Ramucirumab: A Novel Antiangiogenic Agent for Gastric Cancer and Gastroesophageal Junction Cancer

Usha Malhotra, MD

Assistant Professor,

Department of Medicine,

Roswell Park Cancer Institute

Abstract

Advanced gastric cancer (GC) and gastroesophageal junction (GEJ) cancers are highly aggressive cancers with poor prognosis and limited treatment options. The vascular endothelial growth factor (VEGF) pathway has been one of the key signaling pathways under investigation for these cancers. Ramucirumab is a fully humanized monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and inhibiting downstream signaling. In addition to establishing the safety and maximum-tolerated dose (MTD) of this agent, phase I studies also demonstrated striking disease control rate leading to further evaluation of ramucirumab in various cancers, including gastroesophageal cancers. Two recent phase III studies have reported benefit of this agent in advanced gastroesophageal cancers. These trials are pivotal studies establishing the role of an antiangiogenic agent in addition to demonstrating single-agent activity of a targeted agent for these cancers.

Introduction

Angiogenesis Pathway and Antiangiogenic Agents in Gastroesophageal Cancer

Clinical Pearls

• Ramucirumab is a fully humanized monoclonal antibody that binds with high affinity to VEGFR-2, thereby inhibiting binding of the ligand to the receptor and further downstream signaling.
• Phase I studies have established the safety and maximumtolerated dose of ramucirumab and also revealed striking disease control rates for patients with refractory solid organ cancers.
• Ramucirumab has been evaluated in two phase III studies and an ongoing phase II study for advanced gastroesophageal cancer.
• REGARD, the first completed randomized, phase III trial of ramucirumab, compared it (8 mg/kg IV every 2 weeks) and best supportive care (BSC) with placebo and BSC and showed a modest but statistically significant improvement in secondline setting.
• REGARD is the first trial to establish the efficacy of an antiangiogenic agent in addition to validating single-agent activity of a targeted therapy for gastroesophageal cancers.
• The RAINBOW trial is the second phase III study that demonstrated a benefit in overall survival (OS) and progressionfree survival (PFS) when ramucirumab (8 mg/kg IV every 2 weeks) is used in combination with paclitaxel (80 mg/m²on days 8 and 15 of a 4-week cycle) versus paclitaxel alone (same dose and schedule as in the combination arm) in second-line treatment for advanced gastroesophageal cancers.
• In all the clinical trials, the adverse effect profile of ramucirumab is similar to other agents in its class and is well tolerated. Common grade ≥3 toxicities reported with singleagent ramucirumab include hypertension, fatigue, anemia, decreased appetite while in combination with chemotherapy; neutropenia and leukopenia have also been reported. Grade 3 hypertension, deep-vein thrombosis, grade 3 vomiting, and grade 3 proteinuria were the dose-limiting toxicities observed in a phase I study.
• There is still a lack of a validated predictive biomarker that can be used for optimal selection of appropriate patients who would attain maximum benefit from this agent.

Gastric cancer remains an enormous health issue worldwide, with extensive regional variations. More than 900,000 new cases of gastric cancer were estimated worldwide in 2008, with 738,000 deaths, accounting for 10% of total cancer-related deaths.¹In the United States, 21,600 new cases of gastric cancer were estimated in 2013, with 10,990 deaths.²There has been a significant increase in the incidence of proximal gastric cancer (GC) and gastroesophageal junction (GEJ) cancer in the US and other western countries over the past few decades. Management of localized and locoregional disease involves a multidisciplinary approach using chemotherapy in conjunction with surgery with a curative intent. For surgically inoperable and metastatic disease, chemotherapy is the mainstay of treatment, with an aim to prolong life and palliate symptoms related to the cancer. Advances have been made in chemotherapy regimens but outcome remains dismal, with 5-year survival rate of less than 25%, underlining the need for more effective strategies. Consequently, interest has increased in evaluating novel therapeutic strategies with targeted agents to increase efficacy without a significant increment in toxicity. Angiogenesis pathway and agents targeting various components of this pathway have been evaluated in multiple cancer types, including GC and GEJ cancer. Two recent randomized, phase III trials reported the benefit of ramucirumab, a monoclonal antibody directed to vascular endothelial growth factor receptor—2 (VEGFR-2), for advanced GC and GEJ cancer. In this review we provide a brief overview of this agent, including the studies evaluating its role in this group of gastrointestinal cancers.Development of new blood vessels is essential for maintaining tumor vascular supply and thereby promoting cancer cell proliferation and metastasis. Various signaling pathways are implicated in driving the process of angiogenesis in cancer, with the VEGF pathway being the most significant. This is a complex pathway whose key components include VEGF ligands, receptors, and downstream cascade that eventually cause upregulation of genes, promoting new vessel formation. VEGF-A, -B, -C -D, and -E, are the implicated ligands, with VEGF-A being most frequently involved in cancer-related angiogenesis. Placental growth factors (PlGFs) 1 and 2 are other growth factors involved. VEGFR-1 (flt 1), VEGFR-2 (KDR,) and VEGFR-3 are the receptors, with some data supporting a crucial role of VEGFR-2 in tumorrelated angiogenesis.³Various agents—including monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) targeting different components of this pathway—have been developed and used in various cancers, including gastroesophageal cancers (Figure 1).

