Manish A. Shah, MD Director, Gastrointestinal Oncology Weill Cornell Medical College...

Manish A. Shah, MDDirector, Gastrointestinal OncologyWeill Cornell Medical CollegeNewYork-Presbyterian HospitalNew York, New York

Treatment of HER2-Positive Gastroesophageal Carcinoma

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clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy

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Program Faculty

Program Director:Manish A. Shah, MDDirector, Gastrointestinal OncologyWeill Cornell Medical CollegeNewYork-Presbyterian HospitalNew York, New York


Faculty Disclosure

Manish A. Shah, MD, has disclosed that he has received consulting fees and contracted research support from Genentech and sanofi-aventis.


Gastroesophageal Cancer: Treatment Overview Surgery is primary treatment for medically fit, resectable cases[1]

For advanced disease, treatment may include perioperative chemotherapy or preoperative chemoradiation

Postoperative treatment options

– Chemoradiation (fluoropyrimidine-based or capecitabine)

– Palliative chemotherapy or best supportive care

Recurrent or metastatic disease

– Chemotherapy

– Palliative chemotherapy, clinical trial, or best supportive care

Significant need exists for deeper understanding of tumor subtypes, biomarkers for treatment response[2]

1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. 2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392.


Gastroesophageal Cancer: Systemic Therapy for Metastatic Disease First-line options[1]

– DCF/modified DCF

– ECF/modified DCF

– Single agent or combination regimens (fluoropyrimidine or taxane based)

– Trastuzumab + standard chemotherapy for HER2- positive tumors

Second-line options[1]

– Trastuzumab + standard chemotherapy for HER2-positive tumors if no first-line trastuzumab

– Paclitaxel or docetaxel

– Single agent irinotecan or irinotecan-based combination

– Phase III trials under way with other targeted agents[2]

1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. 2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392.


Targeted Therapies

Conventional, cytotoxic chemotherapy has limited benefit

Targeted agents: attempt to block specific tumor growth pathways

– Monoclonal antibodies

– Tyrosine kinase inhibitors

– Soluble receptors to growth factors

– Inhibition of pathways involved in protein synthesis and degradation


Molecular Targets: Esophagogastric Cancer KRAS mutation: < 5% to 10%[1,2]

BRAF mutation: < 5%[1,2]

EGFR overexpression: ~ 50% to 80%[3,4]

– TKIs inactive[4]

– Cetuximab monotherapy inactive[5]

EGFR mutation: very low[4,6]

HER2 overexpression: 10% to 25%[7]

HGF/c-Met: over/aberrant expression reported in various human cancers, including gastric cancer[8]

1. Lee SH, et al. Oncogene. 2003;22:6942-6945. 2. Kim IJ, et al. Hum Genet. 2003;114:118-120. 3. Galizia G, et al. World J Surg. 2007;31:1458-1468. 4. Dragovich T, et al. J Clin Oncol. 2006;24:4922-4927. 5. Chan JA, et al. Ann Oncol. 2011;22:1367-1373. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550. 7. Yano T, et al. Oncol Rep. 2006;15:65-71. 8. Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:915-925.


ToGA: Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer Rationale: a subpopulation of gastric cancers overexpress HER2

Primary endpoint: OS

*Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6.

(n = 584)

R

Patients with advanced

gastric cancer screened for HER2 status(N = 3803)

Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ,

measurable disease, capecitabine vs 5-FU

Patients with HER2-positive

advanced gastric cancer

(n = 810; 22% of successful screenings)

5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 +

Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose)

(n = 294)

5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6

(n = 290)

Bang YJ, et al. Lancet. 2010;376:687-697.


