Copyright © 2010, Research To Practice, All rights reserved. Part VI: HER2-Positive Gastric Cancer...

Copyright © 2010, Research To Practice, All rights reserved.

Part VI: HER2-Positive Gastric CancerMonday, October 25, 20107:30 PM - 8:30 PM ET

Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

Jaffer A Ajani, MDProfessor of MedicineDepartment of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHouston, Texas

Jeffrey S Ross, MDCyrus Strong Merrill Professor and ChairDepartment of Pathology and Laboratory MedicineAlbany Medical CollegeAlbany, New York

Neil Love, MDModeratorResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

Disclosures for Jaffer A Ajani, MD

Consulting Agreements

Abraxis BioScience, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis

Paid Research

ACT Biotech Inc, Bristol-Myers Squibb Company, Genta Inc, ImClone Systems Incorporated, Sanofi-Aventis, Taiho Pharmaceutical Co Ltd

Disclosures for Jeffrey S Ross, MD

Advisory CommitteeEMD Serono Inc, Genentech BioOncology, Novartis Pharmaceuticals Corporation

Speakers Bureau Genentech BioOncology

Case History: Dr Ajani

• A 47 year old man with history of inflammatory bowel disease and intrahepatic sclerosing cholangitis

• Patient presented with epigastric pain

• Endoscopy and CT scans: Mass in lower esophagus, GE junction, proximal stomach, lung metastasis

Initial PET Evaluation

1) Would you want HER2 testing done before deciding on a treatment plan?

Yes, in almost all situations

Yes, in some situations

Yes, but it’s difficult to get the pathologist

to do it

No 7%

23%

57%

13%

0% 10% 20% 30% 40% 50% 60%

2) What treatment would you generally recommend if the patient’s tumor was HER2-negative?

2%

9%

13%

4%

4%

40%

28%

0%

0% 10% 20% 30% 40% 50%

DCF or DCF modification

ECF or ECF modification

Irinotecan plus cisplatin

Irinotecan plus fluoropyrimidine

Oxaliplatin plus fluoropyrimidine

Cisplatin plus fluoropyrimidine

Paclitaxel-based regimen

Other

Case History: Dr Ajani (continued)

• The patient’s tumor is HER2-positive (IHC3+, FISH-positive)

3) Would you recommend trastuzumab-based therapy for this patient?

5%

95%

0% 20% 40% 60% 80% 100%

Yes

No

4) If you would recommend trastuzumab, which chemotherapy regimen would you use?

No chemotherapy – trastuzumab alone

DCF or DCF modification

ECF or ECF modification

Irinotecan plus cisplatin

Irinotecan plus fluoropyrimidine

Oxaliplatin plus fluoropyrimidine

Cisplatin plus fluoropyrimidine

Paclitaxel-based regimen

Other

32%

4%

5%

5%

46%

3%

0%

0%

5%

0% 10% 20% 30% 40% 50%

Case History: Dr Ajani (continued)

• Patient treated with

– Docetaxel 40 mg/m2 q2wks

– Capecitabine 1,500 mg/m2 7d on/7d off

– Oxaliplatin 85 mg/m2 q2wks

– Trastuzumab 6 mg/kg q3wks

Response Evaluation in 10/2008

Patient Continues Trastuzumab as of 10/2010


Trastuzumab in Combination with Chemotherapy versus Chemotherapy Alone for Treatment of HER2-Positive Advanced Gastric or GE Junction Cancer (ToGA): A Phase 3, Open-Label, Randomised Controlled Trial

Bang YJ et al.Lancet 2010;376(9742):687-97.

HER2-positive (IHC3+ or FISH+), inoperable, locally advanced, recurrent or metastatic GE junction or gastric adenocarcinoma

ToGA: Trial Schema

Bang YJ et al. Lancet 2010;376(9742):687-97.

