Review
1.
Introduction
2.
EGFR inhibitors: the failure of a promise?
3.
Old and novel HER2 inhibitors: improving efficacy while overcoming
The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey Giuseppe Aprile†, Riccardo Giampieri, Marta Bonotto, Alessandro Bittoni, Elena Ongaro, Giovanni Gerardo Cardellino, Francesco Graziano, Francesco Giuliani, Gianpiero Fasola, Stefano Cascinu & Mario Scartozzi †
University and General Hospital, Department of Oncology, Udine, Italy
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resistance 4.
Angiogenesis inhibitors: are we finally hitting the target?
5.
HGF-cMET axis and its signaling network
6.
The role of mTOR inhibitors
7.
IGF: portal of discovery?
8.
What is the impact of germline mutations in target therapy?
9.
The evolution of translational research in GC in the next few years: will micro-RNA have a role?
10.
Expert opinion
Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements. Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment. Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments. Keywords: gastric cancer, MET-inhibitors, pertuzumab, ramucirumab, target therapy Expert Opin. Investig. Drugs (2014) 23(7):925-942
1.
Introduction
Gastric cancer (GC) constitutes a major worldwide health problem with a yearly global incidence approaching 1 million new cases and representing one of the leading causes of cancer-related deaths [1]. Although 70% of cases occur in Asian countries, 140,000 new patients were diagnosed in 2012 across European nations [2] and over 21,000 in the United States [3]. As for other solid tumors, GC 5-year survival rates significantly improved over the last decade, increasing from 15 to 27% [4], even if this improvement in outcome was limited to patients with early disease stage. On the other hand, the 5-year survival for advanced or metastatic disease still is < 5% and median overall survival (OS) remains limited to 1 year [5]. Still, palliative chemotherapy is the mainstay of treatment for locally advanced or metastatic GC patients [6] and platinum-containing regimens represent the current gold standard in first line [7]. The addition of a third drug (usually epirubicin or a 10.1517/13543784.2014.912631 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
925
G. Aprile et al.
Article highlights. .
.
.
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
.
.
Gastric cancer (GC) constitutes a major worldwide health problem with a yearly global incidence approaching 1 million new cases. Median overall survival for patients with advanced disease treated with chemotherapy is limited to ~ 12 months. A scope of driver mutations has been documented in ~ 40% of advanced GCs and creates the backbone for novel research on targeted treatments. Trastuzumab contributes to survival extension of HER2-positive GC patients (ToGA trial). To date, trastuzumab is the only one to have obtained regulatory approval for the treatment of HER-positive GC patients. EGFR inhibitors failed to produce significant results. As showed by the EXPAND and the REAL3 trials, the addition of cetuximab or panitumumab to first-line chemotherapy provided no additional benefit to chemotherapy alone in the treatment of advanced GC patients. There is a renewed interest in angiogenic inhibitors. Despite the poor results of bevacizumab, the VEGFR2-inhibitor ramucirumab has produced positive outcome results in pretreated patients, either used alone (REGARD trial) or in combination with second-line chemotherapy (RAINBOW study).
This box summarizes key points contained in the article.
taxane) to a platinum-based doublet may be a valuable option for selected fit patients [8,9], to obtain an increase in response rate (RR) and a modest survival improvement [10]. Three randomized studies have confirmed the role of second-line chemotherapy for patients with advanced disease [11-13]. Recent advances in the understanding of GC biology [14,15] have served as rationale for the development of novel targeted agents (Figure 1; Tables 1-3). For the time being, a number of driver mutations [16] have been acknowledged to be actionable in ~ 40% of GCs [17]. Those data match and move together with the urgent need of new therapeutic agents for a disease with an overall dismal prognosis. Many biological agents have been tested already in the clinics, although the advance of targeted therapies in this disease is still in its dawn and clinical outcomes have been overall modest. In the past few years, some progress has been achieved. More molecular studies, however, are needed to understand what proportion of patients could benefit from them. 2.
EGFR inhibitors: the failure of a promise?