ToGA: Efficacy Outcome

Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC

Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-mo increase in OS with trastuzumab

– HR: 0.65 (95% CI: 0.51-0.83)

Outcome Chemotherapy + Trastuzumab

(n = 294)

Chemotherapy Alone

(n = 290)

HR (95% CI) P Value

Median OS, mos 13.8 11.1 0.74 (0.60-0.91) .0046

Median PFS, mos 6.7 5.5 0.71 (0.59-0.85) .0002

ORR, % 47 35 -- .0017

CR 5 2 -- .0599

PR 42 32 -- .0145



ToGA: OS by HER2 Status

HER2 Status Subgroup Median OS, Mos(CT + T vs CT Alone)

HR* (95% CI)

All patients (N = 584) 13.8 vs 11.1 0.74 (0.60-0.91)

Preplanned analysis

IHC 0/FISH+ (n = 61) 10.6 vs 7.2 0.92 (0.48-1.76)

IHC 1+/FISH+ (n = 70) 8.7 vs 10.2 1.24 (0.70-2.20)

IHC 2+/FISH+ (n = 159) 12.3 vs 10.8 0.75 (0.51-1.11)

IHC 3+/FISH+ (n = 256) 17.9 vs 12.3 0.58 (0.41-0.81)

IHC3+/FISH- (n = 15) 17.5 vs 17.7 0.83 (0.20-3.38)

Exploratory analysis

IHC 0 or 1+/FISH+ (n = 131) 10.0 vs 8.7 1.07 (0.70-1.62)

IHC 2+/FISH+ or IHC 3+ (n = 446) 16.0 vs 11.8 0.65 (0.51-0.83)


*HR < 1 favors chemotherapy + trastuzumab; HR > 1 favors chemotherapy alone.


Events,n

120136

Mos

228218

218198

196170

170141

142112

12296

10075

8453

6539

5128

3920

2813

2011

124

113

53

40

10

00

Pts at Risk, n

11.8 16.0

00.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Su

rviv

al P

rob

abili

ty FC + TFC

HR

0.65

95% CI

0.51-0.83

MedianOS, Mos

16.011.8

ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis)


FC + TFC


ToGA: Select Toxicities

Adverse Event, % Chemotherapy + Trastuzumab(n = 294)

Chemotherapy Alone(n = 290)

Grade 3/4 hematologic events

Neutropenia 27 30

Anemia 12 10

Grade 3/4 nonhematologic events

Diarrhea 9 4

Nausea 7 7

Cardiac events 6 6

Grade 3/4 1 3

LVEF reduction of ≥ 10% to absolute value < 50%*

5 1


*Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187.


ToGA: HER2 Positivity by IHC

*FISH or other in situ hybridization method recommended by NCCN guidelines panel.

Bang YJ, et al. Lancet. 2010;376:687-697. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011.

Score Surgical Specimen Staining Pattern

Biopsy Specimen Staining Pattern

HER2 Overexpr. Assessment

0

No reactivity or membranous

reactivity in < 10% of tumor cells

No reactivity or no membranous reactivity

in any tumor cellNegative

1+

Faint or barely perceptiblemembranous reactivity in

≥ 10% of tumor cells; cells are reactive only in part of their membrane

Tumor cell cluster with faint or barely perceptible membranous

reactivity regardless of % of tumor cells stained

Negative

2+

Weak to moderate complete, basolateral or

lateral membranous reactivity in ≥ 10% of

tumor cells

Tumor cell cluster with weak to moderate complete, basolateral or lateral membranous reactivity regardless of % of tumor cells

stained

Equivocal*

3+

Strong complete, basolateral or lateral

membranous reactivity in ≥ 10% of tumor cells

Tumor cell cluster with strong complete, basolateral or lateral

membranous reactivity regardless of % of tumor cells

stained

Positive


HER2 more heterogeneous in gastric vs breast cancer

Objectives

– Evaluate IHC-FISH concordance in processed samples

– Determine applicability of ASCO/CAP HER2 breast cancer scoring system to gastroesophageal carcinomas

Tafe LJ, et al. Arch Pathol Lab Med. 2011;135:1460-1465.

FISH IHC 0 IHC 1+ IHC 2+ IHC 3+ Total, n (%)

Positive (HER2/CEP17 > 2.2) 0 1 3 16 (100) 20 (15)

Negative (HER2/CEP17 < 1.8) 60 (97) 39 (93) 4 0 103 (77)

Equivocal (HER2/CEP17 1.8-2.2) 2 (1.9; 2.0)* 2 (2.1; 1.8)* 1 (2.1)* 0 5 (4)

Failure 2 2 0 1 5 (4)

Total, n (%) 64 (48) 44 (33) 8 (6) 17 (13) 133

HER2 Testing in Gastroesophageal Cancer

*Data in parentheses show individual values, not percentages.


