Tumor Biol. DOI 10.1007/s13277-015-4408-9
REVIEW
Monoclonal antibodies-based treatment in gastric cancer: current status and future perspectives Giandomenico Roviello 1 & Karol Polom 2 & Roberto Petrioli 3 & Luigi Marano 4 & Daniele Marrelli 5 & Giovanni Paganini 6 & Vinno Savelli 7 & Daniele Generali 8 & Lorenzo De Franco 5 & Andrea Ravelli 9 & Franco Roviello 2
Received: 30 August 2015 / Accepted: 9 November 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Gastric cancer (GC) is the second leading cause of cancer-related death, and despite having improved treatment modalities over the last decade, for most patients, only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and the related signaling pathways offers, from the clinical point of view, promising advances for selected groups of patients. In the past, targeted therapies have significantly impacted the treatment strategy of several common solid tumors such as breast, colorectal, and lung cancers. Unfortunately, translational and clinical research shows fewer encouraging targeted treatments with regards to the GC. To date, only two monoclonal antibodies (mAb), named trastuzumab and ramucirumab, are approved for the treatment of advanced GC, suggesting that in GC, maybe more than in other cancers, effective targeted therapy requires patient selection based on precise predictive molecular biomarkers. The aim of this review is to summarize the available data on the clinical advantages offered by the use
* Giandomenico Roviello [email protected]
1
2
3
Section of pharmacology and University Center DIFF—Drug Innovation Forward Future, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25124 Brescia, Italy Department of Medical, Surgical and Neuroscience; Unit of General and Minimally Invasive Surgery, University of Siena, Viale Bracci 11, 53100 Siena, Italy Medical Oncology Unit, University of Siena, Viale Bracci 11, 53100 Siena, Italy
of mAbs in the treatment of advanced/metastatic GC. Future perspective is also discussed. Keywords Gastric cancer . Target therapy . Ramucirumab . Trastuzumab . Bevacizumab
Introduction Gastric cancer (GC) is one of the most common malignancies, especially in Eastern countries or in some part of Western countries [1]. Despite the improvements achieved for patients with early stage disease [2, 3], a 5-year overall survival (OS) under 10 % and a median OS under 12 months remains the poor outcome for patients with metastatic disease [4], and chemotherapy is considered to be the cornerstone of treatment in advance/metastatic GC setting. The approved chemotherapeutic agents include platinum-based drugs (cisplatin and
4
General, Minimally Invasive and Robotic Surgery, Department of Surgery, BSan Matteo degli Infermi^ Hospital, ASL Umbria 2, 06049 Spoleto, Italy
5
Department of Medical, Surgical and Neurosciences, Section of Advanced Surgical Oncology, University of Siena, Viale Bracci 11, 53100 Siena, Italy
6
Unit of General Medicine, Azienda Ospedaliera BC. Poma ^ Presidio ospedaliero di Pieve di Coriano, Mantova, Italy
7
Department of Surgery and Bioengineering, Section of Surgery, University of Siena, Viale Bracci 11, 53100 Siena, Italy
8
Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, Italy
9
Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
Tumor Biol.
oxaliplatin), taxane-based agents (docetaxel and taxol), fluoropyrimidines such as 5-fluorouracil and capecitabine, and anthracyclines mainly epirubicin and doxorubicin [5, 6]. Interestingly, treatment with the combination of three agents has been shown to lead to modest improvements in survival compared to two agents, but with an increase of toxicity [7]. Unfortunately, not many treatment options are available after the failure of first-line therapy. Irinotecan (as single-agent or in combination with other cytotoxic agents) and paclitaxel have also been evaluated as a second-line therapy [8, 9]. Nonetheless, their outcomes are poor. These results highlight the need for less toxic and more effective therapeutic options. Monoclonal antibodies (mAbs) are laboratory-produced molecules that have been carefully engineered to attach to specific sites. These drugs mimic our body’s naturally produced antibodies as part of our immune system’s response. Monoclonal antibodies are used to treat many diseases, including some types of cancer. They are engineered to recognize and attach to superficial cell membrane-specific proteins and act in different ways depending on the protein they are targeting. The pathogenesis of GC cancers involves multiple altered molecular pathways that can be targeted by specific mAbs. Therefore, novel mAbs have emerged for the management of GC. In this context, the addition of trastuzumab has significantly improved survival in patients with HER2-positive GC [10]. However, this therapeutic option is available only for a few patients, as the overexpression (IHC) or amplification (FISH) of HER2 has been identified in less than 20 % of patients [10–12]. Additionally, ramucirumab has been approved as a second-line treatment in patients with advanced or metastatic GC who progressed on fluoropyrimidine- or platinum-containing first-line chemotherapy [13, 14]. Unfortunately, other agents targeting oncogenic mediators such as EGFR, mTOR, and c-Met have not been shown to improve survival [15–21]. The aim of this review is to summarize the available data on mAbs that are clinically used for the treatment of advanced or metastatic GC.