Preliminary data strongly suggested a potential role of the EGFR as a prognostic determinant and therapeutic target in GC cells [18-22]. However, the interpretation of these results was inconsistent across different studies and only recently a meta-analysis of five different studies comprising over 1600 GC patients failed to confirm the prognostic value of EGFR expression [23]. Nonetheless, the EGFR status is thought to play an important role in GC pathogenesis [17] as it can potentially identify a 926
particular subgroup of patients as optimal candidates for anti-EGFR treatment. Alas, results from randomized clinical trials seem to point out at a different direction. At least three small Phase II trials tested cetuximab in previously untreated GC patients. In the first trial by Pinto et al. [24], 38 patients with advanced disease were treated with 5-fluorouracil (5-FU), irinotecan and cetuximab. RR was 44.1%, median time to progression (TTP) was 8 months and median OS was 16 months, suggesting an interesting activity in a unselected population. The second study from the same group [25] enrolled 72 patients to receive cetuximab in combination with cisplatin (75 mg/m2) and docetaxel (75 mg/m2) every 3 weeks. Although the observed RR was 41.2%, median TTP and median OS were limited to 5 and 9 months, respectively. In a third study [26], 38 patients received cetuximab in combination with oxaliplatin and 5-FU. Overall RR was 50%, whereas median TTP was 5.5 months and median OS was 9.9 months. Interestingly, an exploratory analysis showed that patients with high EGFR expression and low baseline ligand levels had higher RR than the remaining patients (100 vs 37%, p < 0.001). On this basis, two Phase III first-line randomized clinical trials tested the efficacy of EGFR-inhibitors in combination with standard chemotherapy. In the REAL3 trial [27], 553 advanced GC patients were randomized to epirubicin, oxaliplatin and capecitabine (EOC) or modified EOC plus panitumumab. Median OS in the 275 patients allocated to EOC arm was 11.3 months, whereas it was 8.8 months (7.7 -- 9.8) in the 278 patients allocated to modified EOC plus panitumumab. In contrast with biological rationale and preliminary results, these findings seemed then to suggest a potential harmful effect of panitumumab in this setting. Overall RR was comparable between treatment arms (42 vs 46%, p = 0.42). Median progression-free survival (PFS) was also similar between the two treatment arms (7.4 vs 6 months, p = 0.068). A prespecified analysis on KRAS status and effect of treatment was conducted in only 174 patients. Although a nonsignificant association was found between KRAS mutation and benefit from the experimental arm, the rate of patients harboring mutated tumors was very small (6.3%) and these biomarker analyses have limited clinical value. The EXPAND study randomized 904 GC patients to receive capecitabine plus cisplatin either with or without once-weekly cetuximab [28]. The study failed the primary end point with a 4.4 months median PFS for patients in the experimental arm compared with 5.6 months for the standard arm. Median OS was neither significantly different between the two treatment arms. Accordingly, similar RRs (30 vs 29%) were reported. In the HER2-positive population (144/679, 21% of patients), a nonstatistically significant trend towards a worse OS for the treatment was reported for patients included in the cetuximab-containing arm. The reason why Phase III trials failed to confirm promising results achieved in preclinical and Phase II trials with a strong biological rationale is still a matter of scientific debate.
Expert Opin. Investig. Drugs (2014) 23(7)
The challenge of targeted therapies for gastric cancer patients
L L
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
Ramucirumab
L
L
HGF
Figitumumab
VEGF
Cetuximab panitumumab Trastuzumab T-DM1
Bevacizumab
Pertuzumab
Rilotumumab
Onartuzumab
Multitarget TKI VEGFR-2 Flt1/KDR
HER1
HER2
HER3
HER4
IGF-1R
MET Foretinib Crizotinib Tivantinib
Vasculogenesis
RAF
PI3K
Lympangiogenesis
Akt
p53
mTOR Everolimus
RAS
MEK BCL2
BIM
Apoptosis
Survival
ERK
Proliferation
Figure 1. Signaling pathway and promising molecular-targeted therapy for advanced gastric cancer. HER: Human epidermal growth factor receptor; HGF: Hepatocyte growth factor; IGF-1R: IGF-1 receptor; L: Ligand; mTOR: Mammalian target of rapamycin; PI3K: Phosphoinositide-3-kinase; TKI: Tyrosine-kinase inhibitor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.
Whether part of the failure may be attributable to the chemotherapy schedules is uncertain, and potentially harmful interactions between capecitabine and EGFR inhibitors have yet to be fully disclosed. Notably the biomarker evaluation of both randomized trials failed to identify a subset of patients who was more likely to benefit from the target treatment.
Old and novel HER2 inhibitors: improving efficacy while overcoming resistance
3.
The relevant biological role of HER2 expression in GC was discovered over 25 years ago [29]. HER2 positivity in GC widely ranges from 7 to 42%, mainly because of the intratumoral heterogeneity in HER2 expression/amplification and the lack of uniformity and reproducibility in the criteria for defining HER2 positivity [30]. Despite a frequently reported intraglandular or intratumoral heterogeneity for HER2 immunohistochemical (IHC) overexpression or amplification, a high level of agreement between HER2 status in primary gastric or
gastroesophageal cancers and corresponding metastatic sites has been described [31-33]. The prognostic role of HER2 in GCs has been debated for years [34,35]. Although HER2 positivity appears to have no prognostic value in early disease stages [36], a recent systematic revision has suggested a limited, but consistent, negative prognostic value in the advanced phase [37]. According to what has been demonstrated for breast cancers [38], however, the exposure to HER2 inhibitors may balance or even revert the negative prognosis [39]. Initial Phase II trials showed a high overall RR for HER2-positive metastatic GC patients exposed to trastuzumab and cisplatin-based chemotherapy [40,41]. Soon after, the results of ToGA trial [42] marked the dawn of a new era. The investigators screened over 3600 patients and enrolled 594 HER2-positive locally advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer patients in 24 countries. Participants were randomly assigned to receive a standard chemotherapy regimen consisting of cisplatin plus capecitabine or 5-FU given every 3 weeks or the same regimen in combination
Expert Opin. Investig. Drugs (2014) 23(7)
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G. Aprile et al.