Median OS Increased to > 1 Yr With Trastuzumab-Based Therapy

0 5 10 15Trastuzumab + XP/FP[8]

EOX[6]

XP[7]

ECX[6]

ECF[6]

DCF[4]

EOF[6]

IF[5]

CF[4]

FAMTX[2]

BSC[1]

C + S1[3]

Median OS in Patients With Advanced Gastric Cancer (Mos)

12 mos

1. Murad AM, et al. Cancer. 1993;72:37-41. 2. Vanhoefer U, et al. J Clin Oncol. 2000;18:2648-2657.3. Ajani JA, et al. J Clin Oncol. 2010;28:1547-1553. 4. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.5. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 6. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 7. Kang YK, et al. Ann Oncol. 2009;20:666-673. 8. Bang YJ, et al. Lancet. 2010;376:687-697.


Definition of HER2 Positivity for Gastroesophageal Carcinoma

HER2-Positivity Requirements for Approved Trastuzumab Use

US European Union

IHC 3+ or

FISH+ (ratio > 2.0)

IHC 3+ or

IHC 2+ and FISH+ (ratio > 2.0)


Prognostic Role of HER2 in Gastric Cancer Prognostic value of HER2 controversial with > 20 yrs of conflicting data

Systematic literature analysis involving 12,749 patients in 42 studies[1]

– 71% of studies demonstrated association between HER2 positivity and poor survival (40%) or clinicopathologic features (31%; eg, serosal invasion, LN metastases, disease stage, or distant metastases)

– However, multivariate analyses performed in only ~ 50% of studies

Systematic literature review involving 11,337 patients in 49 studies included 35 studies evaluating effect of HER2 overexpression on survival[2]

– 57%: no effect on OS

– 6%: significantly longer OS with HER2 overexpression

– 37%: significantly poorer OS with HER2 overexpression

1. Jørgensen JT, et al. J Cancer. 2012;3:137-144. 2. Chua TC, et al. Int J Cancer. 2012;130:2845-2856.


Gastric Cancer

Surgical cure rates are high with lesions limited to the mucosa or submucosa (ie, T1)

However, for patients with stage II or higher, 5-yr survival remains poor

Patients increasingly presenting with T1 N0 disease, but proportion remains low

40% to 50% of patients will present with unresectable disease

Overall 5-yr survival remains low

This is a bad disease

– After surgery, chances of long-term survival for most patients remains < 50%. Can we do better??


Gastric INT 116: Postoperative Chemoradiotherapy vs Surgery Alone

20% were GEJ tumors

– Similar survival benefit in this subset

OS

Pat

ien

ts (

%)

Macdonald JS, et al. N Engl J Med. 2001;345:725-730.

Mos After Registration

0

20

40

60

80

100

0 24 48 72 96 120

Surgery only

Chemoradiotherapy


70

HR: 0.82 (95% CI: 0.76-0.90; P < .001)

GASTRIC Group, et al. JAMA. 2010;303:1729-1737.

Meta-analysis: Surgery vs Surgery + Any Adj CT in Resectable GC Survival benefit for addition of chemotherapy

Su

rviv

al (

%)

Yrs From Randomization

0

20

40

60

80

100

0 2 3 7 9

10

30

50

90

1 4 5 6 8 10

Any chemotherapySurgery alone

Pts at Risk, nAny chemotherapySurgery along

19241857

16881568

13851300

12171092

1080952

929782

709583

526407

390267

297172

243138


Chemotherapy in Resectable Gastric Cancer Addition of pre/peri/postsurgery chemotherapy consistently

demonstrates benefit vs surgery alone

Study Regimens Primary Endpoint

Primary Endpoint Results

P Value

CLASSIC[1] Surgery vs surgery + adjuvant

capecitabine/oxaliplatin3-yr DFS 59% vs 74% < .0001

MAGIC[2] Surgery vs surgery + periop ECF

5-yr OS 23% vs 36% .009

Sakuramoto et al[3]

Surgery vs surgery + adjuvant S-1

3-yr OS 70% vs 80% .003

1. Bang YJ, et al. Lancet. 2012;379:315-321. 2. Cunningham D, et al. N Engl J Med. 2006;355:11-20. 3. Sakuramoto S, et al. N Engl J Med. 2007;357:1810-1820.


