© Springer International Publishing Switzerland 2015
Vivian E. Strong (ed.)Gastric Cancer10.1007/978-3-319-15826-6_2424. Targeted Therapy and Novel Agents for the Treatment of Gastric Cancer: A View Toward the Future
Georgios D. Lianos1, Alberto Mangano2, Stefano Rausei3, Aikaterini Lianou4, Zoi Anastasiadi4, Gianlorenzo Dionigi5 and Dimitrios H. Roukos1
(1)
General Surgery and Centre for Biosystems and Genomic Network Medicine, University Hospital, Ioannina, Greece
(2)
General Surgery, University of Insubria, Varese-Como, Italy
(3)
Department of Surgery, University of Insubria, Varese, Italy
(4)
Department of Surgery, University Hospital, Ioannina, Greece
(5)
Department of Surgical Sciences, School of Medicine, University of Insubria, Varese, Italy
Keywords
Gastric cancerTargeted therapiesTrastuzumabLapatinibTrastuzumab-EmtansineDrug therapyNovel gastric cancer targeted agentsNext generation sequencing analysesIntroduction
Gastric cancer is an aggressive disease and although its incidence has declined, still remains the fourth most common type of cancer and the second leading cause of cancer-related death around the world [1]. Surgical approach is the only potential curative treatment, but despite optimization of surgery (R0 resection), radiotherapy, and cytotoxic chemotherapy, the 5-year survival rate is really poor [1].
It is reported that each year 900,000 patients are diagnosed with this disease [1]. Potentially, approximately 25 % of these patients may benefit by adding trastuzumab to current standard treatment. The 5-year survival rate after R0 resection and adjuvant multimodal treatment is approximately 40 %. Despite adjuvant perioperative chemotherapy for stages II and III, the overall treatment failure rate measured as 5-year recurrence or death rate is over 60 % in Western patients. Similarly poor are the results from the USA despite standardization of adjuvant chemoradiotherapy. The higher 5-year survival rate of 60 % in Japan as compared to the Western world can be explained by standardization of D2 lymphadenectomy in Japan and differences in tumor biology [2, 3].
Targeted therapy provides the potential for improving oncological outcomes [4]. Over the past decade, several agents targeting key components of important downstream signaling have been developed and approved by the Food and Drug Administration (FDA) for a series of cancers [4]. In this way, the latest deeper understanding of molecular “pathways” involved in many types of cancers shaping the way for the discovery of novel exciting targeted therapies [5].
In this chapter, we address with the latest scientific information on targeted drugs for the treatment of this aggressive disease and we provide a view toward the future on this issue.
Gastric Cancer Guidelines
Gastric cancer is the fourth most common cause of death from cancer worldwide. Undoubtedly, accurate tumor staging is essential for prognostic purposes. Recently, the Japanese Gastric Cancer Association (JGCA) published new versions of the guidelines. In western countries, the tumor-node-metastasis (TNM) system has been proposed by both the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Nowadays, there has been an agreement between the TNM categories in the new JGCA and the UICC/TNM seventh edition system. The most relevant modifications were the adoption of the classification proposed by the TNM and a simplification of the definitions for the types of lymphadenectomy. An important aspect to keep in mind is that the UICC, the AJCC, and the JGCA have made a great effort toward the establishment of a common “language” for gastric cancer treatment [6, 7].
This common language includes that endoscopic mucosal resection is recommended for patients with Tis or T1a tumors [7, 8]. Moreover, surgery is the cornerstone of treatment for T1b-2 stage or higher and any N stage. Adequate gastrectomy is recommended for T1b-3 tumors, while T4 tumors require resection of involved structures. As for D2, lymph node dissection has undoubtedly been the standard procedure for curable gastric cancer in eastern Asia for many years. On the other hand, in western countries and in the USA, D2 only recently became a recommended surgical option [9].