Anti-VEGF/VEGFR agents Angiogenesis is today universally considered as a cancer hallmark because it is one of the main processes for tumor progression. The increase of tumor size and the functional abnormalities of the tumor vasculature lead to tissue hypoxia that induces neoangiogenesis [22, 23]. The primary proangiogenic driver of this process is vascular endothelial growth factor (VEGF), also known as VEGF-A. The family of VEGF molecules also includes VEGF-B, VEGFC, VEGF-D, VEGF-E, and placental growth factor (PGF). Each component of this family can bind to several VEGF receptors (VEGFR), known as VEGFR1 (fms-like
tyrosine kinase 1/Flt-1), VEGFR2 (Flk-1/KDR), and VEGFR3 (Flt-4), and 2 co-receptors, neuropilin 1 and 2 (NRP1/2). In particular, VEGF-A binds to VEGFR-1 and VEGFR-2, VEGF-B and PGF to VEGFR-1, and VEGF-C and -D to VEGFR-2 and -3 [23, 24]. The most important receptor is VEGFR-2 [25], which regulates the proliferation of endothelial cells through a number of different mechanisms [23, 26]. The expression of VEGFR2 in intestinal-type GC was found to correlate with the vessel count and the stage of disease [27]. In addition, in patients with GC, several studies have investigated the clinical and prognostic significance of circulating VEGF levels [27–32]. Other proteins, such as hypoxia inducible factor (HIF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiopoietin (Ang), and Notch, play important roles in angiogenesis [33, 34]. VEGF/VEGFR pathway and relative target of mAbs are reported in Fig. 1. Bevacizumab Bevacizumab is a humanized monoclonal antibody against VEGF; this binding inhibits tumor angiogenesis. Bevacizumab is currently approved for the treatment of colon, lung, breast, ovarian, endometrial, and clear cell renal carcinoma in the metastatic stage [35–39]. Several phase II trials of bevacizumab plus chemotherapy have been reported for GC patients [40–42]. An overall response rate (ORR) of 42 to 67 % was achieved. The median progression free survival (PFS) was 6.6–12 months, whereas the OS was 8.9– 16.2 months. Grades 3–4 thromboembolic diseases were reported in approximately 25 % of the patients, and gastric perforation was observed in up to 8 % of the patients. Based on these results, an international, randomized, double-blind, placebo-controlled phase III trial, the Avastin for Advanced Gastric Cancer trial (AVAGAST), was conducted. The AVAGAST trial was designed to evaluate the benefit of adding bevacizumab to first-line capecitabine-cisplatin treatment for patients with advanced gastric cancer. Overall, 774 patients were randomly selected to receive the combination of capecitabine with cisplatin with or without bevacizumab [43]. Cisplatin was administered for 6 cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The ORR significantly improved with the addition of bevacizumab (46 vs. 37 %; P=0.0315), and the median PFS was also significantly longer (6.7 vs. 5.3 months, HR= 0.80, 95 % CI 0.68–0.93; P=0.0037). The median OS was 12.1 months with the presence of bevacizumab and only 10.1 months with the combination fluoropyrimidine-cisplatin. However, this did not reach the specified criteria for statistical significance (HR=0.87, 95 % CI 0.73–1.03; P=0.1002) [43]. Interestingly, the preplanned subgroup analyses revealed regional differences in efficacy outcomes. Indeed, the beneficial
Tumor Biol. Fig. 1 Monoclonal antibodies targeting VEGF/VEGFR pathway
