Ramucirumab for gastric cancer

Approved indication: gastric cancer
Cyramza (Eli Lilly)
vials containing 100 mg in 10 mL and 500 mg in 50 mL as concentrate
Australian Medicines Handbook section 14.2.1

Ramucirumab is indicated for patients with advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma when the disease has progressed after cytotoxic chemotherapy. This drug is used in combination with paclitaxel or as monotherapy if paclitaxel cannot be given.

Ramucirumab is a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF) receptor 2. This blocks the binding of several vascular endothelial growth factors (A, C and D) to the receptor. Signalling mediated by these growth factors in endothelial cells is important in the progression of gastric cancer.

The efficacy and safety of ramucirumab has been assessed in two trials – RAINBOW¹ and REGARD.² The trials enrolled patients who had locally advanced or metastatic gastric adenocarcinoma which had progressed after chemotherapy with platinum, fluoropyrimidine or both. Patients with a history of arterial thromboembolic events, gastrointestinal bleeding, or uncontrolled hypertension were excluded from the trials. Participants received treatment until their disease progressed (confirmed by radiography) or they had unacceptable adverse effects. In both trials, the primary end point was overall survival.

The RAINBOW trial randomised patients to ramucirumab plus paclitaxel or placebo plus paclitaxel. Ramucirumab (8 mg/kg) or placebo was given on day 1 and 15 and paclitaxel (80 mg/m²) was given on days 1, 8 and 15 of a 28-day cycle. Median overall survival was significantly longer in the ramucirumab arm than in the placebo arm (9.6 vs 7.4 months) (see Table).¹

In the REGARD trial, patients were randomised to ramucirumab monotherapy (8 mg/kg fortnightly) or placebo. All participants received best supportive care. Although median overall survival times were generally shorter in this trial, ramucirumab significantly prolonged survival compared with placebo (5.2 months vs 3.8 months) (see Table).²

In the RAINBOW trial, the most common adverse events with ramucirumab were fatigue (56.8%), neutropenia (54.4%), decreased appetite (40%), abdominal pain (36%), nausea (35.1%), leucopenia (33.9%), diarrhoea (32.4%), epitaxis (30.6%), vomiting (26.9%), peripheral oedema (25%), hypertension (23.8%), stomatitis (18%), proteinuria (16.5%) and thrombocytopenia (13.1%). All of these events were more common with ramucirumab than with placebo. There were six deaths that were thought to be related to ramucirumab plus paclitaxel. Causes included sepsis, septic shock, malabsorption, gastrointestinal haemorrhage and pulmonary embolism.¹

The most common adverse events with ramucirumab in the REGARD trial included fatigue (35.5%), abdominal pain (28.8%), decreased appetite (24.1%), vomiting (19.9%), hypertension (16.1%) and bleeding (12.7%). The five deaths thought to be related to ramucirumab were due to myocardial infarction, gastric haemorrhage, intestinal perforation (2 cases) and pneumonia.²

As hypertension can be a problem with ramucirumab, blood pressure should be monitored regularly. If it occurs, treatment should be interrupted until blood pressure is controlled.

Although patients with a history of thromboembolic events or gastrointestinal bleeding were excluded, myocardial infarction, cardiac arrest, cerebrovascular accident, cerebral ischaemia, gastrointestinal perforations and gastrointestinal bleeding have been reported with ramucirumab. These events have been fatal in some cases and treatment should be stopped if patients show symptoms. Blood clotting should be monitored in those with an increased risk of bleeding. Regular blood counts are also important as neutropenia was common with combination ramucirumab therapy.

As ramucirumab can affect angiogenesis, the drug could potentially reduce wound healing. Treatment should be stopped four weeks before elective surgery and only started again after adequate healing.

Interactions with other drugs have not been observed with ramucirumab. The drug is diluted and given by intravenous infusion over 60 minutes. Infusion reactions can occur and are more common during the first and second infusion. Premedication to prevent infusion reactions is recommended. Antibodies to ramucirumab were detected in 2–3% of patients. However, these were found not to be neutralising antibodies.^1,2

Although ramucirumab improves the survival times of patients with advanced or metastatic gastric cancer, the benefit is modest. In the trials, median survival was prolonged by 8–9 weeks with ramucirumab and paclitaxel, and by 5–6 weeks with ramucirumab alone. Adverse reactions are common with ramucirumab and some are fatal so patient monitoring is essential.

Manufacturer did not respond to request for data.

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.