HER2/CEP17ratio determined

IHC/FISH results compared to SUV measured on PET/CT and pre-operative

biopsy IHC/FISH (if available)

Target accrual: 22 patients

Summary

• Current methods of HER2 detection may underestimate the number of patients eligible for trastuzumab therapy

• Our novel, non-invasive imaging method may improve localization of HER2-overexpressing tissue and aid in the identification of trastuzumab-eligible patients in gastric cancer

Thank You

Clinical trial (NCT01939275) contact information:City of Hope National Medical CenterDuarte, CA 91010Principle investigator: Vincent Chung, MDContact: (626) 471-9200; vchung@coh.org