Another critical area is chemotherapy. The Japanese guidelines are different from the European and American (National Comprehensive Cancer Network [NCCN]) guidelines [10]. In adjuvant chemotherapy, S-1 is strongly recommended in Japan in patients with stage II or III gastric cancer following D2 gastrectomy. In the ACTS-GC trial, S-1 patients demonstrated significantly better survival than those undergoing surgery alone. In the west, surgery alone is considered an insufficient treatment for most patients [11]. NCCN recommends, in accordance with the results of the MAGIC trial, perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil regimen or its modifications for patients with T2 or higher and any N tumors (category 1 of evidence). Moreover, preoperative chemoradiation may also be evaluated for these patients (category 2B of evidence). For patients who have not received preoperative therapy, postoperative chemoradiation (5-fluorouracil ± leucovorin or capecitabine before and after fluoropyrimidine-based chemoradiation) is recommended for selected patients (T3 and 4, any N and T2N0 patients with poorly differentiated tumors, lymphatic invasion, and neural invasion and age younger than 50 years) [10]. In addition, based on the results of the CLASSIC trial in the east, postoperative chemotherapy is included with capecitabine and oxaliplatin after D2 gastrectomy in patients with T3, T4, and any N tumor. Moreover, for M1 or unresectable tumors docetaxel, cisplatin, and fluorouracil regimen or its modifications is recommended by NCCN, while in Japan the S-1 plus cisplatin regimen is widely used [10, 12].
Trastuzumab with active chemotherapy is considered for HER2/neu-positive patients [13, 14]. In order to highlight the existing differences, we can mention that survival in western countries seems improved after adjuvant chemoradiation therapy and neoadjuvant chemotherapy, while this evidence is not yet established in Japan. Despite the differences in treatment, management, and chemotherapy regimens for gastric cancer between Japan and the west, the different biological behavior of the tumors seems to influence the overall survival of these patients. Biological and oncological differences of gastric cancer in East Asia and the western world can be explained by genetic variation among populations and whole-genome function. The interpretation of genetic variants in patients with gastric cancer should be within the context of the local geographic genetic background [7, 15].
The ERBB/HER/EGFR Epidermal Growth Factor Receptor Family
The discovery of the epidermal growth factor (EGF) and its receptor (EGFR) in 1962 and 1978, respectively, opened the way for a new era of molecular oncology [16]. However, successful translation of these basic research findings into the clinic has occurred only during the past decade. The ERBB/HER or epidermal growth factor receptor (EGFR) family is represented by 4 receptor tyrosine kinases with similar architectural properties. Notably, these 4 kinases are HER1 (EGFR), HER2, HER3, and HER4, each comprising an extracellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain [16, 17]. Ligand binding to the extracellular domain of EGFR results in either homodimerization (binding to another EGFR) or heterodimerization (binding to another member of the ERBB family). It is reported that normal expression of EGFR is seen in intestinal and renal tissue, while overexpression has been documented in many tumor types [16].
Notably, EGFR overexpression has been demonstrated up to 44 % of gastric cancers, with rates increasing to up to 64 % with proximity to the gastroesophageal junction, where it is reported to be associated with poorly differentiated histology, increased invasion, and worse prognosis. HER2 amplification and overexpression plays a central role in initiation, progression, and metastasis of breast and gastric cancer [17]. HER2 status has been recognized as an important prognostic factor. Patients with breast cancer or gastric cancer and HER2-positive disease have significantly worse survival than those with HER2-negative tumors. Thus, this important receptor is a potential therapeutic target and in this way, the crucial activity of the EGF receptor family may be significantly inhibited by extracellular or intracellular “block” by novel sophisticated agents [17, 18]. Notably, monoclonal antibodies (mAbs) targeted against the extracellular binding site inhibit ligand binding and subsequent activation of the intracellular tyrosine kinase domain. On the other hand, tyrosine kinase inhibitors (TKIs) of the EGFR pathway exhibit activity in the intracellular domain of the receptor, by blocking the ATP-binding site [17, 19].
Anti-EGFR mAbs
We highlight that till date 3 mAbs (cetuximab, panitumumab, and matuzumab) targeting EGFR have been evaluated in clinical trials for patients with gastric cancer.
Cetuximab (Erbitux ®, Imclone Systems, NY, USA)
It is reported that cetuximab is a partially humanized murine anti-EGFR mAb. This agent is approved by FDA for the treatment of irinotecan refractory metastatic colorectal cancer. This drug has been studied in several phase II nonrandomized trials in combination with standard cytotoxic chemotherapy as first-line treatment for advanced gastric cancer [20]. These studies have reported overall survival (OS) rates ranging from 9 to 16 months. The randomized phase II CALGB80403/ECOG 1206 study compared the addition of cetuximab to three cytotoxic chemotherapy regimens (irinotecan–cisplatin, folinic acid–fluorouracil–oxaliplatin [FOLFOX], and epirubicin–cisplatin–fluorouracil) in patients with advanced esophagogastric cancer. Both ECF-C and FOLFOX-C demonstrated response rates of > 50 % and comparable overall survival, however, FOLFOX-C had a decreased rate of ≥ grade 3 toxicity when compared with ECF-C (78 vs. 61 %). OS observed was not significantly greater than that observed in studies evaluating these chemotherapy regimens alone [21]. In comparison with cetuximab, the anti-EGFR mAbs matuzumab and panitumumab have both been associated with potentially decreased efficacy and increased toxicity when added to cytotoxic chemotherapy for advanced gastric cancer [22].
