Targeted Therapy Drugs: Ramucirumab

Targeted Therapy Drugs: Ramucirumab-Introduction

Ramucirumab, developed by Eli Lilly, a recombinant monoclonal antibody of the IgG1 class that binds to vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks the activation of the receptor. It is approved for the treatment of multiple sollid tumors: metastatic colorectal cancer, platinum-resistant metastatic non-small cell lung cancer, advanced gastric or gastroesophageal junction adenocarcinoma and gastric or gastroesophageal junction adenocarcinoma.

Targeted Therapy Drugs: Ramucirumab-Target

The target of this drug is VEGFR2. VEGFR2 is largely considered the primary VEGF family receptor driving angiogenesis. A critical pillar of angiogenesis is the interaction of the VEGF family of pro-angiogenic cytokines and their respective receptors. The VEGF family includes VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and placental growth factor (PlGF) with three receptors: VEGFR1, VEGFR2, and VEGFR3 with associated co-reptors neuropillin 1 and 2. VEGFR2 expression is typically limited to vessel endothelial cells and binds VEGFA, VEGFE and processed forms of VEGFC and VEGFD. VEGFR2 is widely considered the main receptor driving angiogenesis. Upregulation of VEGFR2 expression is seen in the tumor vasculature in a variety of malignancies.

Targeted Therapy Drugs: Ramucirumab-Disease

In 2014, Ramucirumab is appproved for use in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and as a single agent for the treatment of patients with advanced gastric or GEJ adenocarcinoma refractory to or progressive following first-line therapy with platinum or fluoropyrimidine chemotherapy. And it is appproved for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. In 2015, Ramucirumab is applied for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen.

Targeted Therapy Drugs: Ramucirumab-Efficacy

For metastatic colorectal cancer: the clinical trial accrued 1072 patients who were randomly allocated (1:1) to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab (N=536 per arm). Treatment cycles on both arms were repeated every 2 weeks and ramucirumab was administered at a dose of 8 mg/kg by intravenous infusion every two weeks. Ramucirumab was continued until disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by geographic region (North America vs. Europe vs. other regions), KRAS status (wild-type vs. mutant) and time to progression for the beginning of first-line treatment (< 6 months vs. greater than or equal to 6 months).
The median age of the study population was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1. A statistically significant OS improvement was observed in patients receiving FOLFIRI plus ramucirumab compared to those receiving FOLFIRI plus placebo [HR 0.85 (95% CI: 0.73, 0.98), p=0.023, stratified log-rank test]. Median OS was 13.3 and 11.7 months for patients on the FOLFIRI plus ramucirumab and FOLFIRI plus placebo arms, respectively. PFS was also significantly improved in patients who received ramucirumab in combination with FOLFIRI [HR 0.79 (95% CI: 0.70, 0.90), p<0.001]. Median PFS was 5.7 and 4.5 months, respectively.
For platinum-resistant metastatic non-small cell lung cancer: the approval of ramucirumab in combination with docetaxel in NSCLC was based on the demonstration of improved overall survival (OS) in a multicenter, double-blind, placebo-controlled study (I4T-MC-JVBA) that enrolled 1253 patients with previously treated metastatic NSCLC. Patients were randomized to receive either ramucirumab (10 mg/kg every three weeks) in combination with docetaxel (75 mg/m2 every 3 weeks) on day 1 of a 21-day cycle (n=628) or matching placebo plus docetaxel (n=625).
A statistically significant prolongation of OS was demonstrated [HR 0.86; (95% CI: 0.75, 0.98); p=0.024]; median OS was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm. Progression-free survival was also significantly longer for patients receiving ramucirumab plus docetaxel [HR=0.76 (95% CI: 0.68, 0.86); p<0.001)].
For advanced gastric or gastroesophageal junction adenocarcinoma: the approval of ramucirumab in combination with paclitaxel was based on the demonstration of improved overall survival (OS) in a multicenter, double-blind, placebo-controlled study (I4T-IE-JVBE) that enrolled 665 patients with previously-treated advanced or metastatic gastric or GEJ adenocarcinoma. Patients were randomized to receive either ramucirumab (8 mg/kg every two weeks) in combination with paclitaxel (80 mg/m2 once a week for 3 weeks of every 28-day cycle) (n=330) or matching placebo plus paclitaxel (n=335).
A statistically significant prolongation of OS was demonstrated [HR 0.81; (95% CI: 0.68, 0.96); p=0.017]; median OS was 9.6 and 7.4 months in the ramucirumab plus paclitaxel arm and placebo plus paclitaxel arm, respectively. Progression-free survival was also significantly longer for patients receiving ramucirumab plus paclitaxel [HR=0.64 (95% CI: 0.54, 0.75); p<0.001)].

Targeted Therapy Drugs: Ramucirumab-Side Effect

For advanced gastric or gastroesophageal junction adenocarcinoma: safety data was evaluated in 656 patients who received at least one dose of study drug. The most frequently reported adverse reactions with ramucirumab plus paclitaxel (incidence greater than or equal to 30%) were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. The most common serious adverse reactions with ramucirumab plus paclitaxel were neutropenia and febrile neutropenia (3.7% and 2.4%, respectively).
For platinum-resistant metastatic non-small cell lung cancer: safety data was evaluated in 1245 patients who received at least one dose of study drug. The most frequently reported adverse reactions with ramucirumab plus docetaxel (incidence greater than or equal to 30%) were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. The most common serious adverse reactions with ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%).
For metastatic colorectal cancer: in general, the safety data was consistent with the known safety profile established in previously approved indications. However, thyroid dysfunction (hypothyroidism) was reported in 2.6% of patients based on thyroid monitoring in patients with mCRC.

Targeted Therapy Drugs: Ramucirumab-Reference

Clarke J et al. Targeted inhibition of VEGF Receptor-2: An update on Ramucirumab. Expert opinion on biological therapy. 2013;13(8):1187-1196. doi:10.1517/14712598.2013.810717.

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Side Effects of Targeted Therapy
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