Table 1. Outcome results of major randomized Phase III trials testing target therapies in treatment of advanced gastric or gastroesophageal cancer patients. Key Phase III randomized clinical trials Class of target agent Anti-HER2
Trial (ref) ToGA [42]
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LOGIC [53]
Angiogenesis inhibitors
EGFR inhibitors
Comparator arm
Capecitabine or fluorouracil/cisplatin + trastuzumab Capecitabine/oxaliplatin + lapatinib
Capecitabine or fluorouracil/ cisplatin Capecitabine/ oxaliplatin + placebo Paclitaxel
Paclitaxel + lapatinib
AVAGAST [77]
Capecitabine/oxaliplatin + bevacizumab
REGARD [83]
Ramucirumab
RAINBOW [84]
Paclitaxel + ramucirumab
REAL3 [27]
Epirubicin/oxaliplatin/ capecitabine + panitumumab Capecitabine/cisplatin + cetuximab Everolimus
GRANITE-1
Outcome results
Experimental arm
TYTAN [54]
EXPAND [28] mTOR inhibitors
Regimen
Capecitabine/ oxaliplatin + placebo Placebo Paclitaxel + placebo Epirubicin/ oxaliplatin/ capecitabine Capecitabine/ cisplatin Placebo
Line
ORR (%)
PFS (months)
OS (months)
I
47 vs 35 p = 0.0017
6.7 vs 5.5 p = 0.0002
13.8 vs 11.1 p = 0.0046
I
53 vs 40
6.0 vs 5.4 NS
12.2 vs 10.5 NS
II
27 vs 9
I
46 vs 37 p = 0.03
5.4 vs 4.4 NS 6.7 vs 5.3 p = 0.0037
11 vs 8.9 NS 12.1 vs 10.1 NS
II
3 vs 3 NS 28 vs 16 p < 0.001 46 vs 42
2.1 vs 1.3 p < 0.0001 4.4 vs 2.9 p < 0.05 6.0 vs 7.4 NS
5.2 vs 3.8 p = 0.047 9.6 vs 7.4 p < 0.05 11.3 vs 8.8 p = 0.013
30 vs 29 NS 5 vs 2
4.4 vs 5.6 NS 1.7 vs 1.4 p < 0.001
9.4 vs 10.7 NS 5.4 vs 4.3 NS
II I
I II
[125]
Positive trials are presented in bold. HER: Human epidermal growth factor receptor; mo: Months; mTOR: Mammalian target of rapamycin; NS: Not significant; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; vs: Versus.
with intravenous trastuzumab (induction dose of 8 mg/kg, following doses 6 mg/kg). In the intention-to-treat (ITT) population, median OS was 13.8 months in those assigned to trastuzumab plus chemotherapy compared with 11.1 months in those assigned to chemotherapy alone (HR 0.74; 95% CI 0.60 -- 0.91; p = 0.0046). Median PFS also favored patients exposed to trastuzumab (6.7 vs 5.5 months, HR 0.71; 95% CI 0.59 -- 0.85; p = 0.0002). Moreover, a statistically significant increase in RR (47 vs 35%, OR 1.70; 95% CI 1.22 -- 2.38; p = 0.0017) was reported for the trastuzumab-containing arm. In the population with highest HER2 expression (IHC 3+ or IHC 2+/fluorescent in situ hybridization (FISH) positive), the survival advantage was even more pronounced (16 vs 11.8 months, HR 0.65; 95% CI 0.51 -- 0.83). Grade 3 -4 adverse events (AEs) occurred at very similar frequencies in both treatment groups apart from diarrhea, which was reported more frequently in the experimental arm (32 vs 28%). To date, trastuzumab is the only targeted agent to have obtained US FDA and European Medicines Agency (EMA) approval for the treatment of HER2 overexpressing metastatic gastric adenocarcinomas [40]. The most appropriate method of evaluating HER2 in GC is not fully clear. Currently, tumors semiquantitatively scored as 0 (no staining or < 10% of positive cells) or 1+ (faint perceptible 928
staining, > 10%) by means of IHC are considered HER2-negative, whereas cases scored as 3+ (moderate to strong; complete or basolateral membranous staining; > 10%) are considered HER2-positive. If the score is 2+, in situ hybridization methods such as FISH or chromogenic in situ hybridization are used to further define the HER2 status. As determining HER2 positivity with FISH alone may lead to a significantly high percentage of nonresponders to trastuzumab, IHC has been established as the preferred upfront method to evaluate candidates to HER2 inhibitors. However, the link between the level of HER2 gene amplification and the outcome in patients treated with trastuzumab has been demonstrated [43]. Although the EMA limited the approval to patients with IHC score of 3+ or 2+ (confirmed by positive FISH result), FDA granted approval of trastuzumab for patients with positive FISH result or IHC score of 3+. More recently, research in HER2-positive GCs has followed four major directions, aiming at the following.
Optimizing the use of chemotherapy to be associated with trastuzumab
3.1
The benefit of trastuzumab was formally established when the HER2 inhibitor was used in association with cisplatin plus either infusional 5-FU or capecitabine [42]. Many clinicians,
Expert Opin. Investig. Drugs (2014) 23(7)
The challenge of targeted therapies for gastric cancer patients
Table 2. Novel target drugs in development for gastric cancer according to different molecular pathways. Target Anti-HER2
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Angiogenesis
HGF-cMET signaling network
IGFs/IGF-1R system Other
Target agent
Mechanism of action
Lapatinib T-DM1 Afatinib Pertuzumab SRC inhibitors PI3K inhibitors MET inhibitors mTOR inhibitors Ramucirumab Sunitinib Sorafenib Cediranib Trebananib Apatinib Regorafenib Rilotumumab Onartuzumab Foretinib Crizotinib Tivantinib Figitumumab Olaparib PF-00299804
TKI Antibody drug conjugated (trastuzumab-emtansine) Irreversible TKI Anti-HER2 monoclonal antibody Potential way to restore cell sensitivity to trastuzumab and anti-HER2 drugs
Anti-VEGFR2 monoclonal antibody Multitarget TKI Multitarget TKI VEGFR TKI Anti-angiopoietin 1 and 2 peptibody VEGFR TKI Multitarget TKI Anti-HGF monoclonal antibody Anti-HGF monoclonal antibody Intracellular MET kinase inhibitor Intracellular MET kinase inhibitor Small MET kinase inhibitor Anti-IGF-1R monoclonal antibody PARP inhibitor Pan-HER inhibitor
HGF: Hepatocyte growth factor; HER: human epidermal growth factor receptor; IGF-1R: IGF-1 receptor; mTOR: Mammalian target of rapamycin; PARP: Poli ADPribosio polimerasi; PI3K: Phosphatidylinositol 3-kinase; TKI: Tyrosine-kinase inhibitor.