Markers of Response to Cetuximab
The relationship between EGFR expression in gastric cancer and response to cetuximab remains unclear: two trials with folinic acid–fluorouracil–irinotecan (FOLFIRI), and FOLFOX chemotherapy demonstrated no correlation between EGFR positivity and response to cetuximab, whereas a trial with FOLFOX demonstrated an overall response rate (ORR) of 100 % for patients with EGFR expression [23]. However, in colorectal cancer, overexpression of EGFR by immunohistochemistry has failed to be predictive of potential benefit of either cetuximab or panitumumab. Furthermore, in contrast to colorectal cancer, where K-Ras mutation occurs in 40 % of patients and correlates robustly with no response to cetuximab and panitumumab, the presence of a K-Ras mutation is rare in gastric cancer and has not been associated with resistance to these agents [24].
Matuzumab (EMD72000, Merck)
The randomized phase II MATRIX trial examined the addition of matuzumab, a humanized anti-EGFR mAb to epirubicin–cisplatin–capecitabine (ECX) chemotherapy in the first-line treatment of advanced esophagogastric cancer [25]. A nonsignificant trend was seen toward worse progression-free survival (PFS) and OS in the matuzumab-ECX group (4.8 vs. 7.1 months) and (9.4 vs. 12.2 months), respectively, underlying the need to evaluate the effect of new agents added to conventional chemotherapy in the setting of a randomized, controlled trial [25].
Anti-EGFR Tyrosine Kinase Inhibitors (Erlotinib-Gefitinib)
Erlotinib (Tarceva®, Genentech, CA, USA) and gefitinib (Iressa®, AstraZeneca, London, UK) are orally available TKIs targeting the EGFR, and both of them have been approved for the treatment of metastatic non-small-cell lung cancer, where responses are more common in patients with activating mutations of the EGFR gene [26]. In addition, erlotinib has also been licensed for the treatment of pancreatic cancer in combination with gemcitabine chemotherapy regimen.
Both agents have been evaluated in treating advanced gastric cancer with controversial and nonpositive results. Of 30 patients with advanced early gastric cancer treated with erlotinib in a phase II second-line setting, only two responses were reported, both in EGFR-positive squamous cell carcinoma [27]. Moreover, median time to progression in adenocarcinoma was only 1.6 months. In the first-line setting, single-agent erlotinib had an ORR of 0 % in gastric and 9 % in gastroesophageal junction adenocarcinomas, with median OS of 4 and 7 months in these groups, respectively [28]. Similarly, gefitinib in the first-and second-line setting has demonstrated ORR of only 3–11 % and median OS of 4–6 months. For these reasons, it is more than clear that till date neither erlotinib nor gefitinib have significant activity in advanced gastric cancer [29].
Targeting HER2 in Gastric Cancer: Current Evidence
Recently more than 35 anticancer targeted drugs have been approved by the FDA, and about 150 agents are in preclinical and clinical staging, aiming at the discovery of more effective therapies [30].
In the vast majority, these anticancer agents target a single specific mutation or gene amplification. By inhibiting deregulated single-cellular signaling pathways, such agents can restore pathologic cell proliferation, survival, growth, apoptosis, invasion, angiogenesis, metabolism, and metastasis, which are thought to be the hallmarks of cancer [31]. Despite the explosion in the single-gene-targeting approach, with intensive research efforts and major investment by the pharmaceutical industry and the public sector, the efficacy of these single signaling transduction pathway inhibitors is in most cases modest. This is translated into a few weeks or months survival prolongation in the metastatic setting, which is not surprising if we consider substantial limitations of currently available targeting therapies [32].
The reasons for high intrinsic and acquired resistance rates to available targeting drugs include their temporary antitumor activity, lack of consideration of interpatient and intratumor heterogeneity, little attention to dynamics of transcriptional circuitry, and lack of a comprehensive view on how the cancer genome structure and molecular networks drive gene expression regulation [33].
The most important of these agents is now trastuzumab [34].
