Overview of Trastuzumab’s Utility for Gastric Cancer pdf

The majority of GC patients in clinical practice have advanced or metastatic disease, where chemotherapy is considered standard treatment, to provide palliation and prolong survival; how

Overview of Trastuzumab’s Utility for Gastric Cancer

Judith Meza-Junco, MD Heather-Jane Au, MD, FRCPC, MPH Michael B Sawyer, MD, BScPhm, FRCPC

Department of Oncology Cross Cancer Institute

11560 University Avenue Edmonton, Alberta, Canada, T6G 1Z2

Abstract

Gastric Cancer (GC) is the second leading cause of cancer-related

death worldwide, and has been managed with different treatment

strategies around the world Surgery is the mainstay of treatment for

non-metastatic disease Because recurrences are common after curative

resection, adjuvant radio-chemotherapy or perioperative chemotherapy

is recommended The majority of GC patients in clinical practice have

advanced or metastatic disease, where chemotherapy is considered

standard treatment, to provide palliation and prolong survival; however,

prognosis remains poor This paper reviews chemotherapy and targeted

therapies for GC, focusing on trastuzumab

Key Words: Gastric Cancer, HER2, Trastuzumab

Introduction

Gastric cancer (GC) treatment and prognosis vary in different regions

of the world; incidence of the disease, approach to early diagnosis and

treatment varies greatly between western and the eastern hemispheres

It is the second leading cause of cancer-related death worldwide (1)

In the US, it was estimated there would be 21,500 new cases and

10,880 deaths from GC in 2008; whereas more than 100,000 new

cases are diagnosed and 50,000 die annually of this cancer in Japan

Approximately 50% of GC cases in Japan are diagnosed at an early

stage, with 5-year survival for stage I GC reported above 90% In the Western world only 27% of cases are diagnosed at early stage and 5-year survival for stage II-III disease is 20-50%, and 5-10% for stage IV Different strategies have been tested around the world and have resulted in different approaches for localized and advanced GC

as summarized in Figure 1

Chemotherapy for GC

Locoregional and distant recurrences are frequently seen after surgery for GC, therefore, different approaches as adjuvant and perioperative therapies have been tested Three strategies have successfully demonstrated a survival benefit compared with surgery alone

Postoperative administration of 5-fluorouracil (5FU) and leucovorin, in combination with external beam radiation therapy, is routinely used

in the US (2) Perioperative chemotherapy with a combination of epirubicin, cisplatin and 5FU (ECF), is becoming standard practice

in many countries for resectable GC patients (3) In Japan, adjuvant monotherapy with surgery + adjuvant chemotherapy (S-1) (Fig 1) is common practice (4)

Chemotherapy for advanced unresectable or recurrent GC, in selected fit patients, offers significant advantages, such as increased survival,

Trastuzumab

Treatment Options for Gastric Cancer

Localized disease

Advanced disease

Preoperative CT (ECF)

Surgery + Adjuvant CRT(5FU/LV)

Surgery + Adjuvant CT(S-1)

ECF,ECX,DCF

Cisplatin + S1

Irinotecan

CT: chemotherapy; CRT: chemoradiotherapy; ECF: epirubicin, cisplatin, 5FU; ECX: epirubicin, cisplatin, capecitabine;

DCF: docetaxel, cisplatin, 5FU; CT§: chemotherapy with cisplatin and 5FU/capecitabine

Paclitaxel

Trastuzumab + CT§

HER2 Positive

Treatment Options for Gastric Cancer

First line therapies Second line therapies

(No Standard)

symptom control and quality of life, compared to best supportive care

(BSC) alone (5) A recent meta-analysis, showed that chemotherapy

improved overall survival (OS) for 6 months over BSC (Hazard Ratio or

HR of 0.39, 95% Confidence Interval or CI: 0.28-0.52) Best survival rates

were achieved with combined regimens including 5FU, anthracycline,

and cisplatin with a HR of 0.83 (95% CI, 0.74 to 0.93) over single-agent

5FU-based chemotherapy Response rates (RR) using ECF are 40%,

median survival of 9.4 months and 40% of patients alive at 1 year (6)

