Drug Evaluation For reprint orders, please contact: [email protected]
Potential role of rilotumumab in the treatment of gastric cancer
In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in ‘METpositive’ gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.
Tom Waddell*,1, Sing Yu Moorcraft1 & David Cunningham1 Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK *Author for correspondence: tom.waddell@ rmh.nhs.uk 1
Keywords: biomarker • gastric/gastro-esophageal junction cancer • MET-positive • rilotumumab • targeted therapy
Gastric cancer is the fourth most common cancer in the world and is estimated to affect close to one million people every year, with the incidence being approximately twice as high in men compared with women. The majority of cases occur in developing countries and almost 50% of all cases occur in eastern Asia, particularly China. Importantly, gastric cancer remains less treatable than many other common cancers and it therefore represents the second commonest cause of cancer-related death, being responsible for almost 10% of all cancer-related deaths worldwide [1] . In Western countries, the last 4 decades have seen a gradual decline in the incidence of distal gastric cancers accompanied by an increased incidence of proximal tumors affecting the gastric cardia and gastro-esophageal junction [2] . The exact reasons for this are not fully understood but it is primarily thought to be due to factors such as increased gastroesophageal reflux, Barrett’s metaplasia of the lower esophagus, obesity, smoking and western diet [3] . In countries without established endoscopic screening programs the major-
10.2217/IMT.14.91 © 2014 Future Medicine Ltd
ity of patients will present with metastatic disease. In this setting, best supportive care results in a median overall survival (OS) of only 3 months [4] . Current treatment guidelines Whilst combination chemotherapy regimens have demonstrated efficacy in both the perioperative and advanced disease settings, OS outcomes remain extremely poor. Outside of clinical trials the average survival in western patients is approximately 8–10 months with current palliative chemotherapy regimens [4,5] . Internationally, there is no single accepted standard-of-care regimen in advanced esophago-gastric adenocarcinoma (OGA), although the majority of centers use a doublet or triplet chemotherapy combination based around a platinum-fluoropyrimidine backbone. Historically the triplet chemo therapy combination of epirubicin, cisplatin and 5-fluorouracil has been regarded as a standard treatment option in many centers [6] . Reported in 2008, the REAL-2 non inferiority study confirmed that oxaliplatin and capecitabine represented effective alter-
Immunotherapy (2014) 6(12), 1243–1253
part of
ISSN 1750-743X
1243
Drug Evaluation Waddell, Moorcraft & Cunningham natives to cisplatin and 5-fluorouracil, respectively. This served to establish epirubicin, oxaliplatin and capecitabine as a standard first-line option in this setting, with an associated median OS of 11.2 months [5] . Other approved first-line treatment regimens include the combination of docetaxel and irinotecan, or use of either of these drugs in doublet and triplet chemotherapy regimens in combination with platinum agents and/or fluoropyrimidines [7–12] . However, with median survival times remaining consistently less than 12 months in clinical trials, there is clearly still a considerable unmet need in terms of effective therapies in advanced OGA. Targeted therapies have led to significant advances in the treatment of other solid organ tumors of the gastrointestinal tract including the use of anti-EGFR therapy in KRAS wildtype colorectal cancer [13,14] , and the development of imatinib, which has revolutionized the treatment of gastrointestinal stromal tumors [15] . In OGA, the last few years have finally seen the incorporation of a targeted therapeutic, trastuzumab, into the standard treatment paradigm for a molecularly defined subset of patients. This important therapeutic development resulted from the Phase III ToGA trial (n = 594) which confirmed that the addition of trastuzumab to chemotherapy was associated with a median OS of 16.0 months in patients with HER-2 IHC 2+ and FISH-positive tumors or IHC 3+ tumors [16] . Compared with patients treated with chemotherapy alone, this