effect of bevacizumab on all of the study outcome measures was substantially higher among patients recruited in the Americas, pan-American regions as opposed to patients recruited in Europe (intermediate effect). In contrast, no benefit of bevacizumab was observed in Asian patients, 90 % of whom were recruited from Japan and Korea. Differences in population genetics, patient selection, and second-line chemotherapy may account for these results. Moreover, in this study, the baseline plasma levels of VEGF-A and tumor expression of neuropilin-1 were identified as potential predictors of bevacizumab efficacy. Patients with high baseline plasma levels of VEGF-A showed a trend toward improved OS (hazard ratio [HR] 0.72; 95 % CI 0.57–0.93) compared to patients with low VEGF-A levels (HR 1.01; 95 % CI 0.77–1.31; interaction P=0.07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved OS (HR 0.75; 95 % CI 0.59–0.97) compared to patients with high neuropilin-1 expression (HR 1.07; 95 % CI 0.81–1.40; interaction P=0.06). For both biomarkers, subgroup analyses demonstrated statistical significance only in patients from non-Asian regions [44]. The most common grades 3–5 adverse events in both arms of the trial were neutropenia, anemia, and appetite loss. These events occurred at similar rates with or without bevacizumab [43]. Another smaller phase III study, which mimicked the design of the AVAGAST trial, was conducted in 202 Chinese patients. These patients differed from Asian patients enrolled in the AVAGAST trial [45]; the latter being mainly from Japan and Korea with a greater incidence of liver metastases and gastroesophageal junction tumors with a low rate of previous gastrectomy. Another remarkable finding is that patients in the AVAGAST trial were less likely to receive a second and/or additional line of therapy after disease progression as the medical insurance in China does not cover second-line drugs. Therefore, Chinese patients
were more comparable to the European-American subgroup than the Asian-Pacific subgroup of the AVAGAST trial. This study showed no significant differences between chemotherapy plus bevacizumab vs. chemotherapy alone (OS 10.5 vs. 11.4 months; PFS 6.3 vs. 6.0 months). Both the incidence of grade ≥3 adverse events and the incidence of grade ≥3 adverse events of special interest for bevacizumab were comparable between the treatment arms. The ST03 was a multicenter, randomized, phase II/III study comparing peri-operative epirubicin, cisplatin, and capecitabine (ECX) with or without bevacizumab designed with the first 200 patients contributing to a phase II assessment of safety powered to exclude unacceptable rates of gastrointestinal perforation and cardiotoxicity. In the interim analysis based on the safety issue, the incidence of cardiac complications was similar in both arms, except for arterial thromboembolic events and more asymptomatic left ventricular ejection fraction drops, which were more frequent in ECX plus bevacizumab arm [46]. Therefore, the addition of bevacizumab to peri-operative ECX chemotherapy seems feasible with acceptable toxicity without negative impact on surgical outcomes; the phase III trial based on the combination of chemotherapy with bevacizumab is ongoing. In consideration of the disappointing results obtained by the use of bevacizumab in the treatment of metastatic GC, the final results of ST03 trial are awaited to define the role of bevacizumab in peri-operative setting only. Ramucirumab Ramucirumab, a humanized IgG1 monoclonal antibody against VEGFR-2, prevents ligand binding and receptormediated pathway activation in endothelial cells [47]. Preclinical studies have shown that targeting VEGF receptors with
Tumor Biol.
