Ramucirumab (Cyramza)

Number: 0883

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses ramucirumab (Cyramza) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of ramucirumab (Cyramza) is required of all Aetna participating providers and members in applicable plan designs. For precertification of ramucirumab (Cyramza), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers ramucirumab (Cyramza) medically necessary for the following indications:  

   1. Gastric, Gastro-esophageal Junction (GEJ), Esophagogastric Junction (EGJ), and Esophageal Adenocarcinoma

      For treatment of gastric, gastro-esophageal junction (GEJ), esophagogastric junction (EGJ), and esophageal adenocarcinoma for members who are not surgical candidates or who have unresectable locally advanced, recurrent or metastatic disease, when used as subsequent therapy as a single agent, in combination with paclitaxel, or in combination with irinotecan with or without fluorouracil;

   2. Non-Small Cell Lung Cancer (NSCLC)

      For treatment of recurrent, advanced or metastatic NSCLC when either of the following criteria is met:

      1. Used in combination with docetaxel as subsequent therapy; or
         
      2. Used in combination with erlotinib for EGFR exon 19 deletion or exon 21 (L858R) substitution mutation positive disease;
         

   3. Colorectal Cancer (CRC)

      For treatment of advanced or metastatic colorectal cancer, including anal adenocarcinoma and appendiceal adenocarcinoma, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) or irinotecan;
      

   4. Hepatocellular Carcinoma (HCC)

      For subsequent treatment of progressive hepatocellular carcinoma as a single agent in members who have an alpha fetoprotein (AFP) of greater than or equal to 400 ng/mL;

   5. Mesothelioma

      For the subsequent treatment of pleural mesothelioma, pericardial mesothelioma, or tunica vaginalis testis mesothelioma when used in combination with gemcitabine.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   1. NSCLC

      Aetna considers continuation of ramucirumab (Cyramza) therapy medically necessary in members requesting reauthorization for NSCLC when either of the following criteria is met:

      1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; or
      2. Disease is T790M negative and there is no evidence of unacceptable toxicity.

   2. All Other Indications

      Aetna considers continuation of ramucirumab (Cyramza) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Cyramza (ramucirumab) is available for injection as 100 mg/10 mL (10 mg/mL) or 500 mg/50 mL (10 mg/mL) solution in a single-dose vial.

Gastric Cancer

The recommended dosage of Cyramza, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous (IV) infusion over 60 minutes. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Non-Small Cell Lung Cancer

EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – Cyramza in Combination with Erlotinib

The recommended dosage of Cyramza is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue Cyramza until disease progression or unacceptable toxicity.

Disease Progression On Or After Platinum-based Chemotherapy – Cyramza in Combination with Docetaxel

The recommended dosage of Cyramza is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Colorectal Cancer

The recommended dosage is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Hepatocellular Carcinoma

The recommended dosage is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Source: Eli Lilly, 2022

Experimental and Investigational

Aetna considers ramucirumab experimental and investigational for the treatment of the following indications (not an all-inclusive list):

• Biliary tract cancer
• Bladder (urothelial) cancer
• Breast cancer
• Chondrosarcoma
• Gastric neuroendocrine carcinoma
• Genitourinary tumor
• Fallopian tube cancer
• Head and neck cancer
• Malignant pleural diseases (e.g., mesothelioma)
• Melanoma
• Ovarian cancer
• Peritoneal carcinoma
• Prostate cancer
• Renal cell carcinoma
• Rheumatoid arthritis
• Soft tissue sarcoma
• Thymic carcinoma.

Aetna considers combined ramucirumab with irinotecan plus cisplatin for small-cell lung cancer experimental and investigational.

Aetna considers combined ramucirumab and atezolizumab for non-small cell lung cancer experimental and investigational.

Aetna considers combined ramucirumab and sorafenib for hepatocellular carcinoma experimental and investigational.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Gastric Cancer: Cyramza as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy.
• Non-Small Cell Lung Cancer (NSCLC):
  
  
  • Cyramza, in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza.
  • Cyramza, in combination with erlotinib, is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. 
    
