Cyramza (Ramucirumab) Receives New FDA Indication for Second-Line Treatment of Patients with Metastatic Colorectal Cancer

Colorectal cancer (CRC) is a major health problem, with high financial and personal costs.¹ CRC is the third most common cancer in the United States, and is the second leading cause of US cancer death.¹ According to the American Cancer Society, approximately 132,700 Americans were diagnosed with CRC in 2015, and an estimated 49,700 people died from this disease.¹

Improvements in CRC screening and treatment have favorably affected patient outcomes associated with CRC; the death rate from CRC has declined significantly during the past 20 years.¹ CRC is highly curable if it is diagnosed early, and the 5-year survival rates for patients with stage I CRC exceed 90%.²

Surgery, radiation therapy, chemotherapy, and targeted therapies are viable treatment options for patients with CRC.³ Depending on the disease stage, these modalities can be used in sequence or in combination to optimize the treatment responses and long-term outcomes.³

Systemic therapy options for patients with metastatic CRC that is not amenable to surgical resection or radiation include cytotoxic chemotherapy and targeted therapies.³ The most frequently used chemotherapy regimens in metastatic CRC include FOLFOXIRI (leucovorin, 5-fluorouracil [5-FU], oxaliplatin, irinotecan), FOLFOX (leucovorin, 5-FU, oxaliplatin), FOLFIRI (leucovorin, 5-FU, irinotecan), CapeOx (capecitabine plus oxaliplatin), FL (5-FU plus leucovorin), capecitabine, irinote­can, and trifluridine plus tipiracil.³

The National Comprehensive Cancer Network guidelines recommend the adjunctive use of targeted agents with specific first-line and subsequent therapies, noting that the addition of targeted agents improved efficacy outcomes, but also increased the toxicity rates.⁴

Angiogenesis is an important process in tumor growth, and is mediated by vascular endothelial growth factor (VEGF).⁵ The blockade of VEGF signaling with small molecules or antibody-based agents, such as bevacizumab, inhibits angiogenesis and affects tumor blood supply.^6,7 For patients with metastatic CRC who are receiving subsequent lines of chemotherapy, the addition of bevaciz­umab, other angiogenesis inhibitors, or EGFR inhibitors, such as cetuximab or panitumumab, can be considered.⁴

CRC is one of the most costly tumor types to manage, second only to breast cancer in the United States.⁸ Of the more than $124 billion spent on cancer care in 2010, CRC represented $14 billion.⁸ By 2020, the cost associated with CRC care for patients aged ≥65 years is expected to increase by at least 53%.⁹

Although advances in screening, prevention, genomic analysis, and management of CRC have had an impor­tant impact on clinical outcomes, a high proportion of patients with advanced disease will die from this disease.² Statistics are particularly dire for metastatic CRC, with 5-year survival rates reaching only 11%, highlighting the need for treatment advances for metastatic CRC.²

Ramucirumab Approved for Metastatic Colorectal Cancer

On April 24, 2015, the US Food and Drug Administration (FDA) approved ramucirumab (Cyramza; Eli Lilly) in combination with FOLFIRI for the treatment of patients with metastatic CRC whose disease progressed during or after previous therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.^10,11

Ramucirumab was originally approved in April 2014 as a single agent or in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma whose disease progressed during or after previous fluoropyrimidine- or platinum-containing chemotherapy.¹² In December 2014, ramucirumab received a new indication in combination with docetaxel for patients with metastatic non–small-cell lung cancer whose disease progressed during or after platinum-based chemotherapy.¹³

The approval of ramucirumab for metastatic CRC was based on results from the RAISE study, a randomized, double-blind, multinational, phase 3 clinical trial.^11,14 Ramucirumab plus FOLFIRI significantly prolonged overall survival and progression-free survival compared with placebo plus FOLFIRI.¹⁴

Mechanism of Action

Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that inhibits angiogenesis or blood supply to tumor cells.¹¹ It is a VEGF receptor-2 antagonist that binds VEGF receptor-2 and blocks the binding of VEGF receptor ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF receptor-2, as well as ligand-induced proliferation and migration of human endothelial cells.¹¹