represented a statistically significant and clinically important 4.2 month median survival advantage. The ToGA trial is the first Phase III success for targeted therapy in esophago-gastric cancer, and confirms that careful selection of patients for therapy based upon tissue biomarkers can result in meaningful benefits. In addition to the evaluation of HER-2 status, there is considerable interest in identifying other, frequently dysregulated growth factor receptors which may represent viable therapeutic targets. Putative targets which are currently of interest include the MET, FGFR and IGF1R surface receptors and downstream effectors including PI3K, MEK, Akt and mTOR. There is also considerable interest in drugs which may disrupt tumor angiogenesis, primarily by targeting VEGF or its surface receptors. Body of review
1244
OGA and have entered randomized Phase II/III trials. These will be discussed in the following paragraphs. MET-targeted therapies
Rilotumumab (AMG102) is produced by Amgen and is the focus of this article. This drug will therefore be discussed in detail in the sections that follow. Onartuzumab (MetMAb) is a monoclonal antibody produced by Roche which binds to the extracellular domain of the MET receptor. In Phase I this drug has demonstrated activity against a range of tumor types including gastric cancer, and in a Phase II proof-of-concept study in nonsmall-cell lung cancer it was confirmed that patients with MET overexpression on immunohistochemistry (IHC) derived increased benefit compared with those without [17,18] . Onartuzumab is currently being evaluated in firstline OGA in a randomized Phase III trial in combination with a platinum-fluoropyrimidine chemotherapy doublet. A number of small-molecule inhibitors of MET receptor signaling have also recently launched into clinical trials in a variety of solid tumors, with examples including tivantinib, crizotinib and foretinib [19] . Unlike the monoclonal antibodies mentioned above, these molecules target the intracellular domain of the MET tyrosine kinase receptor, preventing the phosphorylation events necessary for signal transduction. These molecules may be ATP-competitive or noncompetitive and with varying degrees of selectivity for the MET receptor. In the setting of OGA, these small molecule inhibitors are currently in Phase II trials, and amplification of the MET gene is often the molecular aberration being used to select patients for therapy. HER-2 targeted therapies
Trastuzumab (Herceptin, Roche) – this drug now represents a standard of care in HER-2 positive disease following the previously described ToGA trial results [16] . Evaluation in the peri-operative and adjuvant settings is ongoing in Phase II trials. The success of trastuzumab has led to further randomized Phase II/III studies of other HER-2 targeted agents in advanced OGA including trastuzumab emtansine (antibody-drug conjugate with trastuzumab linked to a cytotoxic), pertuzumab (HER-2 dimerization inhibitor) and MM-111 (bi-specific antibody targeting HER-2 and HER-3).
Overview of the market
Anti-angiogenic therapies
As in all solid organ tumor types, there are currently a wide range of novel therapeutics being evaluated in Phase I–III clinical trials in advanced OGA (see the clinicaltrials.gov website). However, of the many agents under evaluation there are a few which have already demonstrated encouraging results in advanced
The Phase III AVAGAST trial evaluated bevacizumab in combination with first-line chemotherapy in advanced OGA [20] . Bevacizumab is a monoclonal antibody targeting the VEGF-A ligand, and was confirmed to result in a 1.4 -month improvement in median progressionfree survival (PFS) but no OS benefit. The Phase III
Immunotherapy (2014) 6(12)
future science group
Potential role of rilotumumab in the treatment of gastric cancer
ST03 trial is currently ongoing and is evaluating bevacizumab alongside peri-operative epirubicin, cisplatin and capecitabine (ECX) in the setting of operable OGA. Ramucirumab, a monoclonal antibody directed against VEGFR2, has recently demonstrated improved OS compared with placebo in second-line OGA as a single agent (REGARD trial) [21] . In the same setting, the randomized Phase III RAINBOW trial has also confirmed a survival benefit when ramucirumab is added to singleagent paclitaxel chemotherapy (median OS 9.6 months compared with 7.4 months with paclitaxel alone [22]). Introduction to rilotumumab