    
• Colorectal Cancer: Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
• Hepatocellular Carcinoma: Cyramza as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.

Compendial Uses

• Esophageal adenocarcinoma
• Colorectal cancer, advanced, including anal adenocarcinoma and appendiceal adenocarcinoma
• NSCLC, EGFR mutation positive, recurrent, advanced
• Mesothelioma

Ramucirumab is a VEGFR2 antagonist that specifically binds VEGFR2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model (Eli Lilly, 2020).

Angiogenesis is a hallmark of malignancy, and attempts to inhibit this process have characterized the age of biologic anti-cancer therapies for solid tumors.  Vascular endothelial growth factor receptor-2 (VEGFR-2) is the premier receptor responsible for many of the cancer-driven VEGF-induced spectrum of biologic changes, including modification of blood vessel structure and function, proliferation and migration. 

Unlike all clinically approved angiogenesis inhibitors, the fully human monoclonal antibody ramucirumab, specifically inhibits VEGFR-2.  Phase I clinical trials have shown safety across a wide range of ramucirumab doses with impressive, albeit early, evidence of both stable disease and partial responses in a variety of tumor types (Spratlin et al, 2010).

Per labeling for Cyramza (ramucirumab), the most common adverse reactions observed in single agent Cyramza-treated gastric cancer patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common adverse reactions observed in patients treated with Cyramza with paclitaxel at a rate of ≥30% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. The most common adverse reactions observed in patients treated with Cyramza with erlotinib at a rate of ≥30% and ≥2% higher than placebo with erlotinib were, infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities at a rate of ≥30% and ≥2% higher difference in incidence between arms were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. The most common adverse reactions observed in patients treated with Cyramza with docetaxel at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. The most common adverse reactions observed in patients treated with Cyramza with FOLFIRI at a rate of ≥30% and ≥2% higher than placebo with FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. The most common adverse reactions observed in single agent Cyramza-treated HCC patients at a rate of ≥15% and ≥2% higher than placebo were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities at a rate of ≥30% and a ≥2% higher difference in incidence between arms were thrombocytopenia, hypoalbuminemia, and hyponatremia (Eli Lilly, 2020).

Biliary Tract Cancer

Arkenau and colleagues (2018) stated that few therapeutic options exist for patients with advanced biliary tract cancer (BTC) following progression on gemcitabine-cisplatin. Pre-clinical evidence suggested that simultaneous blockade of VEGFR-2 and programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) enhances anti-tumor effects. In a non-randomized, open-label, phase-I clinical trial, these researchers evaluated the safety and efficacy of ramucirumab with pembrolizumab in biomarker-unselected patients with previously treated advanced or metastatic BTC. Patients had previously treated advanced or metastatic adenocarcinoma of the gallbladder, intra-hepatic and extra-hepatic bile ducts, or ampulla of Vater. Ramucirumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous pembrolizumab 200 mg on day 1 every 3 weeks. The primary end-point was safety and tolerability of the combination; secondary end-points included ORR, PFS, and OS. A total of 26 patients were treated at 12 centers in 5 countries. Hypertension was the most common grade 3 treatment-related AE (TRAE), occurring in 5 patients; 1 patient experienced a grade 4 TRAE (neutropenia), and no treatment-related deaths occurred; ORR was 4 %. Median PFS and OS were 1.6 months and 6.4 months, respectively. The authors concluded that ramucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliary tract cancer, which was consistent with reports of other tumor cohorts within this phase-Ia/b trial. Ramucirumab plus pembrolizumab did not demonstrate an improvement in OS when compared with historical controls in biomarker unselected, heavily pre-treated patients with advanced or metastatic biliary tract cancer. Patients with PD-L1-positive tumors had improved OS compared with patients with PD-L1-negative disease. These investigators noted that the survival signal in PD-L1-positive patients was interesting, but they were limited by sample size and had no historical reference for the natural history of patients with PD-L1 positivity relative to the wider population, and it may represent selection bias. Moreover, they stated that ramucirumab is concurrently being investigated in the phase-II setting for advanced or metastatic BTC in combination with gemcitabine-cisplatin for 1st-line treatment and as monotherapy in patients previously treated with a gemcitabine-based regimen.