FCFluoropyrimidine (F) (5-FU or capecitabine at investigator discretion) + Cisplatin (C)

R

FC + Trastuzumab (T)

Primary Analysis: N = 584

5-FU = 800 mg/m2/day continuous infusion d1-5 q3wks x 6Capecitabine = 1,000 mg/m2 bid d1-14 q3wks x 6Cisplatin = 80 mg/m2 q3wks x 6Trastuzumab = 8 mg/kg loading dose followed by 6 mg/kg q3wks until PD

Efficacy of Trastuzumab + Chemotherapy versus Chemotherapy Alone in HER2-Positive Advanced Gastric or GE Junction Tumors

FC (n = 290)

FC + T (n = 294) Hazard Ratio p-value

Overall Survival

11.1 months 13.8 months 0.74 0.0046

PFS 5.5 months 6.7 months 0.71 0.0002

Overall Response

35% 47%1.70

(Odds Ratio)0.0017


ToGA: Median Overall Survival


ToGA: Progression-Free Survival


Cardiac Safety of Trastuzumab + Chemotherapy versus Chemotherapy Alone in HER2-Positive Advanced Gastric or GE Junction Tumors

FC FC + T

Cardiac AEs (All Grades)

6% 6%

Cardiac AEs (Grade 3/4)

3% 1%

Cardiac Failure < 1% < 1%

Cardiac Dysfunction (≥ 10% drop in LVEF to an absolute value < 50%)

1% 5%



Quality of Life Results from a Phase III Study of Trastuzumab Plus Chemotherapy as First-Line Therapy in Patients with HER2-Positive Advanced Gastric and Gastro-Oesophageal Junction Cancer

Ohtsu A et al.Proc 12th WCGC 2010;Abstract O-0011.

ToGA QoL Analysis: Proportion of Patients with Global Health Status, Physical Functioning, Nausea and Vomiting, Dysphagia and Pain Intensity Scores Improving by at Least 10% from Baseline at Week 37

0% 10% 20% 30% 40% 50% 60% 70%

Global health status

Physical functioning

Nausea/vomiting

Dysphagia

Pain intensity

Chemotherapy aloneTrastuzumab + chemotherapy

Ohtsu A et al. Proc 12th WCGC 2010;Abstract O-0011.

ToGA ASCO 2009 Discussion: Trastuzumab in Gastro-Oesophageal Cancer – Future Directions (David Cunningham, MD)

• Efficacy of trastuzumab monotherapy?

• Maintenance monotherapy after triplet regimens?

• Continuation beyond progression in association with second-line therapy as in breast cancer (Von Minckwitz et al, JCO 2009)?

• Role of trastuzumab in the perioperative setting?

• Other potential biomarkers to further select patients (currently under evaluation in breast cancer)?

Ongoing Studies of Targeting HER2-Positive Metastatic or Unresectable Gastric Cancer

Trial Name/Phase Treatment Regimen Accrual Trial

LOGiC Phase IIICapecitabine, oxaliplatin

+/- lapatinib410 Open

TYTANPhase III

Paclitaxel +/- 2nd-line lapatinib 314 Open

HERMESPhase IV

Trastuzumab in routine clinical practice

1,500 Open

DFCI 09-457 Phase II

Capecitabine, oxaliplatin, bevacizumab, trastuzumab

36Not yet open

NCT01145404Phase II

Lapatinib +/- capecitabine 76 Open

EORTC-40071Phase II

Epirubicin, cisplatin, 5-FU or capecitabine, lapatinib or placebo

192Not yet open

www.clinicaltrials.gov, October 2010


Interim Safety Analysis from TYTAN: A Phase III Asian Study of Lapatinib in Combination with Paclitaxel as Second-Line Therapy in Gastric Cancer

Satoh T et al.Proc ASCO 2010;Abstract 4057.


A Phase III Study of CapeOX +/- Lapatinib in FISH-Positive HER2 Locally Advanced/Metastatic Upper Gastrointestinal Adenocarcinoma: Interim Safety ResultsHecht JR et al.Proc ECCO-15 2009;Abstract 6584.