Chemotherapy in Resectable Gastric Cancer However, resounding lack of progress in improving patient

outcomes with any specific CT/CRT regimen vs any other chemotherapy regimen

1. Fuchs CS, et al. ASCO 2011. Abstract 4003. 2. Lee J, et al. J Clin Oncol. 2012;30:268-273.

Study Regimens Primary Endpoint

PrimaryEndpointResults

P Value

CALGB 80101[1]

Postop 5-FU/LV CRT vs ECF CRT

OS 37 vs 38 mos .80

ARTIST[2] Postop CT vs CRT (capecitabine/cisplatin)

3-yr DFS 74% vs 78% .086


RTOG 1010: Neoadjuvant Phase III Trial in Esophageal/GEJ Adenocarcinoma

Primary endpoint: DFS (15 → 27 mos; HR: 0.56)

Patients with confirmed HER2-overexpressing

esophageal or GEJ adenocarcinoma

(Planned N = 160)

Radiation (50.4 Gy) + Paclitaxel +

Carboplatin + Trastuzumab

Radiation (50.4 Gy) + Paclitaxel + Carboplatin

Stratified by presence of adenopathy and involved celiac nodes

Surgery 5-8 wks after radiation

completion

Surgery 5-8 wks after radiation

completion

Maintenance Trastuzumab

q3w x 13

Principal investigator: H. Safran, Providence, RI. ClinicalTrials.gov. NCT01196390.


Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or

GEJ cancer(Planned N = 535)

CapeOx + Lapatinib

CapeOx + Placebo

ClinicalTrials.gov. NCT00680901.

LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer

Primary endpoint: OS (was PFS)

Data expected mid-2012


Pertuzumab & Trastuzumab Bind Distinct Epitopes on HER2 Extracellular Domain

Activates ADCC Prevents HER2 domain

cleavage Inhibits HER2-mediated

signaling pathways

Activates ADCC Has a major effect on role of

HER2 as a coreceptor with HER3 or EGFR

Inhibits multiple HER-mediated signaling pathways

TrastuzumabPertuzumab

Hubbard SR. Cancer Cell 2005;7:287-288.


Second-line Paclitaxel + Lapatinib vs Paclitaxel for Advanced Gastric Cancer

Patients with HER2-amplified gastric cancer and PD

after 1 previous 5-FU and/or cisplatin regimen

(N = 273)

Paclitaxel + Lapatinib

Paclitaxel

ClinicalTrials.gov. NCT00486954.

Primary endpoint

– Initial pilot analysis: tolerability to determine optimal dosing

– Randomized part: OS


Phase II Studies of Targeted Agents in HER2-Positive Disease PF-00299804, pan-EGFR inhibitor (NCT01152853)

AUY922, Hsp90 inhibitor (NCT01402401)

Pertuzumab + trastuzumab + chemotherapy (NCT01461057)

Bevacizumab + trastuzumab + docetaxel, oxaliplatin and capecitabine chemotherapy (NCT01359397)

Bevacizumab + trastuzumab + capecitabine and oxaliplatin (NCT01191697)

Afatinib (NCT01522768)

ClinicalTrials.gov.


Summary

HER2 represents the first validated target in gastric and gastroesophageal junction adenocarcinoma

All patients with metastatic gastric/GEJ adenocarcinoma who are HER2 positive should be considered for trastuzumab-based therapy

There are few data on the use of trastuzumab in the pre-operative or adjuvant setting, or on its continued use after progression on trastuzumab-based therapy

Drug development targeting HER2 in gastric cancer is active and ongoing

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Manish A. Shah, MD Director, Gastrointestinal Oncology Weill Cornell Medical College...

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