Valle and colleagues (2021) noted that BTCs are aggressive, rare, gastro-intestinal (GI) malignancies with a poor prognosis; about 50 % of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. In a randomized, double-blind, phase-II clinical trial, these researchers examined the safety and effectiveness of ramucirumab or merestinib in addition to 1st-line cisplatin-gemcitabine in patients with locally advanced or metastatic BTC. This 18-country study enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an ECOG performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Eligible subjects were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once-daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All subjects received intravenous cisplatin 25 mg/m2 and gemcitabine 1,000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of 8 cycles. Randomization was carried out by an interactive web response system using a permuted block method (blocks of 6) and was stratified by primary tumor site, geographical region, and presence of metastatic disease. Subjects, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed PFS (in the intention-to-treat [ITT] population). The safety analysis was performed in all patients who received at least 1 dose of their assigned treatment. Between May 25, 2016 and August 8, 2017, a total of 450 patients were examined for eligibility and 309 (69 %) were enrolled and randomly assigned to ramucirumab (n = 106), merestinib (n = 102), or pooled placebo (n = 101); 306 received at least 1 dose of study treatment. The median follow-up time for PFS at data cut-off (February 16, 2018) was 10.9 months (inter-quartile range [IQR] 8.1 to 14.1). Median PFS was 6.5 months (80 % CI: 5.7 to 7.1) in the ramucirumab group, 7.0 months (6.2 to 7.1) in the merestinib group, and 6.6 months (5.6 to 6.8) in the pooled placebo group (ramucirumab versus placebo HR of 1.12 [80 % CI: 0.90 to 1.40], 2-sided stratified p = 0.48; merestinib versus placebo 0.92 [0.73 to 1.15], 2-sided stratified p= 0·64). The most common grade 3 or worse AEs were neutropenia (51 [49 %] of 104 patients in the ramucirumab group; 48 [47 %] of 102 in the merestinib group; and 33 [33 %] of 100 in the pooled placebo group), thrombocytopenia (36 [35 %]; 19 [19 %]; and 17 [17 %]), and anemia (28 [27 %]; 16 [16 %]; and 19 [19 %]). Serious AEs occurred in 53 (51 %) patients in the ramucirumab group, 56 (55 %) in the merestinib group, and 48 (48 %) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in 1 (1 %) of 104 patients in the ramucirumab group (cardiac arrest) and 2 (2 %) of 102 patients in the merestinib group (pulmonary embolism [n = 1] and sepsis [n = 1]). The authors concluded that the addition of ramucirumab or merestinib to 1st-line cisplatin-gemcitabine was well-tolerated, with no new safety signals, but neither improved PFS in patients with molecularly unselected, locally advanced or metastatic BTC. These researchers stated that the role of these targeted inhibitors remains investigational, highlighting the need for further understanding of BTCs and the contribution of molecular selection.