however, incorporate trastuzumab into their first-line regimen of choice (including cisplatin-free regimens such as FOLFOX), despite the absence of published data to support this practice. Few trials were designed to explore the efficacy of trastuzumab in combination with other chemotherapy regimens. A dose-finding study was planned to determine the maximum tolerated dose of docetaxel, oxaliplatin and capecitabine in combination with trastuzumab given every third week as first-line treatment in patients with HER2-positive advanced GC [44]. Results support the possibility of using trastuzumab in association with a three-drug combination. HELOISE, an ongoing Phase IIIb trial, aims to examine whether a higher trastuzumab maintenance dose (loading dose of 8 mg/kg followed by 10 vs 6 mg/kg maintenance doses given every 3 weeks) in combination with cisplatin/ capecitabine chemotherapy may improve survival. Approximately 400 patients are planned to be enrolled [45]. Testing novel, more potent HER2 inhibitors Among alternative HER2 inhibitors, lapatinib is the most studied compound. This orally available, tyrosine kinases inhibitor (TKI) targets the intracellular domain of both HER1 and HER2. After binding, lapatinib blocks receptor activation and signal transmissions, thus interfering with cell proliferation and survival. Preclinical studies showed its activity in esophageal and gastric adenocarcinoma cell lines overexpressing HER2, and its synergic effect when combined with chemotherapy [46]. Other interesting characteristics of the drug are its ability to 3.2
sensitize GC cells to the irinotecan active metabolite SN-38 [47], its potential synergism with trastuzumab [48] and its putative activity in trastuzumab-resistant GC cell lines [49]. Despite poor results of two pivotal clinical studies of lapatinib monotherapy, which showed a disappointing RR [50,51], and a third trial that was prematurely closed due to slow accrual [52], two independent Phase III randomized trials were planned to test lapatinib in combination with chemotherapy. TRIO-013/LOGiC is a Phase III double-blind trial that compares lapatinib (1,250 mg/day) in combination with capecitabine and oxaliplatin to capecitabine and oxaliplatin alone in 545 patients with centrally reviewed HER2-positive advanced GC. OS was the primary end point, and cosecondary end points included RR, PFS and safety. Although a higher RR (53 vs 40%) and a longer median OS (12.2 vs 10.5 months) were reported, the trial failed to meet its primary survival end point (HR 0.91; 95% CI 0.73 -- 1.12, p = 0.35). Nevertheless, OS advantage was statistically significant in the Asian population (HR 0.68), suggesting a benefit of the molecule in specific patients’ subsets [53]. TYTAN is a randomized, open-label, Phase III study of second-line therapy of paclitaxel (80 mg/m2 d1, 8, 15 q28) with or without lapatinib (daily dose of 1500 mg) in 261 Asian patients with HER2-positive GC that had failed a 5-FU and/or cisplatin-based first-line chemotherapy. The primary end point was OS. Although in the ITT population the primary end point was not met, a difference in median survival of 2 months was reported (8.9 vs 11 months, HR 0.84).
Expert Opin. Investig. Drugs (2014) 23(7)
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G. Aprile et al.
Table 3. Safety data from key randomized Phase III gastric cancer trials (toxicity events suffered in at least 5% of patients are reported). Trial
ToGA [42]
Capecitabine or fluorouracil/ cisplatin ± trastuzumab
LOGIC [53]
Capecitabine/oxaliplatin ± lapatinib Paclitaxel ± lapatinib
TYTAN [54] Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
Experimental arm versus control arm
Toxicity
AVAGAST [77]
Capecitabine/oxaliplatin ± bevacizumab
REGARD [83]
BSC ± ramucirumab
RAINBOW [84] REAL3 [27]
Paclitaxel ± ramucirumab Epirubicin/oxaliplatin/ capecitabine ± panitumumab
EXPAND [28]
Capecitabine/cisplatin ± cetuximab
Experimental arm (%)
Control arm (%)
Nausea Vomiting Diarrhea Neutropenia Anemia Anorexia Diarrhea
7 6 9 27 12 6 12
7 8 4 30 10 6 3
Rash Neutropenia Diarrhea Neutropenia Anemia Decreased appetite Nausea Vomiting Diarrhea Hypokalemia Hand-foot syndrome Venous thromboembolic event Hypertension Fatigue Abdominal pain Anemia Dyspnea Hypertension Vomiting Diarrhea Lethargy Hand-foot syndrome Peripheral neuropathy Pulmonary embolism Rash Infection Febrile neutropenia Neutropenia Anemia Hypokalemia Neutropenia Hypokalemia Hypomagnesaemia Anemia Fatigue Diarrhea Nausea Decreased appetite Vomiting Rash Hand-foot syndrome Hyponatremia Pulmonary embolism Asthenia Skin reactions Acne-like rash Cardiac events
8 89 16 35 10 8 7 6 8 3 6 6
37 14 11 10 9 4 6 3 9
6 6 6 6 2 8 8 17 17 6 1 7 11 10 7 13 4 4 22 13 10 9 8 7 7 7 8 7 7 7 6 4 13 11 7
1.