Trastuzumab (Herceptin®, Genentech): A Translational Triumph
It is out of question that targeted therapy represents the major hope in the “war” against cancer and a substantial step toward personalized medicine. An overenthusiasm and explosion in drug development followed the evidence of clinical success with trastuzumab [35].
HER2 (ERBB2) is variably overexpressed in gastric cancer; it is described that expression is highest in tumors of the gastroesophageal junction (> 20–30 %), lowest in diffuse-type tumors (6 %), and intermediate (10–15 %) in intestinal-type tumors of the distal stomach [36].
Trastuzumab is a fully humanized mAb that binds to the extracellular domain of the receptor, acting by blockage of the HER2 receptor, inhibition of dimerization, as well as by the induction of antibody-dependent cellular cytotoxicity (ADCC), and increasing endocytosis of the receptor and possibly through antiangiogenic effects [37]. It was developed in the 1990s, after murine monoclonal antibodies directed to the extracellular domain of HER2 were produced and evaluated in cell lines and xenografts [38].
Clinical Data
Although information on the specific genetic pathways involved is poor, HER2 has been shown to be amplified and overexpressed in gastric cancer. Notably, HER2 is progressively considered by the researchers as an important biomarker in gastric cancer, with studies pointing out amplification or overexpression in 7– 34 % of tumors, mainly in the intestinal type and in esophagogastric junction and proximal tumors [39].
Cortés-Funes et al. presented preliminary results of a phase II study involving 21 chemotherapy-naïve patients with HER2 overexpressing locally advanced or metastatic gastric cancer. Trastuzumab at a loading dose of 8 mg/kg and maintenance dose of 6 mg/kg and cisplatin 75 mg/m2 were administered every 21 days until progression, unacceptable toxicity, or withdrawal of consent. Response rate was of 35 %, with 17 % of patients achieving stabilization. The tolerability profile was favorable; no grade 4 toxicity was observed and mostly the frequent grade 3 events were asthenia, nausea or vomiting, diarrhea, hiporexia, and neutropenia. Data from another preliminary phase II study involving 16 gastric cancer patients were presented by Egamberdiev et al. Trastuzumab 6 mg/kg was administered once in addition to cisplatin 100 mg/m2 during 3 days + fluorouracil (5-FU) 1000 mg/m2 3 days + leicovirin 100 mg/m2 3 days, every 3 week. Authors reported an objective response rate of 54.5 % in the combined therapy group vs. 33.3 % in the chemotherapy-only group and a median remission duration of 8.3 months vs. 5.2 months. In a recent phase II study carried out by Grávalos et al., chemo-naïve patients with nonresectable advanced or metastatic gastric or esophagogastric adenocarcinoma overexpressing HER2 were treated with trastuzumab 8 mg/kg as loading dose and 6 mg/kg in subsequent cycles + cisplatin 75 mg/m2 every 3 weeks. Twenty-two out of 228 patients (9.6 %) enrolled had HER2 overexpression. An overall response rate of 32 % was found, with disease control achieved in 64 % of patients; median time to progression was 5.1 months. No grade 4 toxicities occurred, whereas most frequent grade 3 adverse events were asthenia, neutropenia, anorexia, diarrhea, and abdominal pain. Interestingly, higher baseline HER2 extracellular domain levels associated with better response to therapy. In more recent studies, HER2 overexpression was found to be lower than previously reported, especially in distant gastric cancers. Resectable gastric cancer has reported HER2-positive ratios of 8.1 and 11.7 %, suggesting that in resectable gastric cancer HER2 positive status might be less frequent than in advanced gastric cancer [40, 41].