Dosing and Administration

In metastatic CRC, the recommended dose of ramucirumab is 8 mg/kg every 2 weeks until disease progression or until unacceptable toxicity. Ramucirumab is administered intravenously for 60 minutes before FOLFIRI administration. Ramucirumab should not be administered as an intravenous (IV) push or bolus.¹¹

Ramucirumab vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL of ramucirumab.¹¹

The RAISE Clinical Trial

The efficacy and safety of ramucirumab in metastatic CRC was demonstrated in the RAISE clinical trial, a phase 3, multinational, randomized, double-blind study that compared ramucirumab plus FOLFIRI with placebo plus FOLFIRI in patients with metastatic CRC whose disease progressed during or after previous therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (ie, FOLFOX or CapeOx).^11,14 More than 1000 patients
were randomized to receive ramucirumab 8 mg/kg (as an IV infusion) plus FOLFIRI (N = 536) or placebo plus FOLFIRI (N = 536).¹¹

In both study arms, the treatment cycles were repeated every 2 weeks. Patients who discontinued ≥1 components of treatment because of an adverse event were allowed to continue therapy with the other treatment component until disease progression or until unacceptable toxicity.¹¹

The primary efficacy end point was overall survival, and the secondary end point included progression-free survival.¹¹ Patients were stratified by the geographic region, tumor KRAS mutation status, and the time to disease progression after beginning first-line treatment (ie, <6 months vs ≥6 months).¹¹

The patients’ median age was 62 years. Overall, 49% of patients had a KRAS mutation.¹¹ In addition, 24% of patients had disease relapse within 6 months of their first-line treatment.¹¹

Overall survival and progression-free survival were significantly improved in patients receiving ramucir­umab plus FOLFIRI versus placebo plus FOLFIRI (Table).¹¹ The median overall survival was 13.3 months in the ramucirumab plus FOLFIRI arm compared with 11.7 months in the FOLFIRI plus placebo arm (hazard ratio, 0.85; 95% confidence interval, 0.73-0.98; P = .023). The treatment effect seen with ramucirumab plus FOLFIRI was consistent across the prespecified stratification factors.¹¹

Adverse Events

The safety of ramucirumab was assessed in 529 patients who received ramucirumab plus FOLFIRI in the RAISE study. Patients received a median of 8 doses of ramucirumab (range, 1-68), with a median duration of exposure of 4.4 months. Overall, 32% of patients received ramucirumab for at least 6 months.¹¹

The most common adverse reactions (all grades) reported with ramucirumab plus FOLFIRI at ≥30% and ≥2% higher than in patients receiving placebo plus FOLFIRI included diarrhea (60%), neutropenia (59%), decreased appetite (37%), epistaxis (33%), and stomatitis (31%). Overall, 20% of patients required granulocyte colony-stimulating factors.¹¹

A subset of 224 patients with normal thyroid-stimulating hormone levels at study enrollment were evaluated throughout the study.¹¹ Increases in thyroid-stimulating hormone levels were observed in 46% of patients receiving ramucirumab plus FOLFIRI compared with 4% in the placebo plus FOLFIRI arm.¹¹

Treatment discontinuation because of adverse reactions occurred more frequently in patients receiving ramucirumab plus FOLFIRI compared with placebo plus FOLFIRI (29% vs 13%, respectively).¹¹ The most common adverse reactions leading to the discontinuation of ramucirumab plus FOLFIRI or placebo plus FOLFIRI were neutropenia (12% vs 5%, respectively) and thrombocytopenia (4% vs 1%, respectively).¹¹

The most common adverse reactions leading to the discontinuation of ramucirumab were gastrointestinal perforation (1.7%) and proteinuria (1.5%).¹¹

Ramucirumab has no contraindications.¹¹

Warnings and Precautions

Boxed warnings. Ramucirumab was approved with a boxed warning regarding the increased risk for hemorrhage, including severe and potentially fatal hemorrhagic events, as well as gastrointestinal perforation and impaired wound healing.¹¹

Hemorrhage. In the RAISE study, the incidence of severe bleeding was 2.5% with ramucirumab plus FOL­FIRI. Ramucirumab should be discontinued if severe bleeding occurs.¹¹