EligibilityLocally advanced, resectable HER2+ gastric or GE junction adenocarcinoma

Phase II Multi-Center Study of Perioperative Chemotherapy/Trastuzumab (NCT01130337)

www.clinicaltrials.gov, October 2010

Preoperative Therapy x 3 CyclesCapecitabine + Oxaliplatin (CAPOX)

Trastuzumab

SurgeryIf complete resection, R0 or microscopic R1

Accrual: N = 45

Postoperative Therapy x 3 CyclesCAPOX

Trastuzumab

Trastuzumab completion to 12 months

34

Akt

SOS

RAS

RAF

MEK

VEGF

MAPK

P

P

PP

Receptor specificligands HER1, HER2,

HER3, or HER4HER2

HER1(EGFR)

HER2HER4

HER3

Tyrosine kinasedomains

Plasmamembrane

PI3K

Cell proliferationCell survivalCell mobility and invasiveness

Cytoplasm

Nucleus

Transcription

Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness


Lapatinib, a Dual EGFR and HER2 Kinase Inhibitor, Selectively Inhibits HER2-Amplified Human Gastric Cancer Cells and is Synergistic with Trastuzumab In Vitro and In Vivo

Wainberg ZA et al.Clin Cancer Res 2010;16(5):1509-19.

Synergistic Antitumor Activity of Lapatinib and Trastuzumab in Combination (N87 Xenograft)

Reprinted with permission: Wainberg ZA E et al. Clin Cancer Res 2010;16(5):1509-19.

Tu

mo

r vo

lum

e (m

m3 )

Case History: Dr Ajani

• A 56 year old man presents with abdominal pain and dyspepsia

• Investigations revealed a GE junction mass with liver and adrenal masses as well

• Biopsy of GE junction mass shows HER2-positive (by FISH) moderately differentiated adenocarcinoma

• Patient treated with:– Docetaxel 40 mg/m2 q2wks– Capecitabine 1,500 mg/m2/d 7d on/7d off– Oxaliplatin 85 mg/m2 q2wks– Trastuzumab 6 mg/kg q3wks

Initial CT Evaluation

Recent Evaluation in 8/2010

Patient continues on trastuzumab as of 10/2010 and remains free of obvious cancer

Approximately How Many New Patients With Gastric Cancer Do You See Per Year?

8%

33%

34%

19%

6%

>15

10-15

5-9

1-4

0

Patterns of Care Survey of US-Based Medical Oncologists (n = 100)

Median = 5 patients

Patients

How Many Patients With Gastric Cancer Have You Treated With Trastuzumab +/- Chemo?

7%

38%

55%

≥3

1-2

0


Patients

Which Chemotherapy Did You Generally Administer With Trastuzumab?


6%

2%

10%

10%

31%

41%Platinum/

fluoropyrimidine

Single-agent chemo

Platinum/taxane

Platinum/fluoropyrimidine/

taxane

fluoropyrimidine/taxane

Other

In General, How Long Did You Continue The Trastuzumab?

1%

5%

31%

63%

One year

Indefinitely

Six cycles

Until diseaseprogression


— Neal Fishbach, MDFairfield, CT

I’ve tested every patient with metastatic gastric cancer whom I have cared for recently, and all 10 patients have been HER2-negative.

I don’t know whether there is a lot of geographic variation, but I haven’t seen a lot of HER2 positivity in gastric cancer.

— Karen Green, MDWhite Plains, NY

In a patient with HER2-positive gastric cancer who initially responds to trastuzumab plus chemotherapy and is subsequently maintained on trastuzumab alone, but then progresses, does the panel feel that there is a role for continuing the trastuzumab as is done in breast cancer, or at least changing to another anti-HER2-directed therapy?

— Richard Polkinghorn, MDBrunswick, ME

How should we interpret the results of HER2 testing in gastric cancer? What’s considered positive?

If the specimen is less than IHC3+, is it considered HER2-negative? Or should we use FISH?

Case History: Dr Ross

• A 67 year old woman with history of low grade ductal carcinoma of the breast seven years ago presents with dysphagia

• Endoscopy: polypoid mass beneath gastroesophageal sphincter

• Punch biopsies (three): Gastric adenocarcinoma, intestinal type. HER2-negative

Case History: Dr Ross (continued)

• Patient undergoes primary surgery, and histopathology from surgical specimen shows

– Moderately differentiated intestinal type adenocarcinoma

– Invasion of muscularis propria

– 1/32 regional lymph nodes+

– All margins negative

– T2N1 tumor

5) What treatment would you most likely recommend?