The ToGA Trial: A Milestone in Modern Oncology
The phase III ToGA trial [14] constitutes a milestone in modern oncology, establishing trastuzumab as the first biological therapy with demonstrated survival benefits in gastric cancer. In this way, ToGA trial was a multicenter, international trial, performed in 24 countries. It evaluated the combination of trastuzumab with standard chemotherapy (cisplatin + either capecitabine or 5-FU) in advanced (inoperable locally advanced, recurrent, or metastatic) HER2-positive gastric cancer as a first-line therapy vs. chemotherapy alone. Patients enrolled were treated with six cycles of chemotherapy in both treatment arms, with patients in the experimental arm continuing to be treated with trastuzumab until disease progression. Cisplatin 80 mg/m2 was given on day 1 by intravenous infusion. Capecitabine 1000 mg/m2 was given orally twice a day for 2 weeks followed by a 1-week rest or 5-FU 800 mg/m2 per day was given by continuous infusion on days 1–5 of each cycle. Trastuzumab was given intravenously at a loading dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg afterward. The primary endpoint of the study was to compare OS in both arms, and the secondary endpoints were to compare progression-free survival (PFS), time to progression, overall response rate, disease control, duration of response, and quality of life between the two arms. It is important to highlight that in this “historical” trial, among approximately 3670 tumor tissue specimens screened for HER2 positivity, 22 % were revealed HER2 positive (34 % of the intestinal type vs. 6 % of diffuse and 20 % of mixed types). The highest rate was observed in 34 % of esophagogastric junction cancer and 20 % of gastric cancer samples. The researchers reported that the combination of trastuzumab with chemotherapy in advanced HER2-positive gastric cancer patients showed significantly better OS rates compared to the same chemotherapeutic regimen alone (median OS in the combination treatment group was 13.8 months vs. 11.1 months in the chemotherapy-alone arm). This effect was observed in patients with intestinal type gastric cancer but not in those with diffuse type gastric cancer. Median PFS (6.7 months vs. 5.5 months) and radiological response rate (47 vs. 35 %,) was also revealed improved with trastuzumab therapy. In fact, patients with strongest HER2 expression gained the greatest benefit, with a median survival of 17.9 months in patients treated with trastuzumab against 12.3 months which received chemotherapy alone [14].
As for the adjuvant setting, it is important to consider the possible benefits of trastuzumab in the adjuvant setting for earlier stages of the disease. Important trials have been conducted with the intent to investigate anti-HER2 therapeutics in this setting. Early onset gastric cancer (presenting at or under the age of 45) seems to have lower HER2 overexpression than in late onset cases, with possible different molecular genetic pathways [14].
Based on these results, trastuzumab has been licensed and approved for the treatment of advanced gastric cancer in the USA and Europe [14].
Limitations
The absolute benefit in response rate to trastuzumab addition to chemotherapy was 12.8 % and it resulted in a prolongation of overall survival by 2.4 months. These data indicate resistance to trastuzumab even among HER2-positive selected patients. However, it is likely that, because of less residual disease after surgery in resectable gastric cancer, the trastuzumab therapeutic gain may be larger in the adjuvant setting with substantial 5-year survival rate benefit [42].
However, the absolute survival benefit is small because resistance and relapse or disease progression rates with fatal outcome still remain high. Exciting research has focused on understanding molecular mechanisms underlying this resistance, aiming to develop novel, more effective drugs with higher clinical response rates [42].
Overcoming Resistance
Resistance to molecular targeting therapy is currently the cause of treatment failure in cancer. Similarly, the absolute additional response rate to trastuzumab among HER2-positive advanced gastric cancer in the ToGA study is small: 12.8 %. Given that HER2-positive accounts for approximately 25 %, only 3.12 % of all gastric cancer patients can benefit from trastuzumab treatment [42].
Trastuzumab Emtansine (T-DM1)
The single agent T-DM1 is an ADC that incorporates the HER2-targeted antitumor capacities of trastuzumab with the cytotoxic properties of the microtubule-inhibitory agent DM1 (derivative of maytansine); the antibody and the cytotoxic agent are described to be conjugated by a stable linker . Interestingly, T-DM1 allows intracellular drug delivery specifically to HER2-overexpressing cells, thereby improving the therapeutic rate and minimizing the exposure of normal tissue cells to the complex. It seems that T-DM1 is internalized upon binding to HER2-overexpressing tumor cells. Moreover, it is the first HER2-targeted ADC with a stable and unique linker. T-DM1 is an ADC that is currently being investigated in various clinical trials. Early in its development, studies were conducted to identify the optimal linker to conjugate trastuzumab to DM1. Interestingly, in preclinical studies, it was shown that linking DM1 to trastuzumab via a nonreducible thioether yielded superior activity, improved pharmacokinetics, and presented less toxicity compared with trastuzumab linked to a maytansinoid via a disulfide linker. Furthermore, the T-DM1 was shown to be selective for HER2-positive cells, displayed enhanced potency compared with trastuzumab alone in vitro, and retained activity against trastuzumab-resistant cells in vitro and in vivo. In other words, T-DM1 is an agent that combines an antibody and a cytotoxic agent, which are conjugated by means of a stable linker . A trial is now underway to examine the efficacy and safety of T-DM1 compared with standard taxane therapy in patients with HER2-positive gastric cancer. In this study, patients will be randomized to one of three groups, 3.6 mg/kg T-DM1 every 3 weeks, 2.4 mg/kg T-DM1 every week, or standard taxane therapy, for at least four cycles (12 weeks). The endpoints include overall survival, progression free survival, duration of response, and time to gastric cancer symptom progression, as well as safety. The near future will determine the exact role of T-DM1 in the current therapeutic “armamentarium” for HER2 positive gastric cancer [42, 43] .
