| Connection 2010 28 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 Connection 2010 | 29  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 | Connection 2010 30 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 Amplied number of HER2 genes on chromosome 17 HER2 Blocks HER2 dimerization blinding to ECD IV Extracellular eects Intracellular eects Activation of antibody dependent cell-mediated cytotoxicity tumor cell lysis Receptor down-regulation through endocytosis Antiangiogenic eect (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 Connection 2010 | 31  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: • Getinib • Erlotinib II II Erlotinib showed a RR of 10% in previously untreated patients Gefitinib showed SD in 18% of previously treated patients HER2 antibody: • Trastuzumab III Trastuzmab is the only targeted therapy that has a proven survival benefit VEGFR antibody: • Bevacizumab III 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 | Connection 2010 32 Trastuzumab 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. ” Connection 2010 | 33 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/m 2 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. 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