Epirubicin, oxaliplatin, and capecitabine (Xeloda®) (EOX) combination

treatment has reported a RR of 48%, median survival 11.2 months and

1 year survival of 48% (7)

The DCF regimen (docetaxel, cisplatin, and 5FU) has shown better RR,

longer progression-free survival (PFS) and a small survival advantage

over cisplatin and 5FU (CF) (9.2 vs 8.6 months; P.02) (8) However,

increased toxicity was seen (such as neutropenic infection and diarrhea), especially in patients older than 65

There is no internationally accepted standard of care; monotherapy with 5FU or doublets with 5FU and cisplatin, irinotecan or an anthracycline, are reasonable alternatives for patients who are not candidates for ECF DCF may be recommended as an option in selected very fit patients

Tegafur (S-1), a 5FU prodrug, is standard therapy for metastatic GC in Japan; based on a phase III trial S-1 was not inferior to 5FU in OS, it was associated with a higher RR, longer PFS, longer time to treatment failure and longer non-hospitalized survival (9) S-1 has also been compared

to S-1 plus CPT-11, and no differences were seen (10) However, S-1 plus cisplatin showed significantly longer survival over S-1 alone, with acceptable toxicities

Figure 1. Treatment options for Gastric Cancer.

Abbreviations: CT: chemotherapy; CRT: chemoradiotherapy; ECF: epirubicin, cisplatin, 5FU; ECX: epirubicin, cisplatin, capecitabine;

DCF: docetaxel, cisplatin, 5FU; CT§: chemotherapy with cisplatin and 5FU/capecitabine

There is no standard second or third-line of chemotherapy for advanced

GC; less than 40% of patients may be fit for treatment in that setting One

small phase III study, demonstrated that CPT-11 significantly prolongs

OS (by 50.5 days) and improves tumor related symptoms over BSC (11)

Paclitaxel has showed 20% RR in phase II studies Molecular targeting

agents are being tested in this setting

Targeted Therapy for GC

Although there are benefits of palliative chemotherapy, the prognosis of

advanced GC is still poor (median survival 7-10 months) A great interest

in targeted therapies has emerged and several molecular targeting agents are being tested; including anti-angiogenic agents and epidermal growth factor receptor (EGFR) antagonists, via monoclonal antibodies (MAb) (cetuximab, matuzumab, panitumumab and trastuzumab) or tyrosine kinase inhibitors (TKI) (gefitinib, erlotinib, lapatinib) Matrix metalloproteinase (MMP), insulin-like growth factor-1 receptor, fibroblast growth factor, c-Met and downstream signaling inhibitors, as well as cell cycle associated drugs targets are also under evaluation in phase I and II studies with advanced GC patients (12, 13) So far, trastuzumab

is the only targeted therapy that has a proven survival benefit in GC Table 1 summarizes targeted therapies for GC trials

Figure 2. Anti-tumor effects of Trastuzumab.

Abbreviations: ECD: extracellular domain; VEGF: vascular endothelial growth factor; PI3K: phosphoinositide 3-kinase

Cell Nucleus

HER1, 3 or 4

Breast Cancer Cell

Trastuzumab

Transcription

Amplified number of HER2 genes

on chromosome 17

HER2 Blocks HER2 dimerization blinding to ECD IV

Extracellular effects

Intracellular effects

Activation of antibody dependent cell-mediated cytotoxicity tumor cell lysis

Receptor down-regulation through endocytosis

Antiangiogenic effect (HER-family receptor blockade leads to reductions in VEGF)

G1 phase arrest Inhibits signaling (P13K pathway)

Pro-apoptosis and proliferation arrest í

í í

stop proliferation

Drugs and Their Targets Clinical Phase

EGFR antibody:

• Cetuximab

• Panitumumab

• Matuzumab

III III

I - II Cetuximab showed RR of 5% in pre-treated patients

Cetuximab + 5FU and oxaliplatin or CPT-11, showed a RR of 44-65% in untreated patients

Cetuximab + docetaxel showed SD in 43% of patients as second line treatment

Matuzumab + ECX showed a DCR of 43-57%

EGFR TKI:

• Gefitinib

• Erlotinib

II II Erlotinib showed a RR of 10% in previously untreated patients

Gefitinib showed SD in 18% of previously treated patients

HER2 antibody:

Trastuzmab is the only targeted therapy that has a proven survival benefit

VEGFR antibody:

Phase II studies: bevacizumab with CT (cisplatin and CPT-11; oxaliplatin and docetaxel or 5FU;

DCF) had a RR of 63-71% in untreated patients; but high frequency of toxicity

VEGFR TKI:

• Vatalanib

• Samaxinib

III Preclinical FGFR TKI:

• Brivanib

• Ki23057

II Preclinical IGF-R antibody:

• CP-751,871

IGF-R TKI:

• OSI 906

I - II

I HGF/Met-R antibody:

• AMG 102

HGF/Met-R TKI:

• GSK1363089 (XL880)

• Arqule

I - II

II

I - II Dual TKI EGF/HER2-R:

• Lapatinib

Dual TKI EGF/VEGF-R:

• Vadetenib

II

Preclinical Lapatinib showed a DCR of 25% in previously untreated patients

Multi TKI (Raf, VEGFR-2, VEGFR-3, PDGFR-β:

• Sorafenib

Multi TKI (RET, VEGFR, PDGFR, Flt3, c-KIT):

• Sunitinib

II

II Sunitinib showed a DCR of 40%

Sumilar efficacy was observed with sorafenib combined with docetaxel and cisplatin

Table 1. Targeted Therapies for Advanced Gastric Cancer

Abbreviations: RR: response rate; SD: stable disease; PR: partial response; CR: complete response; DCR: diease control rate (SD, PR, CR); CT: chemotherapy; ECX: epirubicin, cisplatin, capecitabine; DCF: docetaxel, cisplatin, 5FU

HER2/neu and Trastuzumab

HER2/neu (c-erbB-2) is a transmembrane tyrosine kinase (TK) receptor,

member of the human epidermal growth factor-receptor (HER) family

(HER1, 2, 3 and 4) HER2 function and signaling activity requires

receptor dimerization followed by transactivation of the TK portion of the

dimer Phosphorylation allows recruitment and activation of downstream

proteins, and the signaling cascade is initiated Given HER2 functions

as an oncogene, gene amplification induces protein over-expression in

cell membranes and regulates signal transduction in cellular processes,

such as proliferation, differentiation, and cell survival Aberrant HER2

expression or function has been associated in carcinogenesis of breast,

gastric, ovarian, salivary gland, prostate and lung tumors (14)

Trastuzumab is a recombinant humanized anti-HER2 MAb (rhuMAb

HER2; molecular weight 145531.5 g/mol), directed against the HER2

extracelluar domain (ECD) It was engineered from a cloned human

IgG, with structure and antigen-binding residues of a potent murine

MAb 4D5 The antibody was humanized to minimize the immunogenicity

associated with murine MAb and to enhance endogenous immune

antitumor effects (Fig 2) Its exact mechanism is not completely known,

however extracellular and intracellular actions have been postulated:

Extracellular Mechanisms:

Blocks HER2 receptor cleavage and inhibits dimerization,

consequently reducing HER2 signaling

By endocytosis, increases receptor destruction Trastuzumab

seems to induce HER2 down regulation and subsequent

degradation in HER2 over-expressing cancer cells

Intracellular Mechanisms:

Inhibits intracellular signaling pathways, such as

phosphoinositide 3-kinase (PI3K) signaling

Has anti-angiogenesis effect through decreasing vascular

endothelial growth factor (VEGF) produced by tumor cells; it

may indirectly modulate proangiogenic and antiangiogenic

factors, as well as synergistic activity with chemotherapy

Facilitates G1 phase arrest, by inducing cyclin-dependent

kinase (CDK) inhibitor p27Kip1

Has Cytostatic and Cytotoxic activity due to immune

system recruitment by antibody-dependent cell-mediated

cytotoxicity (ADCC)