Gastrointestinal perforations. Because it is an antiangiogenic therapy, ramucirumab can increase the risk for a gastrointestinal perforation.¹¹ Ramucirumab should be permanently discontinued in patients with a gastrointestinal perforation.¹¹

Impaired wound healing. As an antiangiogenic therapy, ramucirumab can adversely affect wound healing. Ramucirumab should be withheld before surgery and resumed after surgery based on adequate wound healing. If wound healing complications develop during treatment, ramucirumab should be withheld until the wound is fully healed.¹¹

Arterial thromboembolic events (ATEs). ATEs associated with ramucirumab include myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia. Ramucirumab should be discontinued if an ATE is observed.¹¹

Hypertension. Severe hypertension occurred more frequently in patients receiving ramucirumab plus FOLFIRI compared with placebo plus FOLFIRI (11% vs 3%, respectively).¹¹ Hypertension should be controlled before starting ramucirumab treatment. Blood pressure should be monitored at least every 2 weeks during treatment, and ramucirumab should be suspended until severe hypertension is controlled.¹¹

Infusion-related reactions. Patients should be monitored during the infusion of ramucirumab for symptoms of infusion-related reactions. Ramucirumab should be immediately and permanently discontinued if grade 3 or 4 infusion-related reactions occur.¹¹

Clinical deterioration of cirrhosis. New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in patients with Child-Pugh class B or C cirrhosis. Ramucirumab should only be used in these patients if its potential benefits outweigh the risk for clinical deterioration.¹¹

Reversible posterior leukoencephalopathy syndrome (RPLS). RPLS has been reported in clinical studies of ramucirumab. Ramucirumab should be discontinued if the diagnosis of RPLS is confirmed by magnetic resonance imaging.¹¹

Proteinuria and nephrotic syndrome. In the RAISE study, severe proteinuria occurred more frequently with ramucirumab plus FOLFIRI compared with placebo plus FOLFIRI.¹¹ Patients should be monitored for proteinuria during ramucirumab treatment. Ramucirumab should be withheld if urine protein levels reach ≥2 during 24 hours, and discontinued if the levels reach ≥3 in 24 hours or if nephrotic syndrome develops.¹¹

Thyroid dysfunction. Thyroid dysfunction was reported in patients receiving ramucirumab plus FOLFIRI in the RAISE study.¹¹ Thyroid function should be monitored during treatment with ramucirumab.¹¹

Use in Specific Populations

Pregnancy. Ramucirumab can cause fetal harm based on its mechanism of action; pregnant women should be advised of this risk.¹¹

Nursing mothers. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, breast-feeding is not recommended during treatment with ramucirumab.¹¹

Females of reproductive potential. Ramucirumab may impair fertility. Females of reproductive potential should use effective contraception while receiving ramucirumab, and for at least 3 months after the last dose.¹¹

Pediatric use. The safety and effectiveness of ramucirumab in pediatric patients have not been established.¹¹

Geriatric use. Among patients who received ramucirumab plus FOLFIRI in the RAISE study, 40% were aged ≥65 years. No differences in the safety or effectiveness were detected when comparing older and younger patients.¹¹

Renal impairment. No dose adjustment is required for patients with renal impairment.¹¹

Hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment.¹¹ Clinical deterioration has been observed after the use of single-agent ramucirumab in patients with Child-Pugh B or C cirrhosis.¹¹

Conclusion

Ramucirumab is the third VEGF inhibitor to demonstrate clinical benefit and an acceptable safety profile in patients with metastatic CRC. The RAISE study demonstrated that the addition of ramucirumab to FOLFIRI significantly improved overall survival and progression-free survival compared with placebo plus FOLFIRI in the second-line treatment of patients with metastatic CRC. All patients had disease progression during or after previous therapy with FOLFOX or CapeOx. Additional clinical studies are exploring the activity of ramucirumab-based combinations in CRC, as well as in other solid tumors.¹⁵

References

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13. US Food and Drug Administration. FDA expands approved use of Cyramza to treat aggressive non-small cell lung cancer. Press release. December 12, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm426720.htm. Accessed January 5, 2016.
14. Tabernero J, Yoshino T, Cohn AL, et al; for the RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499-508. Erratum in: Lancet Oncol. 2015;16:e262.
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