Anti-HER2 Tyrosine Kinase Inhibitors
Lapatinib (Tykerb ®, Glaxosmithkline)
Other HER2 targeting agents have also been developed, including lapatinib. Lapatinib is an orally active synthetic drug that is approved for HER2-positive breast cancer in combination with capecitabine. Lapatinib inhibits HER2 signaling by blocking tyrosine kinase activity. In the lapatinib with paclitaxel (Taxol) in Asian HER2 Gastric Cancer Study (TYTAN), for example, patients across five Asian countries are to be randomly assigned to lapatinib (1500 mg daily) plus paclitaxel (80 mg/m2 weekly) or paclitaxel alone. The primary endpoint of the study is OS. This study did not show an improvement in the primary endpoint. However, the efficacy of lapatinib was strongly suggested in the IHC3 subset. These results indicate that the definition of HER2-positive gastric cancer is very important for the development of new anti-HER2 drugs. As mentioned above, lapatinib is an oral TKI with activity against EGFR and HER2/neu and is licensed for the treatment of HER2 refractory breast cancer. Results from the use of this agent in gastric cancer have not been promising to date. Lapatinib was evaluated as a single agent in an unselected advanced gastric cancer patient population in the first-line treatment setting. In this study (SWOG S041), a confirmed partial response rate of only 7 % was seen, and median OS was 5 months, which compares unfavorably with standard cytotoxic chemotherapy. A study of single-agent lapatinib in 25 previously treated patients selected by EGFR or HER2 positivity by IHC or FISH (HER2 only) demonstrated an ORR of 0 % and stable disease in two patients only. Further evaluation of lapatinib in HER2-positive patients in the phase III setting is ongoing in two trials: the LOGIC trial (NCT0068090), evaluating capecitabine and oxaliplatin with or without lapatinib, and the TYTAN trial, evaluating second-line paclitaxel with or without lapatinib (NCT00486954) [44, 45].
Antiangiogenetic Strategies for Gastric Cancer
Tumor angiogenesis and metastasis are robustly associated with angiogenesis in most solid tumors. Recognition of the vascular endothelial growth factor (VEGF) pathway as a key regulator of angiogenesis has led to the development of several VEGF-targeting agents, including neutralizing antibodies to VEGF or its receptor (VEGFR) and TKIs targeting the VEGFR. New blood vessel formation or neovascularization is crucial for tumor growth and metastasis. VEGF is the most potent mediator of this process. VEGF binds to the high-affinity receptors VEGFR (type 1 and 2) and leads to endothelial cell migration and proliferation and changes in the extracellular matrix resulting in increased vascular permeability and sustained new blood vessel formation. Antiangiogenesis strategies using both mAbs and TKIs have improved OS in several tumors types such as colon, renal, non-small-cell lung cancer, and hepatocellular carcinoma, and have been extensively evaluated in gastric cancer. In gastric cancer setting, it is reported that increased tumor and serum VEGF levels are associated with a poor prognosis [46, 47].
Anti-VEGF mAb Therapy
Bevacizumab (Avastin ®, Genentech)
It is widely known that bevacizumab is a humanized anti-VEGF mAb that is approved for the treatment of metastatic colorectal cancer, breast cancer, renal cell carcinoma, non-small-cell lung cancer, and glioblastoma. There are various promising phase II studies that have evaluated the addition of bevacizumab to first-line chemotherapy in advanced gastric cancer with OS rates reported of up to 17 months. As for phase III trials, the large randomized phase III AVAGAST trial compared the addition of bevacizumab to a cisplatin/fluoropyrimidine doublet in approximately 780 patients receiving first-line treatment for gastric cancer. The researchers reported discouraging results. OS was 10.1 vs. 12.2 months in the chemotherapy-alone and chemotherapy plus bevacizumab groups respectively (HR: 0.87; p = 0.1002). PFS and antitumor response were significantly improved in the bevacizumab-containing arm with response rates increasing from 37 to 46 % and PFS from 5.3 to 6.7 months with the addition of this agent [48–53].
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