Epirubicin, cisplatin, 5-FU (ECF)

Docetaxel, cisplatin, 5-FU (DCF)

Radiation 5-FU/leucovorin

Docetaxel or paclitaxel plus fluoropyrimidine

(5-FU or capecitabine)

Cisplatin, 5-FU

Oxaliplatin plus fluoropyrimidine (5-FU or capecitabine)

Irinotecan plus fluoropyrimidine (5-FU or capecitabine)

2%

31%

15%

9%

27%

2%

14%

0% 5% 10% 15% 20% 25% 30% 35%


HER2 testing is repeated on the surgical specimen by both IHC and FISH, and now reported as HER2-positive

IHC3+

FISH+

Low Magnification of Original Endoscopic Biopsy Showing a Negative IHC for HER2 Protein Expression

Resection Specimen Demonstrating 3+ IHC Staining for HER2 in the Same Patient

Negative HER2 Staining in Original Biopsy versus IHC 3+ Staining in Surgical Specimen

6) How would you treat this patient in the adjuvant setting?

No adjuvant therapy

Adjuvant 5-FU/irinotecan chemotherapy

Adjuvant cisplatin/5-FU chemotherapy

Adjuvant cisplatin/5-FU chemotherapy trastuzumab

(ToGA trial regimen)

Another non-trastuzumab chemotherapy regimen

Another trastuzumab-based regimen

Adjuvant chemo-radiation

2%

51%

0%

2%

2%

39%

4%

0% 10% 20% 30% 40% 50% 60%


• Patient received adjuvant platinum/5-FU plus trastuzumab ToGA trial regimen

• Remains alive and progression-free four months postresection


Pathological Features of Advanced Gastric Cancer (GC): Relationship to Human Epidermal Growth Factor Receptor 2 (HER2) Positivity in the Global Screening Programme of the ToGA Trial

Bang Y et al.Proc ASCO 2009;Abstract 4556.

Modified HercepTest™ HER2 Scoring System for GC

Staining characteristics Score/classification

No staining or membrane staining in <10% of cells 0/negative

Faint/barely perceptible membrane staining in >10% of cells; cells are only stained in part of their membrane

1+/negative

Weak to moderate complete or basolateral membrane staining in >10% of tumor cells

2+/equivocal

Moderate to strong complete or basolateral membrane staining in >10% of tumor cells

3+/positive

Biopsy (not surgery) samples with cohesive IHC 3+ and/or FISH+ clones are considered positive irrespective of size, ie, <10% of tumor cells

Bang Y et al. Proc ASCO 2009;Abstract 4556.

HER2 Positivity Screening Results


• 3,807 tumor samples from 24 countries assessed for HER2 status in a central laboratory using the modified scoring system

– 3,667 samples evaluable

– HER2 positivity rate: 22.1%

• Concordance rate between IHC and FISH with modified HER2 scoring system: 87.2%

HER2 Positivity Screening Results (continued)


• HER2 positivity varied by:

– Tumor site: GEJ cancer vs stomach cancer (33.2% vs 20.9%)

– Histologic subtype: Intestinal vs diffuse/mixed (32.2% vs 6.1%/20.4%)

– Sample preparation: Biopsy vs surgery (23.1% vs 19.9%)

• Biopsy samples more likely to be HER2-positive than surgery samples when analyzed by FISH rather than by IHC

— Erik Rupard, MDFort Gordon, GA

I see between 5-10 patients with gastric cancer per year. To a lesser extent, we have the same problem that we have in lung cancer with EGFR mutations in that we often have to talk our pathologist into looking for HER2 status in our patients with gastric cancer.


Pathological Complete Response After Neoadjuvant Chemotherapy With Trastuzumab-Containing Regimen in Gastric Cancer: A Case Report

Wang J et al. J Hematol & Oncol 2010;3.

Case History

• A 49-year-old male with a 2-cm gastric ulcer

• Biopsy: moderately differentiated adenocarcinoma

– HER2-positive by IHC and FISH

• Ultrasound, CT, PET: T3N1M0

• Received capecitabine, oxaliplatin, docetaxel and trastuzumab x 3 cycles

• Gastrectomy with extended D2 lymph node dissections

– Pathologic complete response

• Postoperative chemotherapy x 3 cycles

Wang J et al. J Hematol & Oncol 2010;3.