Trastuzumab Tolerability

Trastuzumab is generally well tolerated The most common side effects are infusion-related reactions (fever, rigors, chills, nausea, dyspnea and hypotension), which may be present in 40% of patients with the first dose, and 5% with subsequent administrations Myelosuppression, nausea and emesis are rare and alopecia has not been reported when trastuzumab is used alone; however, when it is given with chemotherapy, it is difficult to quantify its contributions to these effects Cardiotoxicity (impairment of left ventricular ejection fraction) was evident in 27% of patients treated with trastuzumab and anthracyclines, 13% with trastuzumab and paclitaxel, and 5% with trastuzumab alone

in a pivotal study in breast cancer

Post-marketing surveillance reported that 62 of 25,000 (0.002%) patients had serious adverse events due to trastuzumab, including hypersensitivity reactions, infusion-related reactions and pulmonary events Adult respiratory distress syndrome, anaphylaxis, and death within 24 hours of a trastuzumab infusion were reported; most of these occurred in patients with preexisting pulmonary dysfunction (15)

Trastuzumab Efficacy in GC

Over-expression and amplification of HER2/ErbB2 in GC varies widely (6-45%) The largest data set of 3,883 advanced GC samples, found HER2-positivity rates of 22.9%; immunohistochemical (IHC) and

fluorescence in situ hybridization (FISH) concordance was 87.3%

No differences were seen between European and Asian countries HER2-positivity was higher in intestinal than diffuse/mixed cancer (32.2 vs 6.1%/20.4%; p<0.001) and in gastro-esophageal junction cancers than GC (33.2 vs 20.9%; p<0.001) (16)

Early studies in GC cell lines which over-expressed HER2 showed growth inhibition by trastuzumab; when it was combined with doxorubicin, cisplatin or paclitaxel it demonstrated increased cytotoxicity (17)

A small phase II study including 21 advanced GC patients with

“ Trastuzumab in combination with chemotherapy is a reasonable treatment option for patients with HER2-positive advanced GC, although this includes only approximately 20% of patients as potential candidates.”

over-expression/amplification of HER2; showed that (18) after

trastuzumab treatment (8 mg/kg loading dose in the first cycle followed

by 6 mg/kg every 21 days) and cisplatin (75 mg/m2 every 21 days),

response rates were 35% and stable disease was 17% The therapy was

well tolerated and no grade 4 toxicities were seen

The first randomized, controlled phase III trial, (ToGA) evaluated

trastuzumab efficacy and safety in HER2-positive advanced GC Patients

were randomized to receive trastuzumab with 5FU or capecitabine and

cisplatin versus chemotherapy alone Preliminary results showed better

median survival with the combination (13.5 vs 11.1 month, p=0.0048;

HR 0.74; 95% CI 0.60, 0.91), with a 26% reduction in risk of death PFS

was 6.7 vs 5.5 months (p=0002); and disease control (DC) was 47.3%

vs 34.5% (p=0.0017) with the addition of trastuzumab vs chemotherapy

alone Toxicity profiles were similar in both groups Subgroup analysis

(site of tumor, performance status, fluoropyrimidine used, histology,

age, region, prior gastrectomy and number of metastatic sites) for

survival favored trastuzumab throughout Additionally, patients with high

HER2-positivity by IHC had a trend for better survival in the pre-planned

analysis; patients with HER2 IHC2+/FISH+ or IHC3+ had a longer

survival (16 months) with trastuzumab compared to chemotherapy alone

(11.8 months) (19)

Conclusion

Prognosis of GC remains poor even after advances in diagnostics, surgical techniques, chemotherapy and radiotherapy regimens, thus, novel treatment options and predictors of treatment response are needed Advanced or metastatic GC constitutes most of patients seen in western clinical practice For them, chemotherapy has been considered standard with significant advantages (increased survival, symptom control and quality of life) compared to BSC alone Trastuzumab is the only targeted therapy that has now shown in a randomized trial modest but clinically significant improvement in survival, with no increases in toxicity, for patients with a poor prognosis Trastuzumab in combination with chemotherapy is a reasonable treatment option for patients with HER2-positive advanced GC, although this includes only approximately 20% of patients as potential candidates

Further investigation are required to evaluate trastuzumab’s efficacy for advanced GC as monotherapy, maintenance treatment after doublet or triplet regimens, in continuation beyond progression, and in combination with second line therapy; as well, in curative treatment trials for GC patients, such as peri-operative or postoperative therapy

Glossary

Curative resection: Complete tumor resection with

negative surgical margins

Adjuvant radio-chemotherapy: Combination of

radiotherapy and chemotherapy given after a radical

treatment (e.g., surgery), to destroy undetectable

residual tumor cells

Perioperative chemotherapy: Chemotherapy given

before and after surgery.