Bladder (Urothelial) Cancer

In an open-label, 3-arm, randomized controlled phase II clinical trial, Petrylak and colleagues (2016) evaluated the safety and effectiveness of docetaxel monotherapy or docetaxel in combination with ramucirumab (VEGFR2 antibody) or icrucumab (VEGFR 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic bladder (urothelial) carcinoma.  Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m(2) intravenously (IV) on day 1 of a 3-week cycle (arm-A), docetaxel 75 mg/m(2) IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm-B), or docetaxel 75 mg/m(2) IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm-C).  Treatment continued until disease progression or unacceptable toxicity.  The primary end-point was investigator-assessed PFS.  A total of 140 patients were randomly assigned and treated in arm-A (n = 45), arm-B (n = 46), or arm-C (n = 49); PFS was significantly longer in arm-B compared with arm-A (median of 5.4 months; 95 % CI: 3.1 to 6.9 months versus 2.8 months; 95 % CI: 1.9 to 3.6 months; stratified HR, 0.389; 95 % CI: 0.235 to 0.643; p = 0.0002).  Arm-C did not experience improved PFS compared with arm-A (1.6 months; 95 % CI: 1.4 to 2.9; stratified HR, 0.863; 95 % CI: 0.550 to 1.357; p = 0.5053).  The most common grade 3 or worse adverse events (AEs) (arm-A, arm-B, and arm-C) were neutropenia (36 %, 33 %, and 39 %, respectively), fatigue (13 %, 30 %, and 20 %, respectively), febrile neutropenia (13 %, 17 %, and 6.1 %, respectively), and anemia (6.7 %, 13 %, and 14 %, respectively).  The authors concluded that the addition of ramucirumab to docetaxel met the pre-specified effectiveness end-point for prolonging PFS in patients with locally advanced or metastatic bladder carcinoma receiving 2nd-line treatment and warrants further investigation in the phase III clinical trials.

Aragon-Ching and Trump (2017) noted that progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years.  However, the recent approval of immunotherapy with atezolizumab and nivolumab for 2nd-line salvage therapy may usher in an era of more rapid improvement.  Systemic treatment is suboptimal and is an area of substantial unmet medical need.  The recent findings from the Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies.  Promising results with VEGF inhibitors (e.g., ramucirumab, sunitinib or bevacizumab), and HER2-targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials.

In a randomized, double-blind, phase-III clinical trial, Petrylak et al (2017) evaluated the safety and the efficacy of treatment with docetaxel plus either ramucirumab or placebo in patients with platinum-refractory advanced or metastatic urothelial carcinoma.  Patients were enrolled from 124 sites in 23 countries.  Previous treatment with 1 immune-checkpoint inhibitor was permitted.  Patients were randomized (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met.  The primary end-point was investigator-assessed progression-free survival (PFS), analyzed by intention-to-treat in the first 437 randomized patients.  Between July, 2015, and April, 2017, a total of 530 patients were randomly allocated either ramucirumab plus docetaxel (n = 263) or placebo plus docetaxel (n = 267); PFS was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median of 4.07 months [95 % CI: 2.96 to 4.47] versus 2.76 months [2.60 to 2.96]; hazard ratio [HR] 0.757, 95 % CI: 0.607 to 0.943; p = 0.0118).  A blinded independent central analysis was consistent with these results.  An objective response was achieved by 53 (24.5 %, 95 % CI: 18.8 to 30.3) of 216 patients allocated ramucirumab and 31 (14.0 %, 9.4 to 18.6) of 221 assigned placebo.  The most frequently reported treatment-emergent adverse events (AEs), regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhea, decreased appetite, and nausea.  These AEs occurred predominantly at grade 1 to 2 severity.  The frequency of grade 3 or worse AEs was similar for patients allocated ramucirumab and placebo (156 [60 %] of 258 versus 163 [62 %] of 265 had an AE), with no unexpected toxic effects; 63 (24 %) of 258 patients allocated ramucirumab and 54 (20 %) of 265 assigned placebo had a serious AE that was judged by the investigator to be related to treatment; 38 (15 %) of 258 patients allocated ramucirumab and 43 (16 %) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which 8(3 %) and 5 (2% ) deaths were deemed related to treatment by the investigator.  Sepsis was the most common AE leading to death on treatment (4 [2 %] versus none [0 %]); 1 fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab.  The authors concluded that to the best of their knowledge, ramucirumab plus docetaxel is the first regimen in a phase-III clinical trial to show superior PFS over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma.  They stated that these data validated inhibition of VEGFR-2 signaling as a potential new therapeutic treatment option for patients with urothelial carcinoma.