Introduction
2.
EGFR inhibitors: the failure of a promise?
3.
Old and novel HER2 inhibitors: improving efficacy while overcoming
The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey Giuseppe Aprile†, Riccardo Giampieri, Marta Bonotto, Alessandro Bittoni, Elena Ongaro, Giovanni Gerardo Cardellino, Francesco Graziano, Francesco Giuliani, Gianpiero Fasola, Stefano Cascinu & Mario Scartozzi †
University and General Hospital, Department of Oncology, Udine, Italy
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
resistance 4.
Angiogenesis inhibitors: are we finally hitting the target?
5.
HGF-cMET axis and its signaling network
6.
The role of mTOR inhibitors
7.
IGF: portal of discovery?
8.
What is the impact of germline mutations in target therapy?
9.
The evolution of translational research in GC in the next few years: will micro-RNA have a role?
10.
Expert opinion
Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements. Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment. Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments. Keywords: gastric cancer, MET-inhibitors, pertuzumab, ramucirumab, target therapy Expert Opin. Investig. Drugs (2014) 23(7):925-942
1.
Introduction
Gastric cancer (GC) constitutes a major worldwide health problem with a yearly global incidence approaching 1 million new cases and representing one of the leading causes of cancer-related deaths [1]. Although 70% of cases occur in Asian countries, 140,000 new patients were diagnosed in 2012 across European nations [2] and over 21,000 in the United States [3]. As for other solid tumors, GC 5-year survival rates significantly improved over the last decade, increasing from 15 to 27% [4], even if this improvement in outcome was limited to patients with early disease stage. On the other hand, the 5-year survival for advanced or metastatic disease still is < 5% and median overall survival (OS) remains limited to 1 year [5]. Still, palliative chemotherapy is the mainstay of treatment for locally advanced or metastatic GC patients [6] and platinum-containing regimens represent the current gold standard in first line [7]. The addition of a third drug (usually epirubicin or a 10.1517/13543784.2014.912631 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
925
G. Aprile et al.
Article highlights. .
.
.
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
.
.
Gastric cancer (GC) constitutes a major worldwide health problem with a yearly global incidence approaching 1 million new cases. Median overall survival for patients with advanced disease treated with chemotherapy is limited to ~ 12 months. A scope of driver mutations has been documented in ~ 40% of advanced GCs and creates the backbone for novel research on targeted treatments. Trastuzumab contributes to survival extension of HER2-positive GC patients (ToGA trial). To date, trastuzumab is the only one to have obtained regulatory approval for the treatment of HER-positive GC patients. EGFR inhibitors failed to produce significant results. As showed by the EXPAND and the REAL3 trials, the addition of cetuximab or panitumumab to first-line chemotherapy provided no additional benefit to chemotherapy alone in the treatment of advanced GC patients. There is a renewed interest in angiogenic inhibitors. Despite the poor results of bevacizumab, the VEGFR2-inhibitor ramucirumab has produced positive outcome results in pretreated patients, either used alone (REGARD trial) or in combination with second-line chemotherapy (RAINBOW study).
This box summarizes key points contained in the article.
taxane) to a platinum-based doublet may be a valuable option for selected fit patients [8,9], to obtain an increase in response rate (RR) and a modest survival improvement [10]. Three randomized studies have confirmed the role of second-line chemotherapy for patients with advanced disease [11-13]. Recent advances in the understanding of GC biology [14,15] have served as rationale for the development of novel targeted agents (Figure 1; Tables 1-3). For the time being, a number of driver mutations [16] have been acknowledged to be actionable in ~ 40% of GCs [17]. Those data match and move together with the urgent need of new therapeutic agents for a disease with an overall dismal prognosis. Many biological agents have been tested already in the clinics, although the advance of targeted therapies in this disease is still in its dawn and clinical outcomes have been overall modest. In the past few years, some progress has been achieved. More molecular studies, however, are needed to understand what proportion of patients could benefit from them. 2.
EGFR inhibitors: the failure of a promise?