Rilotumumab is a fully human monoclonal antibody (IgG2) directed against human HGF also known as scatter factor. HGF is the only known ligand for the MET receptor and rilotumumab therefore acts to entirely block signaling via the MET receptor. Chemistry
Chemical formula: C6464H9932N1708O2010S46. Pharmacodynamics
Rilotumumab successfully binds to human HGF with high affinity, as indicated by an equilibrium dissociation constant (K D) of 19 pmol/l [23] . In human cell lines this leads to potent and complete inhibition of MET phosphorylation with an IC50 value of 0.12 nmol/l. This binding is associated with a number of important pharmacodynamic endpoints including reductions in cell proliferation, cell survival and migration/invasion. Pharmacokinetics & metabolism
Rilotumumab exerts linear pharmacokinetics within the dose range 0.5–20 mg/kg without significant interaction with co-administered compounds [24] . Renal and hepatic functions are also not found to have an effect on rilotumumab pharmacokinetics. The volume of distribution approximates plasma volume with the Cmax being observed at 1–2 h after commencing the 60-minute infusion and typical systemic clearance of 0.184 l/day. The plasma half-life is around 18 days and steady state should generally be reached by the time of the fifth administration. Clinical efficacy
Rilotumumab is currently being evaluated in a number of different clinical settings. The results of the Phase I and II studies initiated to date are summarized in Table 1 and in the text below. Phase I studies A Phase I monotherapy study conducted by Gordon et al. enrolled 40 patients with relapsed and/or refrac-
future science group
Drug Evaluation
tory advanced solid tumors, including renal cell (13%), ovarian (10%) and breast (10%) tumors [25] . Patients were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10 or 20 mg/kg of rilotumumab IV every 2 weeks) and a dose-expansion cohort (20 mg/kg of rilotumumab every 2 weeks). This study demonstrated that rilotumumab was well tolerated and the maximum tolerated dose was not reached. Although no partial or complete responses were seen in the 23 patients with Response Evaluation Criteria in Solid Tumours (RECIST) evaluable disease, 16 patients (70%) had stable disease with PFS ranging from 8 to 40 weeks. Rosen et al. performed a Phase 1b study which evaluated rilotumumab in combination with bevacizumab or motesanib in patients with advanced solid tumors [26] . This combination was selected following preclinical studies which suggested that the VEGF signaling pathway can interact with the HGF pathway to promote tumor growth [33,34] . Motesanib is an oral inhibitor of VEGFR 1, 2 and 3, PDGFR and Kit [35] . This study enrolled 14 patients into four cohorts and included patients with a variety of tumor types including breast, colon and non-small-cell lung cancer. Ten of the 14 patients were evaluable by RECIST and again no complete or partial responses were seen. Nine patients achieved stable disease, with PFS ranging from 8 to 122 weeks. The encouraging safety profile in these two Phase I studies led to the development of a number of subsequent Phase II studies of rilotumumab. Phase II studies There have been seven Phase II studies performed to date evaluating single-agent rilotumumab or rilotumumab in combination with chemotherapy/other targeted agents. None of these studies included a priori selection of patients based upon evidence of MET pathway activation or other biomarkers. Of these Phase II trials, perhaps the most exciting results were demonstrated in the first-line treatment of patients with advanced OGA. These results were recently reported in the Lancet Oncology, having been previously presented at the ECCO-ESMO-ESTRO international conference in 2011 [29] . This study randomized 121 patients from 42 centers to ECX in combination with either rilotumumab or placebo. The primary objective was PFS and there were three arms to this study: • Arm A (40 patients) ECX plus rilotumumab 15 mg/kg Q3W • Arm B (42 patients) ECX plus rilotumumab 7.5 mg/kg Q3W • Arm C (39 patients) was ECX plus placebo Q3W.
www.futuremedicine.com
1245
1246
Recurrent glioblastoma
Ib
II
Rosen et al.
Immunotherapy (2014) 6(12)
Wen et al.
Ib/II
Iveson et al.