Bevacizumab, a monoclonal antibody targeting VEGF-A, has been investigated extensively in several phase II studies and in a randomized phase III trial for gastroesophageal cancer. The initial phase II studies using bevacizumab in combination with chemotherapy reported response rates exceeding 60%, with favorable progression-free survival (PFS) and overall survival (OS).^4-6This led to evaluation of bevacizumab in combination with cisplatin and a fluoropyrimidine in the first-line setting for advanced/ metastatic gastroesophageal cancer. The Avastin in Gastric Cancer (AVAGAST) trial was an international, randomized, phase III study that enrolled 774 patients with advanced esophagogastric adenocarcinoma.⁷Patients were randomized to chemotherapy doublet with placebo or to chemotherapy doublet with bevacizumab in a 1:1 fashion with 387 patients in each arm. Addition of bevacizumab led to improvement of both response rate (46.0% vs 37.4%;P= .03) as well as median PFS (6.7 months vs 5.3 months; hazard ratio [HR] = 0.80; confidence interval [CI]: 0.68-0.93;P= .003). However, the trial did not meet its primary endpoint of a significant improvement in OS, which was 12.1 months in the bevacizumab arm compared with 10.1 months in the control arm (HR = 0.87; CI: 0.73-1.03;P= .1).

A notable finding in this trial was a higher degree of benefit seen in pan-American population compared with patients in Asia, potentially related to regional differences in tumor biology. Biomarker analysis done on blood and tumor tissue available from >90% of patients enrolled in AVAGAST trial identified plasma VEGF-A and tumor neuropilin-1 as potential predictive biomarkers,⁸although the data could not be replicated in metastatic colorectal cancer.

FIGURE 1. Vascular endothelial growth factor (VEGF) pathway inhibition

Ramucirumab: Preclinical and Early Clinical Studies

Additionally, TKIs, including sorafenib (NCT- 00565370, NCT00253370, NCT01262482) and sunitinib^9-11(NCT00524186), have also been evaluated in gastroesophageal cancer but conclusive activity has not been established. Regorafenib, a novel TKI that has been approved for metastatic colorectal cancer, is undergoing evaluation in combination with chemotherapy in an ongoing clinical trial (NCT01913639). To date, the only antiangiogenic agent with reported proven benefit in a randomized phase III trial is ramucirumab, a monoclonal antibody targeting VEGFR-2.Ramucirumab (IMC1121B) is a fully humanized monoclonal antibody that prevents binding of VEGF ligand to VEGFR-2 and thereby inhibits further downstream signaling mediated through this pathway.¹²Ramucirumab selectively binds to the extracellular domain of VEGFR-2 with half-maximal inhibitory concentration (IC50) of 0.8 nM to 1.0 nM.¹³It is administered intravenously; various dosing schedules, including weekly and biweekly administration, have been evaluated. Ramucirumab has an 8-fold higher affinity of VEGFR-2 when compared with its conventional ligand.¹⁴Pharmacodynamic evaluations have confirmed the inhibition of interaction of VEGF with VEGFR-2, an increase in the VEGF ligand, along with a decrease in VEGFR-2, after administration of ramucirumab.¹⁵Pharmacokinetic evaluation has demonstrated a nonlinear pharmacokinetic, with incremental doses of this agent being associated with a decrease in clearance.¹²Doses of 8 mg/kg to 16 mg/kg have been correlated with a halflife of 200 hours to 300 hours at steady state.¹⁵

Preclinical evaluation on mouse xenograft models involved the use of DC- 101, an antibody directed to murine VEGR-2, because of lack of activity of ramucirumab against murine receptors.¹⁶Similar to ramucirumab, DC-101 prevents binding of murine VEGF to the corresponding VEGFR-2. Administration of DC-101 in the mouse model led to inhibition of metastases after tumor resection.¹⁷Detailed evaluations in the preclinical model established a target trough level of 20 μg/mL for adequate antitumor activity.¹⁸

TABLE 1. Clinical Studies Evaluating Ramucirumab for the Treatment of Gastroesophageal Cancer

Clinical Trial

Regimen

N

NCT Identifier

Phase I

Ramucirumab

37

NCT00793975

Phase I

Ramucirumab

25

NCT00786383

Phase I

Ramucirumab

17

NCT01005355

Phase II

FOLFOX+ Ramucirumab

166

NCT01246960

Phase III (REGARD)

Ramucirumab + BSC vs placebo + BSC

355

NCT00917384

Phase III (RAINBOW)

Ramucirumab + paclitaxel vs paclitaxel

655

NCT01170663

BSC indicates best supportive care; FOLFOX, fluorouracil and oxaliplatin.