Preliminary data strongly suggested a potential role of the EGFR as a prognostic determinant and therapeutic target in GC cells [18-22]. However, the interpretation of these results was inconsistent across different studies and only recently a meta-analysis of five different studies comprising over 1600 GC patients failed to confirm the prognostic value of EGFR expression [23]. Nonetheless, the EGFR status is thought to play an important role in GC pathogenesis [17] as it can potentially identify a 926
particular subgroup of patients as optimal candidates for anti-EGFR treatment. Alas, results from randomized clinical trials seem to point out at a different direction. At least three small Phase II trials tested cetuximab in previously untreated GC patients. In the first trial by Pinto et al. [24], 38 patients with advanced disease were treated with 5-fluorouracil (5-FU), irinotecan and cetuximab. RR was 44.1%, median time to progression (TTP) was 8 months and median OS was 16 months, suggesting an interesting activity in a unselected population. The second study from the same group [25] enrolled 72 patients to receive cetuximab in combination with cisplatin (75 mg/m2) and docetaxel (75 mg/m2) every 3 weeks. Although the observed RR was 41.2%, median TTP and median OS were limited to 5 and 9 months, respectively. In a third study [26], 38 patients received cetuximab in combination with oxaliplatin and 5-FU. Overall RR was 50%, whereas median TTP was 5.5 months and median OS was 9.9 months. Interestingly, an exploratory analysis showed that patients with high EGFR expression and low baseline ligand levels had higher RR than the remaining patients (100 vs 37%, p < 0.001). On this basis, two Phase III first-line randomized clinical trials tested the efficacy of EGFR-inhibitors in combination with standard chemotherapy. In the REAL3 trial [27], 553 advanced GC patients were randomized to epirubicin, oxaliplatin and capecitabine (EOC) or modified EOC plus panitumumab. Median OS in the 275 patients allocated to EOC arm was 11.3 months, whereas it was 8.8 months (7.7 -- 9.8) in the 278 patients allocated to modified EOC plus panitumumab. In contrast with biological rationale and preliminary results, these findings seemed then to suggest a potential harmful effect of panitumumab in this setting. Overall RR was comparable between treatment arms (42 vs 46%, p = 0.42). Median progression-free survival (PFS) was also similar between the two treatment arms (7.4 vs 6 months, p = 0.068). A prespecified analysis on KRAS status and effect of treatment was conducted in only 174 patients. Although a nonsignificant association was found between KRAS mutation and benefit from the experimental arm, the rate of patients harboring mutated tumors was very small (6.3%) and these biomarker analyses have limited clinical value. The EXPAND study randomized 904 GC patients to receive capecitabine plus cisplatin either with or without once-weekly cetuximab [28]. The study failed the primary end point with a 4.4 months median PFS for patients in the experimental arm compared with 5.6 months for the standard arm. Median OS was neither significantly different between the two treatment arms. Accordingly, similar RRs (30 vs 29%) were reported. In the HER2-positive population (144/679, 21% of patients), a nonstatistically significant trend towards a worse OS for the treatment was reported for patients included in the cetuximab-containing arm. The reason why Phase III trials failed to confirm promising results achieved in preclinical and Phase II trials with a strong biological rationale is still a matter of scientific debate.
Expert Opin. Investig. Drugs (2014) 23(7)
The challenge of targeted therapies for gastric cancer patients
L L
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
Ramucirumab
L
L
HGF
Figitumumab
VEGF
Cetuximab panitumumab Trastuzumab T-DM1
Bevacizumab
Pertuzumab
Rilotumumab
Onartuzumab
Multitarget TKI VEGFR-2 Flt1/KDR
HER1
HER2
HER3
HER4
IGF-1R
MET Foretinib Crizotinib Tivantinib
Vasculogenesis
RAF
PI3K
Lympangiogenesis
Akt
p53
mTOR Everolimus
RAS
MEK BCL2
BIM
Apoptosis
Survival
ERK
Proliferation
Figure 1. Signaling pathway and promising molecular-targeted therapy for advanced gastric cancer. HER: Human epidermal growth factor receptor; HGF: Hepatocyte growth factor; IGF-1R: IGF-1 receptor; L: Ligand; mTOR: Mammalian target of rapamycin; PI3K: Phosphoinositide-3-kinase; TKI: Tyrosine-kinase inhibitor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.
Whether part of the failure may be attributable to the chemotherapy schedules is uncertain, and potentially harmful interactions between capecitabine and EGFR inhibitors have yet to be fully disclosed. Notably the biomarker evaluation of both randomized trials failed to identify a subset of patients who was more likely to benefit from the target treatment.
Old and novel HER2 inhibitors: improving efficacy while overcoming resistance
3.
The relevant biological role of HER2 expression in GC was discovered over 25 years ago [29]. HER2 positivity in GC widely ranges from 7 to 42%, mainly because of the intratumoral heterogeneity in HER2 expression/amplification and the lack of uniformity and reproducibility in the criteria for defining HER2 positivity [30]. Despite a frequently reported intraglandular or intratumoral heterogeneity for HER2 immunohistochemical (IHC) overexpression or amplification, a high level of agreement between HER2 status in primary gastric or
gastroesophageal cancers and corresponding metastatic sites has been described [31-33]. The prognostic role of HER2 in GCs has been debated for years [34,35]. Although HER2 positivity appears to have no prognostic value in early disease stages [36], a recent systematic revision has suggested a limited, but consistent, negative prognostic value in the advanced phase [37]. According to what has been demonstrated for breast cancers [38], however, the exposure to HER2 inhibitors may balance or even revert the negative prognosis [39]. Initial Phase II trials showed a high overall RR for HER2-positive metastatic GC patients exposed to trastuzumab and cisplatin-based chemotherapy [40,41]. Soon after, the results of ToGA trial [42] marked the dawn of a new era. The investigators screened over 3600 patients and enrolled 594 HER2-positive locally advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer patients in 24 countries. Participants were randomly assigned to receive a standard chemotherapy regimen consisting of cisplatin plus capecitabine or 5-FU given every 3 weeks or the same regimen in combination