142
KRAS wild-type metastatic colorectal cancer
Ib/II
120
Locally advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma
61
60
14
40
Sample size (n)
Ganitumab 12 mg/kg
Rilotumumab 10 mg/kg
Placebo
Panitumumab plus:
Placebo
All rilotumumab
MET-positive patients only
Placebo
Rilotumumab 15 mg/kg
Rilotumumab 7.5 mg/kg
ECX plus:
Rilotumumab 20 mg/kg Q2W
Rilotumumab 10 mg/kg Q2W
Rilotumumab 20 mg/kg Q2W
Rilotumumab 10 mg/kg Q2W
Escalation of rilotumumab 3, 10 or 20 mg/kg IV Q2W in combination with bevacizumab or motesanib
Escalation of rilotumumab 0.5, 1, 3, 5, 10 or 20 mg/kg IV Q2W
Treatment arms
22%
31%
21%
CR/PR: 12%
CR/PR: 50%
CR/PR: 21%
CR/PR: 31%
CR/PR: 48%
SD: 26 (43%) (both cohorts)
PR: 0%
PR: 1 (2.5%)
SD: 3 (15%)
SD: 4 (10%)
SD: 9 pts
CR/PR: 0 pts
10 evaluable pts
SD: 16 pts
CR/PR: 0 pts
23 evaluable pts
RR
5.3 (2.7–5.7) mo
5.2 (3.6–5.4) mo
3.7 (2.5–5.3) mo
4.4 (2.8–5.2) mo
6.8 (4.9–8.5) mo
4.2 (2.9–4.9) mo
5.1 (2.9–7.0) mo
6.8 (4.5–7.5) mo
2.0 (1.8–3.7) mo
3.7 (1.8–7.6) mo
4.3 (4.1–8.1) wks
4.1 (4.0–4.1) wks
7.9–121.9 wks
PFS for patients with SD: 7.9–40 wks
PFS
NR
5.7 (4.2–10.4) mo
10.6 (8.0–13.4) mo
8.9 (5.5–11.2) mo
9.7 (7.7–13.3) mo
11.1 (9.2–13.2) mo
17.6 (7.1–NE) mo
14.9 (9.4–NE) mo
5.4 (3.4–11.4) mo
6.5 (4.1–9.8) mo
NR
NR
OS
[30]
[29]
[28]
[27]
[26]
[25]
Ref.
CR: Complete response; mo: Months; NE: Not estimable; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; pts: Patients; RR: Response rate; SD: Stable disease; wks: Weeks.
Van Cutsem et al.
Metastatic renal cell carcinoma
Schoffksi II et al.
Advanced solid tumors
Advanced solid tumors
I
Gordon et al.
Tumor types
Phase
Study
Table 1. Summary of Phase I and II trials of rilotumumab.
Drug Evaluation Waddell, Moorcraft & Cunningham
future science group
future science group
CR: Complete response; mo: Months; NE: Not estimable; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; pts: Patients; RR: Response rate; SD: Stable disease; wks: Weeks.
[32]
4.27 (1.9–5.9) mo (first quartile only) 1.8 (1.7–1.9) mo CR: 1 (3.2%) PR: 0 SD: 6 (19%) Rilotumumab 20 mg/kg Q2W 31 II Martin et al.
Recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer
11.1 (9.0–12.7) mo 2.9 (2.8–3.6) mo SD: 12 (43%) Placebo IV
13.4 (11.2–15.3) mo 2.8 (2.7–3.3) mo SD: 6 (24%) Rilotumumab 15 mg/kg
11.6 (8.6–15.2) mo 3.6 (2.9–4.5) mo SD: 13 (48%) Rilotumumab 7.5 mg/kg
[31]
Mitoxantrone and prednisolone plus: 144 Ib/II Ryan et al.
Castration-resistant prostate cancer
Treatment arms Sample size (n) Tumor types Phase Study
Table 1. Summary of Phase I and II trials of rilotumumab (cont.).
RR
PFS
OS
Ref.
Potential role of rilotumumab in the treatment of gastric cancer
Drug Evaluation
This trial reported that the patients in the rilotumumab-containing arms (Arms A and B combined) had a statistically significant improvement in median PFS compared with those receiving placebo (5.7 months vs 4.2 months; HR: 0.60, p = 0.016), although this did not translate into a statistically significant improvement in OS (10.6 months vs 8.9 months; HR: 0.70, p = 0.109) in an unselected population [26] . Importantly, this study successfully evaluated the tumor tissue of 91 (77%) participants for MET expression by IHC. Patients were then divided into a MET-positive cohort (≥25% membrane staining on tumor cells at any intensity; n = 58) and a MET-negative cohort (
Potential role of rilotumumab in the treatment of gastric cancer
In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in ‘METpositive’ gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.