TABLE 2. Clinical Studies Evaluating Ramucirumab for the Treatment of Gastroesophageal Cancer

Trial

No. of Patients (randomization)

Regimen

Response Rate

PFS (months) HR

OS (months) HR

REGARD

Total = 355 (2:1)

Arm 1 = 238

Arm 2 = 117

Arm 1: BSC + R

Arm 2:

BSC + P

3%

3%

2·1 m

1.3 m

(HR 0.48,

<.0001

5.2 m

3. 8 m

(HR 0.7,P= .047)

RAINBOW

Total = 665 (1:1)

Arm 1 = 330

Arm 2 = 335

Arm 1:

Pac + R

Arm 2:

Pac + P

28%

16%

P= .0001

4&middot;4 m

2.8 m

(HR 0.63,

P< .0001

9.6 m

7.3 m

(HR 0.8,P= .016)

BSC indicates best supportive care; P, placebo; Pac, paclitaxel; R, ramucirumab; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; m, months.

To date, 3 phase I studies have been conducted to evaluate the safety of ramucirumab (Table 1). The largest of these studies enrolled 37 patients with advanced refractory cancers.¹⁵The trial was conducted in a standard 3+3 dose-escalation manner evaluating

Advanced-Phase Clinical Trials in Gastric Cancer and GEJ Cancer

7 dose levels ranging from 2 mg/kg to 16 mg/ kg administered over 1 hour weekly. Dose-limiting toxicities (DLTs) included grade 3 hypertension and deep-vein thrombosis (DVT), grade 3 vomiting, and grade 3 proteinuria, establishing a maximum-tolerated dose (MTD) of 13 mg/kg for weekly schedule. Some of the other adverse events (AEs) observed were fatigue, headache, diarrhea, peripheral edema, hypertension, abdominal pain, anorexia, vomiting, and proteinuria. All patients achieved a trough level of at least 20 &mu;g/mL. Two patients, one with gastric cancer and one with melanoma, had a partial response, and 15 patients were noted to have stable disease lasting for at least 6 months leading to a total disease control rate of 73%.Ramucirumab has been investigated for GC and GEJ cancer. A phase II trial using this agent in combination with cytotoxic chemotherapy (fluorouracil and oxaliplatin [FOLFOX]) in the first-line setting for advanced gastroesophageal cancer is ongoing with PFS being the primary endpoint, aiming at a total enrollment of 166 patients (Table 1).

Two phase III studies have recently reported positive results in advanced GC and GEJ cancer (Table 1andTable 2). The REGARD trial randomized patients with advanced GC and GEJ cancer who had progressed on first-line therapy with a platinum and fluoropyrimidine combination to ramucirumab and best supportive care (BSC) versus placebo with BSC.¹⁹The trial was initially projected to accrue 615 patients with a 90% power to detect a HR of 0.71, but because of slow accrual, the study was modified to accrue 348 patients with an 80% power to identify a HR of 0.69. The study was initially presented at an American Society of Clinical Oncology-Gastrointestinal Cancer symposium (GI-ASCO) in 2013, with final study published in 2014.19 A total of 355 patients were randomized in a 2:1 fashion to ramucirumab (n = 238) and BSC and to placebo and BSC (n = 117). Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks. The median duration of therapy was 8 weeks in the ramucirumab and 6 weeks in the placebo arms. The primary endpoint of OS was seen to be significantly improved in the ramucirumab arm (median OS 5.2 months vs 3.8 months, HR = 0.77;P= .047). PFS was also significantly higher in the ramucirumab arm (median PFS 2.1 months vs 1.3 months; HR = 0.48;P<.0001). Although there was no significant improvement on response rates (RR), 3.4% versus 2.6% in ramucirumab and placebo arms, respectively, disease control rate was 49% in the ramucirumab arm and 23% in the placebo arm, supporting a statistically significant improvement (P<.0001). This agent was well tolerated, with the most significant treatment-related toxicities being hypertension, anemia, abdominal pain, anorexia, and fatigue. Subgroup analysis revealed benefit across all groups, including prestratified groups based on weight loss, geographic location, and location of the primary tumor. Although modest activity was seen with a median OS advantage of 1.4 months in the ramucirumab arm, this trial was the first trial to demonstrate activity of an antiangiogenic agent for gastroesophageal cancer. In addition, this was the first trial for this cancer that supported the efficacy of single-agent targeted therapy.