ramucirumab was associated with the inhibition of VEGFmediated signaling along with the inhibition of proliferation and migration of endothelial cells exerting simultaneously an anti-tumor activity [47–51]. The phase III, placebo-controlled, double-blinded REGARD trial was conducted with the aim of evaluating the safety and efficacy of ramucirumab as secondline treatment in 355 patients with advanced, unresectable GC [13]. Patients were randomly assigned 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care until disease progression, unacceptable toxicities, or death. The primary endpoint of the trial was OS. Treatment with ramucirumab lead to a statistically significant OS improvement (HR 0.77, 95 % CI 0.60–0.99; P=0.047), with a median OS of 5.2 months for patients who received ramucirumab vs. 3.8 months for those who received placebo. Moreover, an increase in PFS was reported (2.1 months for ramucirumab vs. 1.3 months for placebo; HR = 0.48, P
REVIEW
Monoclonal antibodies-based treatment in gastric cancer: current status and future perspectives Giandomenico Roviello 1 & Karol Polom 2 & Roberto Petrioli 3 & Luigi Marano 4 & Daniele Marrelli 5 & Giovanni Paganini 6 & Vinno Savelli 7 & Daniele Generali 8 & Lorenzo De Franco 5 & Andrea Ravelli 9 & Franco Roviello 2
Received: 30 August 2015 / Accepted: 9 November 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Gastric cancer (GC) is the second leading cause of cancer-related death, and despite having improved treatment modalities over the last decade, for most patients, only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and the related signaling pathways offers, from the clinical point of view, promising advances for selected groups of patients. In the past, targeted therapies have significantly impacted the treatment strategy of several common solid tumors such as breast, colorectal, and lung cancers. Unfortunately, translational and clinical research shows fewer encouraging targeted treatments with regards to the GC. To date, only two monoclonal antibodies (mAb), named trastuzumab and ramucirumab, are approved for the treatment of advanced GC, suggesting that in GC, maybe more than in other cancers, effective targeted therapy requires patient selection based on precise predictive molecular biomarkers. The aim of this review is to summarize the available data on the clinical advantages offered by the use
* Giandomenico Roviello [email protected]
1
2
3
Section of pharmacology and University Center DIFF—Drug Innovation Forward Future, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25124 Brescia, Italy Department of Medical, Surgical and Neuroscience; Unit of General and Minimally Invasive Surgery, University of Siena, Viale Bracci 11, 53100 Siena, Italy Medical Oncology Unit, University of Siena, Viale Bracci 11, 53100 Siena, Italy
of mAbs in the treatment of advanced/metastatic GC. Future perspective is also discussed. Keywords Gastric cancer . Target therapy . Ramucirumab . Trastuzumab . Bevacizumab
Introduction Gastric cancer (GC) is one of the most common malignancies, especially in Eastern countries or in some part of Western countries [1]. Despite the improvements achieved for patients with early stage disease [2, 3], a 5-year overall survival (OS) under 10 % and a median OS under 12 months remains the poor outcome for patients with metastatic disease [4], and chemotherapy is considered to be the cornerstone of treatment in advance/metastatic GC setting. The approved chemotherapeutic agents include platinum-based drugs (cisplatin and
4
General, Minimally Invasive and Robotic Surgery, Department of Surgery, BSan Matteo degli Infermi^ Hospital, ASL Umbria 2, 06049 Spoleto, Italy
5
Department of Medical, Surgical and Neurosciences, Section of Advanced Surgical Oncology, University of Siena, Viale Bracci 11, 53100 Siena, Italy
6
Unit of General Medicine, Azienda Ospedaliera BC. Poma ^ Presidio ospedaliero di Pieve di Coriano, Mantova, Italy
7
Department of Surgery and Bioengineering, Section of Surgery, University of Siena, Viale Bracci 11, 53100 Siena, Italy
8
Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, Italy
9
Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
Tumor Biol.
oxaliplatin), taxane-based agents (docetaxel and taxol), fluoropyrimidines such as 5-fluorouracil and capecitabine, and anthracyclines mainly epirubicin and doxorubicin [5, 6]. Interestingly, treatment with the combination of three agents has been shown to lead to modest improvements in survival compared to two agents, but with an increase of toxicity [7]. Unfortunately, not many treatment options are available after the failure of first-line therapy. Irinotecan (as single-agent or in combination with other cytotoxic agents) and paclitaxel have also been evaluated as a second-line therapy [8, 9]. Nonetheless, their outcomes are poor. These results highlight the need for less toxic and more effective therapeutic options. Monoclonal antibodies (mAbs) are laboratory-produced molecules that have been carefully engineered to attach to specific sites. These drugs mimic our body’s naturally produced antibodies as part of our immune system’s response. Monoclonal antibodies are used to treat many diseases, including some types of cancer. They are engineered to recognize and attach to superficial cell membrane-specific proteins and act in different ways depending on the protein they are targeting. The pathogenesis of GC cancers involves multiple altered molecular pathways that can be targeted by specific mAbs. Therefore, novel mAbs have emerged for the management of GC. In this context, the addition of trastuzumab has significantly improved survival in patients with HER2-positive GC [10]. However, this therapeutic option is available only for a few patients, as the overexpression (IHC) or amplification (FISH) of HER2 has been identified in less than 20 % of patients [10–12]. Additionally, ramucirumab has been approved as a second-line treatment in patients with advanced or metastatic GC who progressed on fluoropyrimidine- or platinum-containing first-line chemotherapy [13, 14]. Unfortunately, other agents targeting oncogenic mediators such as EGFR, mTOR, and c-Met have not been shown to improve survival [15–21]. The aim of this review is to summarize the available data on mAbs that are clinically used for the treatment of advanced or metastatic GC.