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Table 1. Outcome results of major randomized Phase III trials testing target therapies in treatment of advanced gastric or gastroesophageal cancer patients. Key Phase III randomized clinical trials Class of target agent Anti-HER2
Trial (ref) ToGA [42]
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LOGIC [53]
Angiogenesis inhibitors
EGFR inhibitors
Comparator arm
Capecitabine or fluorouracil/cisplatin + trastuzumab Capecitabine/oxaliplatin + lapatinib
Capecitabine or fluorouracil/ cisplatin Capecitabine/ oxaliplatin + placebo Paclitaxel
Paclitaxel + lapatinib
AVAGAST [77]
Capecitabine/oxaliplatin + bevacizumab
REGARD [83]
Ramucirumab
RAINBOW [84]
Paclitaxel + ramucirumab
REAL3 [27]
Epirubicin/oxaliplatin/ capecitabine + panitumumab Capecitabine/cisplatin + cetuximab Everolimus
GRANITE-1
Outcome results
Experimental arm
TYTAN [54]
EXPAND [28] mTOR inhibitors
Regimen
Capecitabine/ oxaliplatin + placebo Placebo Paclitaxel + placebo Epirubicin/ oxaliplatin/ capecitabine Capecitabine/ cisplatin Placebo
Line
ORR (%)
PFS (months)
OS (months)
I
47 vs 35 p = 0.0017
6.7 vs 5.5 p = 0.0002
13.8 vs 11.1 p = 0.0046
I
53 vs 40
6.0 vs 5.4 NS
12.2 vs 10.5 NS
II
27 vs 9
I
46 vs 37 p = 0.03
5.4 vs 4.4 NS 6.7 vs 5.3 p = 0.0037
11 vs 8.9 NS 12.1 vs 10.1 NS
II
3 vs 3 NS 28 vs 16 p < 0.001 46 vs 42
2.1 vs 1.3 p < 0.0001 4.4 vs 2.9 p < 0.05 6.0 vs 7.4 NS
5.2 vs 3.8 p = 0.047 9.6 vs 7.4 p < 0.05 11.3 vs 8.8 p = 0.013
30 vs 29 NS 5 vs 2
4.4 vs 5.6 NS 1.7 vs 1.4 p < 0.001
9.4 vs 10.7 NS 5.4 vs 4.3 NS
II I
I II
[125]
Positive trials are presented in bold. HER: Human epidermal growth factor receptor; mo: Months; mTOR: Mammalian target of rapamycin; NS: Not significant; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; vs: Versus.
with intravenous trastuzumab (induction dose of 8 mg/kg, following doses 6 mg/kg). In the intention-to-treat (ITT) population, median OS was 13.8 months in those assigned to trastuzumab plus chemotherapy compared with 11.1 months in those assigned to chemotherapy alone (HR 0.74; 95% CI 0.60 -- 0.91; p = 0.0046). Median PFS also favored patients exposed to trastuzumab (6.7 vs 5.5 months, HR 0.71; 95% CI 0.59 -- 0.85; p = 0.0002). Moreover, a statistically significant increase in RR (47 vs 35%, OR 1.70; 95% CI 1.22 -- 2.38; p = 0.0017) was reported for the trastuzumab-containing arm. In the population with highest HER2 expression (IHC 3+ or IHC 2+/fluorescent in situ hybridization (FISH) positive), the survival advantage was even more pronounced (16 vs 11.8 months, HR 0.65; 95% CI 0.51 -- 0.83). Grade 3 -4 adverse events (AEs) occurred at very similar frequencies in both treatment groups apart from diarrhea, which was reported more frequently in the experimental arm (32 vs 28%). To date, trastuzumab is the only targeted agent to have obtained US FDA and European Medicines Agency (EMA) approval for the treatment of HER2 overexpressing metastatic gastric adenocarcinomas [40]. The most appropriate method of evaluating HER2 in GC is not fully clear. Currently, tumors semiquantitatively scored as 0 (no staining or < 10% of positive cells) or 1+ (faint perceptible 928
staining, > 10%) by means of IHC are considered HER2-negative, whereas cases scored as 3+ (moderate to strong; complete or basolateral membranous staining; > 10%) are considered HER2-positive. If the score is 2+, in situ hybridization methods such as FISH or chromogenic in situ hybridization are used to further define the HER2 status. As determining HER2 positivity with FISH alone may lead to a significantly high percentage of nonresponders to trastuzumab, IHC has been established as the preferred upfront method to evaluate candidates to HER2 inhibitors. However, the link between the level of HER2 gene amplification and the outcome in patients treated with trastuzumab has been demonstrated [43]. Although the EMA limited the approval to patients with IHC score of 3+ or 2+ (confirmed by positive FISH result), FDA granted approval of trastuzumab for patients with positive FISH result or IHC score of 3+. More recently, research in HER2-positive GCs has followed four major directions, aiming at the following.
Optimizing the use of chemotherapy to be associated with trastuzumab
3.1
The benefit of trastuzumab was formally established when the HER2 inhibitor was used in association with cisplatin plus either infusional 5-FU or capecitabine [42]. Many clinicians,
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The challenge of targeted therapies for gastric cancer patients
Table 2. Novel target drugs in development for gastric cancer according to different molecular pathways. Target Anti-HER2
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Angiogenesis
HGF-cMET signaling network
IGFs/IGF-1R system Other
Target agent
Mechanism of action
Lapatinib T-DM1 Afatinib Pertuzumab SRC inhibitors PI3K inhibitors MET inhibitors mTOR inhibitors Ramucirumab Sunitinib Sorafenib Cediranib Trebananib Apatinib Regorafenib Rilotumumab Onartuzumab Foretinib Crizotinib Tivantinib Figitumumab Olaparib PF-00299804
TKI Antibody drug conjugated (trastuzumab-emtansine) Irreversible TKI Anti-HER2 monoclonal antibody Potential way to restore cell sensitivity to trastuzumab and anti-HER2 drugs
Anti-VEGFR2 monoclonal antibody Multitarget TKI Multitarget TKI VEGFR TKI Anti-angiopoietin 1 and 2 peptibody VEGFR TKI Multitarget TKI Anti-HGF monoclonal antibody Anti-HGF monoclonal antibody Intracellular MET kinase inhibitor Intracellular MET kinase inhibitor Small MET kinase inhibitor Anti-IGF-1R monoclonal antibody PARP inhibitor Pan-HER inhibitor
HGF: Hepatocyte growth factor; HER: human epidermal growth factor receptor; IGF-1R: IGF-1 receptor; mTOR: Mammalian target of rapamycin; PARP: Poli ADPribosio polimerasi; PI3K: Phosphatidylinositol 3-kinase; TKI: Tyrosine-kinase inhibitor.