• A 58 year old man with history of GERD and biopsy proven Barrett’s esophagus presents with anorexia, weight-loss, fatigue and anemia

• Multiple endoscopic biopsies of GE junction reveal adenocarcinoma of GE junction with sub-mucosal invasion

• HER2 testing showed

– Rare microfoci of incomplete staining by IHC, limited to areas of in situ adenocarcinoma

– FISH-negative for HER2 gene amplification

Illustration of IHC 3+ HER2 Immunostaining Limited to the In Situ Component of Invasive Gastric Adenocarcinoma

Hofmann M et al. Histopathology 2008;52:797-805.

Comparison of HER2 Testing in Breast and Gastric/GEJ Cancers

Breast Cancer Gastric/GE Junction Cancer

IHC Membranous Staining Pattern

3+ requires full circumferential staining pattern

3+ score allowed for cases with loss of apical membrane staining

Required Percent of Membranous Staining

ASCO – CAP Guidelines: 30%Trastuzumab Package Insert: 10%

Biopsies: no percentage required. Any cell cluster with membranous staining is HER2+Resections: 10%

Heterogeneity of HER2 Positivity

Well-described; judged as moderate, can influence HER2 test results especially when core biopsies are assessed

More severe than for breast cancer; especially important for endoscopic biopsies

Comparison of HER2 Testing in Breast and Gastric/GEJ Cancers (continued)

Breast Cancer Gastric/GE Junction Cancer

In Situ Component Not scored

Is scored. If in situ component is positive and invasive component is negative, the tumor is still classified as HER2+

IHC – FISH Concordance

High (85-95%) Moderate (83% in the ToGA trial)

Regulatory issuesIHC and FISH tests approved by US FDA

HER2 testing in gastric/GEJ tumors approved in Europe, but not in US.

Approval in US likely to be identical to that in Europe (Dako HercepTest for IHC and Dako pharmDxTM for FISH)

Gastric Cancer

Gastroesophageal Junction Cancer

Breast Cancer

Continuous Complete 360 Degree Membranous HER2 Staining

Incomplete Staining With Loss of Apical Membrane HER2 Expression

Marked Heterogenity of HER2 Immunostaining

Comparison of HER2 IHC Slide Scoring in Gastric/GEJ and Breast Cancers

• Node-positive or high-risk node-negative breast cancer

• IHC 0, 1+, 2+ and FISH-negative

NSABP B-47: A Phase III Trial of Adjuvant Chemotherapy +/- Trastuzumab in HER2 Normal Breast Cancer

NSABP Protocol Summaries, April 2010

Docetaxel/cyclophosphamide (TC)or

AC weekly paclitaxel (WP)

RTC + Trastuzumab (H) H x 1 yr

OrAC WP + H H x 1 yr

Target Accrual: N = 3,260 Protocol undergoing revisions


• A 53 year old woman with history of breast cancer for 15 years presents with symptoms of gastric obstruction with marked gastric distension

• Endoscopic biopsy

– Infiltrating adenocarcinoma on H&E stain

– Cords and columns of cells through the sub-mucosa

– No mucosal site of origin is seen

– Primary diffuse adenocarcinoma of the stomach is diagnosed


• Review of pathology from primary breast cancer revealed infiltrating lobular carcinoma

• Surgical specimen contained a multifocal intramural obstructing mass, and the tumor closely resembled the histology of the primary breast carcinoma

– Strongly ER/PR+

– HER2-negative

– E-cadherin-negative

• A final diagnosis of recurrent lobular breast cancer in the gastric outlet was made


• Patient treated with tamoxifen alone

• Continued symptoms of abdominal pain but no recurrence of gastric outlet obstruction in the last 6 months

Gastric Outlet Obstruction Caused by Metastatic Breast Cancer

Lobular Breast Cancer with Cords and Columns of Infiltrating Malignant Cells

Metastatic Lobular Breast Cancer with Gastric Outlet Obstruction Simulating Primary Gastric Adenocarcinoma

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