Hazard ratio: is the effect of a variable (e.g., treatment)

on the risk of an event (e.g., survival); it is considered an

estimate of relative risk.

References

1 Sugano K Gastric cancer: pathogenesis, screening

and treatment Gastrointest Endocopy Clin N Am 2008;

18:513-22.

2 Macdonald JS, Smalley SR, Benedetti J, et al

Chemoradiotherapy after surgery compared with

surgery alone for adenocarcinoma of the stomach

or gastroesophageal junction N Engl J Med 2001;

345:725-30.

3 Cunningham D, Allum WH, Stenning SP, et al MAGIC

Trial Participants Perioperative chemotherapy versus

surgery alone for resectable gastroesophageal cancer

N Engl J Med 2006; 355:11-20.

4 Sakuramoto S, Sasako M, Yamaguchi T, et al

ACTS-GC Group Adjuvant chemotherapy for gastric cancer

with S-1, an oral fluoropyrimidine N Engl J Med 2007;

357:1810-20.

5 Wagner AD, Grothe W, Haerting J, et al Chemotherapy

in advanced gastric cancer: a systematic review and

meta-analysis based on aggregate data J Clin Oncol

2006; 24:2903-9.

6 Ross P, Nicolson M, Cunningham D, et al Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced

esophagogastric cancer J Clin Oncol 2002;

20:1996-2004.

7 Cunningham D, Starling N, Rao S, et al Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom Capecitabine and oxaliplatin for advanced

esophagogastric cancer N Engl J Med 2008; 358:36-46.

8 Van Cutsen E, Moiseyenko VM, Tjulandin S, et al

Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A Report of the

V325 Study Group J Clin Oncol 2006; 24:4991-7.

9 Boku N, Yamamoto S, Shirao K, et al Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912) Annual meeting of ASCO 2007; (aLBA4513T).

10 Imamura H, IIishi H, Tsuburaya A, et al Randomized phase III study of irinotecan plus S-1 (IRIS) versus S-1 alone as first-line treatment for advanced gastric cancer (GC0301/TOP-002) ASCO Gastrointestinal Symposium 2008; (a5).

11 Wilson D, Hiller L, Geh JI Review of second-line chemotherapy for advanced gastric adenocarcinoma

Clin Oncol (R Coll Radiol) 2005; 17:81-90.

12 Arkenau HT Gastric cancer in the era of molecularly targeted agents: current drug development strategies

J Cancer Res Clin Oncol 2009; 135:855-66.

13 Meza-Junco J, Au HJ, Sawyer MB Trastuzumab for

gastric cancer Expert Opin Biol Ther 2009; 9:1543-51.

14 Hudis CA Trastuzumab – mechanism of action and use

in clinical practice N Engl J Med 2007; 357:39-51.

15 González V, Salgueiro E, Jimeno FJ, et al Post-marketing safety of antineoplasic MAb: rituximab and trastuzumab

Pharmacoepidemiol Drug Saf 2008; 17:714-21.

16 Bang Y, Chung H, Xu J, et al 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 J Clin Oncol 2009; 27:15S (a4556).

17 Gong SJ, Jin CJ, Rha SY, et al Growth inhibitory effects

of trastuzumab and chemotherapeutic drugs in gastric

cancer cell lines Cancer Lett 2004; 214:215-24.

18 Cortés-Funes H, Rivera F, Alés I, et al Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu over-expression/ amplification 2007 ASCO Annual Meeting Proceedings,

J Clin Oncol 2007; 25:18s (a4613).

19 Van Cutsem E, Kang Y, Chung H, et al Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive

advanced gastric cancer (GC) J Clin Oncol 2009;

27:18s(aLBA4509).