Anti-VEGF/VEGFR agents Angiogenesis is today universally considered as a cancer hallmark because it is one of the main processes for tumor progression. The increase of tumor size and the functional abnormalities of the tumor vasculature lead to tissue hypoxia that induces neoangiogenesis [22, 23]. The primary proangiogenic driver of this process is vascular endothelial growth factor (VEGF), also known as VEGF-A. The family of VEGF molecules also includes VEGF-B, VEGFC, VEGF-D, VEGF-E, and placental growth factor (PGF). Each component of this family can bind to several VEGF receptors (VEGFR), known as VEGFR1 (fms-like
tyrosine kinase 1/Flt-1), VEGFR2 (Flk-1/KDR), and VEGFR3 (Flt-4), and 2 co-receptors, neuropilin 1 and 2 (NRP1/2). In particular, VEGF-A binds to VEGFR-1 and VEGFR-2, VEGF-B and PGF to VEGFR-1, and VEGF-C and -D to VEGFR-2 and -3 [23, 24]. The most important receptor is VEGFR-2 [25], which regulates the proliferation of endothelial cells through a number of different mechanisms [23, 26]. The expression of VEGFR2 in intestinal-type GC was found to correlate with the vessel count and the stage of disease [27]. In addition, in patients with GC, several studies have investigated the clinical and prognostic significance of circulating VEGF levels [27–32]. Other proteins, such as hypoxia inducible factor (HIF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiopoietin (Ang), and Notch, play important roles in angiogenesis [33, 34]. VEGF/VEGFR pathway and relative target of mAbs are reported in Fig. 1. Bevacizumab Bevacizumab is a humanized monoclonal antibody against VEGF; this binding inhibits tumor angiogenesis. Bevacizumab is currently approved for the treatment of colon, lung, breast, ovarian, endometrial, and clear cell renal carcinoma in the metastatic stage [35–39]. Several phase II trials of bevacizumab plus chemotherapy have been reported for GC patients [40–42]. An overall response rate (ORR) of 42 to 67 % was achieved. The median progression free survival (PFS) was 6.6–12 months, whereas the OS was 8.9– 16.2 months. Grades 3–4 thromboembolic diseases were reported in approximately 25 % of the patients, and gastric perforation was observed in up to 8 % of the patients. Based on these results, an international, randomized, double-blind, placebo-controlled phase III trial, the Avastin for Advanced Gastric Cancer trial (AVAGAST), was conducted. The AVAGAST trial was designed to evaluate the benefit of adding bevacizumab to first-line capecitabine-cisplatin treatment for patients with advanced gastric cancer. Overall, 774 patients were randomly selected to receive the combination of capecitabine with cisplatin with or without bevacizumab [43]. Cisplatin was administered for 6 cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The ORR significantly improved with the addition of bevacizumab (46 vs. 37 %; P=0.0315), and the median PFS was also significantly longer (6.7 vs. 5.3 months, HR= 0.80, 95 % CI 0.68–0.93; P=0.0037). The median OS was 12.1 months with the presence of bevacizumab and only 10.1 months with the combination fluoropyrimidine-cisplatin. However, this did not reach the specified criteria for statistical significance (HR=0.87, 95 % CI 0.73–1.03; P=0.1002) [43]. Interestingly, the preplanned subgroup analyses revealed regional differences in efficacy outcomes. Indeed, the beneficial
Tumor Biol. Fig. 1 Monoclonal antibodies targeting VEGF/VEGFR pathway
effect of bevacizumab on all of the study outcome measures was substantially higher among patients recruited in the Americas, pan-American regions as opposed to patients recruited in Europe (intermediate effect). In contrast, no benefit of bevacizumab was observed in Asian patients, 90 % of whom were recruited from Japan and Korea. Differences in population genetics, patient selection, and second-line chemotherapy may account for these results. Moreover, in this study, the baseline plasma levels of VEGF-A and tumor expression of neuropilin-1 were identified as potential predictors of bevacizumab efficacy. Patients with