however, incorporate trastuzumab into their first-line regimen of choice (including cisplatin-free regimens such as FOLFOX), despite the absence of published data to support this practice. Few trials were designed to explore the efficacy of trastuzumab in combination with other chemotherapy regimens. A dose-finding study was planned to determine the maximum tolerated dose of docetaxel, oxaliplatin and capecitabine in combination with trastuzumab given every third week as first-line treatment in patients with HER2-positive advanced GC [44]. Results support the possibility of using trastuzumab in association with a three-drug combination. HELOISE, an ongoing Phase IIIb trial, aims to examine whether a higher trastuzumab maintenance dose (loading dose of 8 mg/kg followed by 10 vs 6 mg/kg maintenance doses given every 3 weeks) in combination with cisplatin/ capecitabine chemotherapy may improve survival. Approximately 400 patients are planned to be enrolled [45]. Testing novel, more potent HER2 inhibitors Among alternative HER2 inhibitors, lapatinib is the most studied compound. This orally available, tyrosine kinases inhibitor (TKI) targets the intracellular domain of both HER1 and HER2. After binding, lapatinib blocks receptor activation and signal transmissions, thus interfering with cell proliferation and survival. Preclinical studies showed its activity in esophageal and gastric adenocarcinoma cell lines overexpressing HER2, and its synergic effect when combined with chemotherapy [46]. Other interesting characteristics of the drug are its ability to 3.2
sensitize GC cells to the irinotecan active metabolite SN-38 [47], its potential synergism with trastuzumab [48] and its putative activity in trastuzumab-resistant GC cell lines [49]. Despite poor results of two pivotal clinical studies of lapatinib monotherapy, which showed a disappointing RR [50,51], and a third trial that was prematurely closed due to slow accrual [52], two independent Phase III randomized trials were planned to test lapatinib in combination with chemotherapy. TRIO-013/LOGiC is a Phase III double-blind trial that compares lapatinib (1,250 mg/day) in combination with capecitabine and oxaliplatin to capecitabine and oxaliplatin alone in 545 patients with centrally reviewed HER2-positive advanced GC. OS was the primary end point, and cosecondary end points included RR, PFS and safety. Although a higher RR (53 vs 40%) and a longer median OS (12.2 vs 10.5 months) were reported, the trial failed to meet its primary survival end point (HR 0.91; 95% CI 0.73 -- 1.12, p = 0.35). Nevertheless, OS advantage was statistically significant in the Asian population (HR 0.68), suggesting a benefit of the molecule in specific patients’ subsets [53]. TYTAN is a randomized, open-label, Phase III study of second-line therapy of paclitaxel (80 mg/m2 d1, 8, 15 q28) with or without lapatinib (daily dose of 1500 mg) in 261 Asian patients with HER2-positive GC that had failed a 5-FU and/or cisplatin-based first-line chemotherapy. The primary end point was OS. Although in the ITT population the primary end point was not met, a difference in median survival of 2 months was reported (8.9 vs 11 months, HR 0.84).
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Table 3. Safety data from key randomized Phase III gastric cancer trials (toxicity events suffered in at least 5% of patients are reported). Trial
ToGA [42]
Capecitabine or fluorouracil/ cisplatin ± trastuzumab
LOGIC [53]
Capecitabine/oxaliplatin ± lapatinib Paclitaxel ± lapatinib
TYTAN [54] Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
Experimental arm versus control arm
Toxicity
AVAGAST [77]
Capecitabine/oxaliplatin ± bevacizumab
REGARD [83]
BSC ± ramucirumab
RAINBOW [84] REAL3 [27]
Paclitaxel ± ramucirumab Epirubicin/oxaliplatin/ capecitabine ± panitumumab
EXPAND [28]
Capecitabine/cisplatin ± cetuximab
Experimental arm (%)
Control arm (%)
Nausea Vomiting Diarrhea Neutropenia Anemia Anorexia Diarrhea
7 6 9 27 12 6 12
7 8 4 30 10 6 3
Rash Neutropenia Diarrhea Neutropenia Anemia Decreased appetite Nausea Vomiting Diarrhea Hypokalemia Hand-foot syndrome Venous thromboembolic event Hypertension Fatigue Abdominal pain Anemia Dyspnea Hypertension Vomiting Diarrhea Lethargy Hand-foot syndrome Peripheral neuropathy Pulmonary embolism Rash Infection Febrile neutropenia Neutropenia Anemia Hypokalemia Neutropenia Hypokalemia Hypomagnesaemia Anemia Fatigue Diarrhea Nausea Decreased appetite Vomiting Rash Hand-foot syndrome Hyponatremia Pulmonary embolism Asthenia Skin reactions Acne-like rash Cardiac events
8 89 16 35 10 8 7 6 8 3 6 6
37 14 11 10 9 4 6 3 9
6 6 6 6 2 8 8 17 17 6 1 7 11 10 7 13 4 4 22 13 10 9 8 7 7 7 8 7 7 7 6 4 13 11 7