Tom Waddell*,1, Sing Yu Moorcraft1 & David Cunningham1 Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK *Author for correspondence: tom.waddell@ rmh.nhs.uk 1
Keywords: biomarker • gastric/gastro-esophageal junction cancer • MET-positive • rilotumumab • targeted therapy
Gastric cancer is the fourth most common cancer in the world and is estimated to affect close to one million people every year, with the incidence being approximately twice as high in men compared with women. The majority of cases occur in developing countries and almost 50% of all cases occur in eastern Asia, particularly China. Importantly, gastric cancer remains less treatable than many other common cancers and it therefore represents the second commonest cause of cancer-related death, being responsible for almost 10% of all cancer-related deaths worldwide [1] . In Western countries, the last 4 decades have seen a gradual decline in the incidence of distal gastric cancers accompanied by an increased incidence of proximal tumors affecting the gastric cardia and gastro-esophageal junction [2] . The exact reasons for this are not fully understood but it is primarily thought to be due to factors such as increased gastroesophageal reflux, Barrett’s metaplasia of the lower esophagus, obesity, smoking and western diet [3] . In countries without established endoscopic screening programs the major-
10.2217/IMT.14.91 © 2014 Future Medicine Ltd
ity of patients will present with metastatic disease. In this setting, best supportive care results in a median overall survival (OS) of only 3 months [4] . Current treatment guidelines Whilst combination chemotherapy regimens have demonstrated efficacy in both the perioperative and advanced disease settings, OS outcomes remain extremely poor. Outside of clinical trials the average survival in western patients is approximately 8–10 months with current palliative chemotherapy regimens [4,5] . Internationally, there is no single accepted standard-of-care regimen in advanced esophago-gastric adenocarcinoma (OGA), although the majority of centers use a doublet or triplet chemotherapy combination based around a platinum-fluoropyrimidine backbone. Historically the triplet chemo therapy combination of epirubicin, cisplatin and 5-fluorouracil has been regarded as a standard treatment option in many centers [6] . Reported in 2008, the REAL-2 non inferiority study confirmed that oxaliplatin and capecitabine represented effective alter-
Immunotherapy (2014) 6(12), 1243–1253
part of
ISSN 1750-743X
1243
Drug Evaluation Waddell, Moorcraft & Cunningham natives to cisplatin and 5-fluorouracil, respectively. This served to establish epirubicin, oxaliplatin and capecitabine as a standard first-line option in this setting, with an associated median OS of 11.2 months [5] . Other approved first-line treatment regimens include the combination of docetaxel and irinotecan, or use of either of these drugs in doublet and triplet chemotherapy regimens in combination with platinum agents and/or fluoropyrimidines [7–12] . However, with median survival times remaining consistently less than 12 months in clinical trials, there is clearly still a considerable unmet need in terms of effective therapies in advanced OGA. Targeted therapies have led to significant advances in the treatment of other solid organ tumors of the gastrointestinal tract including the use of anti-EGFR therapy in KRAS wildtype colorectal cancer [13,14] , and the development of imatinib, which has revolutionized the treatment of gastrointestinal stromal tumors [15] . In OGA, the last few years have finally seen the incorporation of a targeted therapeutic, trastuzumab, into the standard treatment paradigm for a molecularly defined subset of patients. This important therapeutic development resulted from the Phase III ToGA trial (n = 594) which confirmed that the addition of trastuzumab to chemotherapy was associated with a median OS of 16.0 months in patients with HER-2 IHC 2+ and FISH-positive tumors or IHC 3+ tumors [16] . Compared with patients treated with chemotherapy alone, this represented a statistically significant and clinically important 4.2 month median survival advantage. The ToGA trial is the first Phase III success for targeted therapy in