high baseline plasma levels of VEGF-A showed a trend toward improved OS (hazard ratio [HR] 0.72; 95 % CI 0.57–0.93) compared to patients with low VEGF-A levels (HR 1.01; 95 % CI 0.77–1.31; interaction P=0.07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved OS (HR 0.75; 95 % CI 0.59–0.97) compared to patients with high neuropilin-1 expression (HR 1.07; 95 % CI 0.81–1.40; interaction P=0.06). For both biomarkers, subgroup analyses demonstrated statistical significance only in patients from non-Asian regions [44]. The most common grades 3–5 adverse events in both arms of the trial were neutropenia, anemia, and appetite loss. These events occurred at similar rates with or without bevacizumab [43]. Another smaller phase III study, which mimicked the design of the AVAGAST trial, was conducted in 202 Chinese patients. These patients differed from Asian patients enrolled in the AVAGAST trial [45]; the latter being mainly from Japan and Korea with a greater incidence of liver metastases and gastroesophageal junction tumors with a low rate of previous gastrectomy. Another remarkable finding is that patients in the AVAGAST trial were less likely to receive a second and/or additional line of therapy after disease progression as the medical insurance in China does not cover second-line drugs. Therefore, Chinese patients
were more comparable to the European-American subgroup than the Asian-Pacific subgroup of the AVAGAST trial. This study showed no significant differences between chemotherapy plus bevacizumab vs. chemotherapy alone (OS 10.5 vs. 11.4 months; PFS 6.3 vs. 6.0 months). Both the incidence of grade ≥3 adverse events and the incidence of grade ≥3 adverse events of special interest for bevacizumab were comparable between the treatment arms. The ST03 was a multicenter, randomized, phase II/III study comparing peri-operative epirubicin, cisplatin, and capecitabine (ECX) with or without bevacizumab designed with the first 200 patients contributing to a phase II assessment of safety powered to exclude unacceptable rates of gastrointestinal perforation and cardiotoxicity. In the interim analysis based on the safety issue, the incidence of cardiac complications was similar in both arms, except for arterial thromboembolic events and more asymptomatic left ventricular ejection fraction drops, which were more frequent in ECX plus bevacizumab arm [46]. Therefore, the addition of bevacizumab to peri-operative ECX chemotherapy seems feasible with acceptable toxicity without negative impact on surgical outcomes; the phase III trial based on the combination of chemotherapy with bevacizumab is ongoing. In consideration of the disappointing results obtained by the use of bevacizumab in the treatment of metastatic GC, the final results of ST03 trial are awaited to define the role of bevacizumab in peri-operative setting only. Ramucirumab Ramucirumab, a humanized IgG1 monoclonal antibody against VEGFR-2, prevents ligand binding and receptormediated pathway activation in endothelial cells [47]. Preclinical studies have shown that targeting VEGF receptors with
Tumor Biol.
ramucirumab was associated with the inhibition of VEGFmediated signaling along with the inhibition of proliferation and migration of endothelial cells exerting simultaneously an anti-tumor activity [47–51]. The phase III, placebo-controlled, double-blinded REGARD trial was conducted with the aim of evaluating the safety and efficacy of ramucirumab as secondline treatment in 355 patients with advanced, unresectable GC [13]. Patients were randomly assigned 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care until disease progression, unacceptable toxicities, or death. The primary endpoint of the trial was OS. Treatment with ramucirumab lead to a statistically significant OS improvement (HR 0.77, 95 % CI 0.60–0.99; P=0.047), with a median OS of 5.2 months for patients who received ramucirumab vs. 3.8 months for those who received placebo. Moreover, an increase in PFS was reported (2.1 months for ramucirumab vs. 1.3 months for placebo; HR = 0.48, P