de Wit and colleagues (2022) noted that patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current therapeutic options. Ramucirumab plus docetaxel significantly improved PFS but not OS in platinum-refractory advanced UC (the RANGE Trial). These investigators reported the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE Trial. Pharmacokinetic (PK) samples were collected (cycle 1-3, 5, 9 [day 1] and 30 days from treatment discontinuation), and PK data were analyzed using population PK (popPK) analysis. The minimum ramucirumab concentration following 1st dose administration (Cmin,1 , or trough concentration immediately before the 2nd dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case-control analyses were used to examine the relationship between Cmin,1 and OS. The Cmin,1 relationship with safety was evaluated descriptively. Several poor prognostic factors (ECOG 1, hemoglobin concentration of less than 100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease-PK interaction. A significant association was identified between Cmin,1 and OS (p = 0.0108). Higher exposure quartiles were associated with longer survival and smaller HRs compared to placebo. No new exposure-safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks). The authors concluded that these pre-specified ER analyses suggested a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Moreover, these researchers stated that further studies are needed to understand and predict exposure based on disease characteristics and antibody clearance.

Colorectal Cancer

The FDA approved ramucirumab for use in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. 

The approval is based on the RAISE trial, a multinational, double-blind Phase III study which compared ramucirumab plus FOLFIRI to placebo plus FOLFIRI in people with metastatic colorectal cancer who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomized in a 1:1 ratio to receive ramucirumab plus FOLFIRI (n=536) or placebo plus FOLFIRI (n=536) every two weeks. Efficacy endpoints in the trial included the major efficacy outcome measure of overall survival (OS) and the supportive efficacy outcome measure of progression-free survival (PFS). 

In the RAISE trial, patients treated with the ramucirumab-FOLFIRI combination achieved a median OS, the study's primary endpoint, of 13.3 months as compared to those treated with placebo-FOLFIRI who achieved 11.7 months, a statistically significant improvement that reduced the risk of patient death by 15 percent (HR 0.85; 95% CI: 0.73-0.98; p = 0.023). The percentage of deaths at the time of analysis was 69 percent (372 patients) and 74 percent (397 patients) in the ramucirumab-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively. The ramucirumab combination also demonstrated a statistically significant improvement in the secondary endpoint of PFS over the placebo-FOLFIRI regimen, with a median PFS of 5.7 months vs. 4.5 months, respectively (HR 0.79; 95% CI: 0.70-0.90; p < 0.001). The percentage of events at the time of analysis was 89 percent (476 patients) and 92 percent (494 patients) in the ramucirumab-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively. In the RAISE trial, randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment (less than 6 months vs. greater than or equal to 6 months). The treatment effect was consistent across the pre-specified stratification factors. 

In an open-label, phase II study, Garcia-Carbonero et al (2014) evaluated the safety and effectiveness of ramucirumab (RAM) combined with mFOLFOX-6 as first-line therapy for metastatic CRC.  Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0 to 1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks.  End-points included PFS, ORR, OS, and safety.  The sample size was based on a potentially improved median PFS from 8 months to 11 months.  A total of 48 patients received therapy.  Median PFS was 11.5 months (95 % CI: 8.6 to 13.1 months).  The ORR was 58.3 % (95 % CI: 43.21 to 72.39).  The DCR (complete or partial response plus stable disease) was 93.8 % (95 % CI: 82.8 to 98.7).  Median OS was 20.4 months (95 % CI: 18.5 to 25.1 months).  The most frequent grade 3 to 4 adverse events included neutropenia (grade 3: 33.3 %; grade 4: 8.3 %), hypertension (grade 3: 16.7 %), and neuropathy (grade 3: 12.5 %).  Two patients died during the study due to myocardial infarction and cardiopulmonary arrest.  The authors concluded that RAM may enhance the effectiveness of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC.