esophago-gastric cancer, and confirms that careful selection of patients for therapy based upon tissue biomarkers can result in meaningful benefits. In addition to the evaluation of HER-2 status, there is considerable interest in identifying other, frequently dysregulated growth factor receptors which may represent viable therapeutic targets. Putative targets which are currently of interest include the MET, FGFR and IGF1R surface receptors and downstream effectors including PI3K, MEK, Akt and mTOR. There is also considerable interest in drugs which may disrupt tumor angiogenesis, primarily by targeting VEGF or its surface receptors. Body of review
1244
OGA and have entered randomized Phase II/III trials. These will be discussed in the following paragraphs. MET-targeted therapies
Rilotumumab (AMG102) is produced by Amgen and is the focus of this article. This drug will therefore be discussed in detail in the sections that follow. Onartuzumab (MetMAb) is a monoclonal antibody produced by Roche which binds to the extracellular domain of the MET receptor. In Phase I this drug has demonstrated activity against a range of tumor types including gastric cancer, and in a Phase II proof-of-concept study in nonsmall-cell lung cancer it was confirmed that patients with MET overexpression on immunohistochemistry (IHC) derived increased benefit compared with those without [17,18] . Onartuzumab is currently being evaluated in firstline OGA in a randomized Phase III trial in combination with a platinum-fluoropyrimidine chemotherapy doublet. A number of small-molecule inhibitors of MET receptor signaling have also recently launched into clinical trials in a variety of solid tumors, with examples including tivantinib, crizotinib and foretinib [19] . Unlike the monoclonal antibodies mentioned above, these molecules target the intracellular domain of the MET tyrosine kinase receptor, preventing the phosphorylation events necessary for signal transduction. These molecules may be ATP-competitive or noncompetitive and with varying degrees of selectivity for the MET receptor. In the setting of OGA, these small molecule inhibitors are currently in Phase II trials, and amplification of the MET gene is often the molecular aberration being used to select patients for therapy. HER-2 targeted therapies
Trastuzumab (Herceptin, Roche) – this drug now represents a standard of care in HER-2 positive disease following the previously described ToGA trial results [16] . Evaluation in the peri-operative and adjuvant settings is ongoing in Phase II trials. The success of trastuzumab has led to further randomized Phase II/III studies of other HER-2 targeted agents in advanced OGA including trastuzumab emtansine (antibody-drug conjugate with trastuzumab linked to a cytotoxic), pertuzumab (HER-2 dimerization inhibitor) and MM-111 (bi-specific antibody targeting HER-2 and HER-3).
Overview of the market
Anti-angiogenic therapies
As in all solid organ tumor types, there are currently a wide range of novel therapeutics being evaluated in Phase I–III clinical trials in advanced OGA (see the clinicaltrials.gov website). However, of the many agents under evaluation there are a few which have already demonstrated encouraging results in advanced
The Phase III AVAGAST trial evaluated bevacizumab in combination with first-line chemotherapy in advanced OGA [20] . Bevacizumab is a monoclonal antibody targeting the VEGF-A ligand, and was confirmed to result in a 1.4 -month improvement in median progressionfree survival (PFS) but no OS benefit. The Phase III
Immunotherapy (2014) 6(12)
future science group
Potential role of rilotumumab in the treatment of gastric cancer
ST03 trial is currently ongoing and is evaluating bevacizumab alongside peri-operative epirubicin, cisplatin and capecitabine (ECX) in the setting of operable OGA. Ramucirumab, a monoclonal antibody directed against VEGFR2, has recently demonstrated improved OS compared with placebo in second-line OGA as a single agent (REGARD trial) [21] . In the same setting, the randomized Phase III RAINBOW trial has also confirmed a survival benefit when ramucirumab is added to singleagent paclitaxel chemotherapy (median OS 9.6 months compared with 7.4 months with paclitaxel alone [22]). Introduction to rilotumumab