Conclusion

References

The RAINBOW trial was reported in an abstract at the GI-ASCO in January 2014 (J Clin Oncol. 2014;32[suppl 3]:Abstract LBA7, NCT01170663). This phase III, randomized, double-blind, placebocontrolled study compared ramucirumab in combination with paclitaxel (R+P) versus placebo with paclitaxel (P) for patients with advanced GC and GEJ cancer after progression on first-line fluoropyrimidine/ platinum combination. A total of 665 patients were randomized to both arms (n = 330 for R+P and n = 335 for P). Median OS was 9.6 in the R+P arm and 7.3 in the P arm (HR = 0.8;P= .0169), while the median PFS was 4.4 in the R+P arm and 2.8 in the P arm (HR = 0.6;P<.0001). Addition of ramucirumab also led to a significant improvement in RR (28% R+P and 16% P,P= .0001). Main AEs observed in the combination arm included neutropenia, leucopenia, hypertension, anemia, and fatigue. Although there was an increase in the rate of grade 3 or more neutropenia, leucopenia, and hypertension, the combination was relatively well tolerated. The trial met its primary endpoint of OS, supporting the use of this combination as a reasonable option in the second-line setting.Targeting the angiogenesis pathway has been an active field of investigation with both preclinical and clinical studies evaluating various agents in advanced GC and GEJ cancer. Before the introduction of ramucirumab, none of the other available drugs was able to demonstrate a benefit in phase III randomized trials. Two recent phase III studies met their endpoints in establishing the clinical efficacy of ramucirumab in advanced GC and GEJ cancer. The potential basis for activity of ramucirumab may be selective targeting of VEGFR-2, which studies suggest may be the predominant receptor involved in cancer-related angiogenesis. Based on data from the REGARD study, the FDA granted ramucirumab priority review status for patients with advanced GC and GEJ cancer.(Editor's note: Ramucirumab has since beenapproved for the treatment of GC and GEJ cancers)Although both these trials (REGARD and RAINBOW) are pivotal in establishing the role of an antiangiogenic agent in this disease, challenges remain regarding the optimal use of this class of agents. While investigators are still analyzing biomarker data, lack of a validated predictive biomarker has been a significant limitation for the use of antiangiogenic agents. These trials support the benefit of ramucirumab for advanced gastroesophageal cancers; the magnitude of benefit could be significantly higher for biomarker-based, optimally selected patients.

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics.CA Cancer J Clin. 2011;61(2):69-90.
2. National Cancer Institute. PDQ Gastric Cancer Treatment. Bethesda, MD. Date last modified, February 15, 2013. http://cancer.gov/cancertopics/ pdq/treatment/gastric/HealthProfessional. Accessed November 20, 2013.
3. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-2049.
4. Enzinger P, et al. Phase II trial of docetaxel, cisplatin, irinotecan, and bevacizumab in metastatic esophagogastric cancer.J Clin Oncol. 2008; 26(suppl 15):4552.
5. Shah MA, Jhawer M, Ilson DH, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma.J Clin Oncol. 2011;29(7):868-874.
6. Shah MA, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma.J Clin Oncol2006;24(33):5201-5206.
7. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study.J Clin Oncol. 2011;29(30):3968-3976.
8. Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial.J Clin Oncol. 2012;30(17):2119-2127.
9. Yi JH, Lee J, Lee J, et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum.Br J Cancer. 2012;106(9): 1469-1474.
10. Lee KW, Park SR, Oh DY, et al. Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer.Invest New Drugs. 2013;31(6):1547-1558.
11. Gomez-Martin C, Salazar R, Montagut C, et al. A phase I, dose-finding study of sunitinib combined with cisplatin and 5-fluorouracil in patients with advanced gastric cancer.Invest New Drugs. 2013;31(2):390-398.
12. Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): a novel attack on angiogenesis.Future Oncol. 2010;6(7):1085-1094.
13. Lu D, Jimenez X, Zhang H, et al. Selection of high affinity human neutralizing antibodies to VEGFR2 from a large antibody phage display library for antiangiogenesis therapy.Int J Cancer. 2002;97(3):393-399.
14. Miao HQ, Hu K, Jimenez X, et al. Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2.Biochem Biophys Res Commun. 2006;345(1):438-445.
15. Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2.J Clin Oncol. 2010;28(5):780-787.
16. Fong GH, Rossant J, Gertsenstein M, et al. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.Nature. 1995;376(6535):66-70.
17. Franklin MC, Navarro EC, Wang Y, et al. The structural basis for the function of two anti-VEGF receptor 2 antibodies.Structure. 2011;19(8): 1097-1107.
18. Wadhwa R, Taketa T, Sudo K, et al. Ramucirumab: a novel antiangiogenic agent.Future Oncol. 2013;9(6):789-795.
19. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet. 2014;383(9911):31-39.