Rilotumumab is a fully human monoclonal antibody (IgG2) directed against human HGF also known as scatter factor. HGF is the only known ligand for the MET receptor and rilotumumab therefore acts to entirely block signaling via the MET receptor. Chemistry
Chemical formula: C6464H9932N1708O2010S46. Pharmacodynamics
Rilotumumab successfully binds to human HGF with high affinity, as indicated by an equilibrium dissociation constant (K D) of 19 pmol/l [23] . In human cell lines this leads to potent and complete inhibition of MET phosphorylation with an IC50 value of 0.12 nmol/l. This binding is associated with a number of important pharmacodynamic endpoints including reductions in cell proliferation, cell survival and migration/invasion. Pharmacokinetics & metabolism
Rilotumumab exerts linear pharmacokinetics within the dose range 0.5–20 mg/kg without significant interaction with co-administered compounds [24] . Renal and hepatic functions are also not found to have an effect on rilotumumab pharmacokinetics. The volume of distribution approximates plasma volume with the Cmax being observed at 1–2 h after commencing the 60-minute infusion and typical systemic clearance of 0.184 l/day. The plasma half-life is around 18 days and steady state should generally be reached by the time of the fifth administration. Clinical efficacy
Rilotumumab is currently being evaluated in a number of different clinical settings. The results of the Phase I and II studies initiated to date are summarized in Table 1 and in the text below. Phase I studies A Phase I monotherapy study conducted by Gordon et al. enrolled 40 patients with relapsed and/or refrac-
future science group
Drug Evaluation
tory advanced solid tumors, including renal cell (13%), ovarian (10%) and breast (10%) tumors [25] . Patients were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10 or 20 mg/kg of rilotumumab IV every 2 weeks) and a dose-expansion cohort (20 mg/kg of rilotumumab every 2 weeks). This study demonstrated that rilotumumab was well tolerated and the maximum tolerated dose was not reached. Although no partial or complete responses were seen in the 23 patients with Response Evaluation Criteria in Solid Tumours (RECIST) evaluable disease, 16 patients (70%) had stable disease with PFS ranging from 8 to 40 weeks. Rosen et al. performed a Phase 1b study which evaluated rilotumumab in combination with bevacizumab or motesanib in patients with advanced solid tumors [26] . This combination was selected following preclinical studies which suggested that the VEGF signaling pathway can interact with the HGF pathway to promote tumor growth [33,34] . Motesanib is an oral inhibitor of VEGFR 1, 2 and 3, PDGFR and Kit [35] . This study enrolled 14 patients into four cohorts and included patients with a variety of tumor types including breast, colon and non-small-cell lung cancer. Ten of the 14 patients were evaluable by RECIST and again no complete or partial responses were seen. Nine patients achieved stable disease, with PFS ranging from 8 to 122 weeks. The encouraging safety profile in these two Phase I studies led to the development of a number of subsequent Phase II studies of rilotumumab. Phase II studies There have been seven Phase II studies performed to date evaluating single-agent rilotumumab or rilotumumab in combination with chemotherapy/other targeted agents. None of these studies included a priori selection of patients based upon evidence of MET pathway activation or other biomarkers. Of these Phase II trials, perhaps the most exciting results were demonstrated in the first-line treatment of patients with advanced OGA. These results were recently reported in the Lancet Oncology, having been previously presented at the ECCO-ESMO-ESTRO international conference in 2011 [29] . This study randomized 121 patients from 42 centers to ECX in combination with either rilotumumab or placebo. The primary objective was PFS and there were three arms to this study: • Arm A (40 patients) ECX plus rilotumumab 15 mg/kg Q3W • Arm B (42 patients) ECX plus rilotumumab 7.5 mg/kg Q3W • Arm C (39 patients) was ECX plus placebo Q3W.
www.futuremedicine.com
1245
1246
Recurrent glioblastoma
Ib
II
Rosen et al.
Immunotherapy (2014) 6(12)
Wen et al.
Ib/II
Iveson et al.
142
KRAS wild-type metastatic colorectal cancer
Ib/II
120
Locally advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma
61
60
14
40
Sample size (n)
Ganitumab 12 mg/kg
Rilotumumab 10 mg/kg
Placebo
Panitumumab plus:
Placebo
All rilotumumab
MET-positive patients only
Placebo
Rilotumumab 15 mg/kg
Rilotumumab 7.5 mg/kg
ECX plus:
Rilotumumab 20 mg/kg Q2W
Rilotumumab 10 mg/kg Q2W
Rilotumumab 20 mg/kg Q2W
Rilotumumab 10 mg/kg Q2W
Escalation of rilotumumab 3, 10 or 20 mg/kg IV Q2W in combination with bevacizumab or motesanib
Escalation of rilotumumab 0.5, 1, 3, 5, 10 or 20 mg/kg IV Q2W
Treatment arms
22%
31%
21%
CR/PR: 12%
CR/PR: 50%
CR/PR: 21%
CR/PR: 31%
CR/PR: 48%
SD: 26 (43%) (both cohorts)
PR: 0%
PR: 1 (2.5%)
SD: 3 (15%)
SD: 4 (10%)
SD: 9 pts
CR/PR: 0 pts
10 evaluable pts
SD: 16 pts
CR/PR: 0 pts
23 evaluable pts
RR
5.3 (2.7–5.7) mo
5.2 (3.6–5.4) mo
3.7 (2.5–5.3) mo
4.4 (2.8–5.2) mo
6.8 (4.9–8.5) mo
4.2 (2.9–4.9) mo
5.1 (2.9–7.0) mo
6.8 (4.5–7.5) mo
2.0 (1.8–3.7) mo
3.7 (1.8–7.6) mo
4.3 (4.1–8.1) wks
4.1 (4.0–4.1) wks
7.9–121.9 wks
PFS for patients with SD: 7.9–40 wks
PFS
NR
5.7 (4.2–10.4) mo
10.6 (8.0–13.4) mo
8.9 (5.5–11.2) mo
9.7 (7.7–13.3) mo
11.1 (9.2–13.2) mo
17.6 (7.1–NE) mo
14.9 (9.4–NE) mo
5.4 (3.4–11.4) mo
6.5 (4.1–9.8) mo
NR
NR
OS
[30]
[29]
[28]
[27]
[26]
[25]
Ref.
CR: Complete response; mo: Months; NE: Not estimable; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; pts: Patients; RR: Response rate; SD: Stable disease; wks: Weeks.
Van Cutsem et al.
Metastatic renal cell carcinoma
Schoffksi II et al.
Advanced solid tumors
Advanced solid tumors
I
Gordon et al.
Tumor types
Phase
Study
Table 1. Summary of Phase I and II trials of rilotumumab.
Drug Evaluation Waddell, Moorcraft & Cunningham
future science group
future science group
CR: Complete response; mo: Months; NE: Not estimable; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; pts: Patients; RR: Response rate; SD: Stable disease; wks: Weeks.
[32]
4.27 (1.9–5.9) mo (first quartile only) 1.8 (1.7–1.9) mo CR: 1 (3.2%) PR: 0 SD: 6 (19%) Rilotumumab 20 mg/kg Q2W 31 II Martin et al.
Recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer
11.1 (9.0–12.7) mo 2.9 (2.8–3.6) mo SD: 12 (43%) Placebo IV
13.4 (11.2–15.3) mo 2.8 (2.7–3.3) mo SD: 6 (24%) Rilotumumab 15 mg/kg
11.6 (8.6–15.2) mo 3.6 (2.9–4.5) mo SD: 13 (48%) Rilotumumab 7.5 mg/kg
[31]
Mitoxantrone and prednisolone plus: 144 Ib/II Ryan et al.
Castration-resistant prostate cancer
Treatment arms Sample size (n) Tumor types Phase Study
Table 1. Summary of Phase I and II trials of rilotumumab (cont.).
RR
PFS
OS
Ref.
Potential role of rilotumumab in the treatment of gastric cancer
Drug Evaluation
This trial reported that the patients in the rilotumumab-containing arms (Arms A and B combined) had a statistically significant improvement in median PFS compared with those receiving placebo (5.7 months vs 4.2 months; HR: 0.60, p = 0.016), although this did not translate into a statistically significant improvement in OS (10.6 months vs 8.9 months; HR: 0.70, p = 0.109) in an unselected population [26] . Importantly, this study successfully evaluated the tumor tissue of 91 (77%) participants for MET expression by IHC. Patients were then divided into a MET-positive cohort (≥25% membrane staining on tumor cells at any intensity; n = 58) and a MET-negative cohort (