Combined Crenolanib with Ramucirumab Plus Paclitaxel for Esophagogastric Adenocarcinoma

Moy and colleagues (2022) noted that paclitaxel plus ramucirumab is a standard 2nd-line regimen for patients with advanced gastric adenocarcinoma; however, clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. In a phase-I/Ib clinical trial, these researchers examined the safety and effectiveness of crenolanib in combination with paclitaxel/ramucirumab. Patients with metastatic esophagogastric adenocarcinoma refractory to 1st-line therapy received escalating doses of crenolanib [60 mg twice-daily (BID) to 100 mg thrice-daily (TID)] in combination with paclitaxel 80 mg/m2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the MTD of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month PFS at the MTD. These researchers enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade-3/4 treatment-emergent AEs included leukopenia (19 %), anemia (11 %) and neutropenia (11 %). In the 14 patients treated at the MTD, 6-month PFS was 43 % (95 % CI: 23 % to 78 %) and the ORR was 42 % (95 % CI: 15 % to 72 %). The trial was terminated early due to withdrawal of crenolanib by the sponsor. The authors concluded that the addition of crenolanib to paclitaxel/ramucirumab was safe and well-tolerated at a dose level up to 100 mg BID. These preliminary findings need to be validated by well-designed studies.

Combined Ramucirumab and Atezolizumab for Non-Small Cell Lung Cancer

Herzog et al (2022) stated that the therapeutic options for patients with stage IV NSCLC who develop tumor progression following platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) are limited. The combination of ICI with inhibitors of VEGFR signaling has shown promising results in previously untreated patients. In a single-center, phase II clinical trial, patients with advanced stage NSCLC previously treated with at least 1 line including ICI received ramucirumab 10 mg/kg and atezolizumab 1,200 mg intravenously every 21 days until tumor progression or intolerable toxicity. The primary endpoint was ORR by the RECIST 1.1 criteria according to the investigator assessment. Secondary endpoints included clinical benefit rate (CBR), OS, PFS and tolerability. A total of 21 patients were enrolled between June 2019 and April 2021. The median age was 67 years (range of 42 to 82), 17 (81 %) were women, and 15 (71 %) had non-squamous histology. The median number of prior systemic treatment lines and prior ICI lines were 3 (range of 2 to 8) and 1 (range of 1 to 3), respectively. One patient achieved a CR for an ORR of 4.8 % while 16 (76.2 %) had SD with a CBR of 80.9 %. The median PFS was 3.4 months, and the median OS was 16.5 months. The most common AEs included hypertension (86 %), proteinuria (67 %), and nausea (52 %). Grade-3 or grade-4 events were observed in 9 (43 %) of patients, with hypertension being the most common (33 %) of the grade-3 or grade-4 events. The authors concluded that although the primary endpoint of ORR was not met, the combined ramucirumab and atezolizumab was associated with a high CBR and the OS was better than expected in heavily pre-treated patients. These researchers stated that despite the low response rate, the OS was promising; thus, further investigation with ICI plus VEGF inhibition is needed.

Combined Ramucirumab with Dacarbazine for Pancreatic Neuroendocrine Tumors

Krug and colleagues (2021) noted that cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs); however, response rates, side effects and outcome data strongly varied among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing; and secondary resistances frequently occur. These researchers presented the protocol of the RamuNET Trial that aims to identify the effectiveness of dual treatment with ramucirumab and dacarbazine (DTIC) in progressive advanced PNET patients. The RamuNET study is a prospective, investigator-initiated, single-arm, multi-center trial to examine the effectiveness of ramucirumab in combination with DTIC over a period of at least 6 months. Patients with progressive well-differentiated and metastatic PNETs were eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months; and secondary endpoints include PFS, biochemical response, OS, QOL and toxicity. Based on the hypothesis that 80 % of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < = p0 = 60 % versus H1: p > = p1 = 80 %, alpha = 0.05, beta = 0.1. The authors concluded that this study examined a new therapeutic approach using the combination of cytotoxic and targeted anti-angiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized 2-arm study to examine the combination of ramucirumab and DTIC against other established therapies in PNET.

Combined Ramucirumab with Irinotecan Plus Cisplatin for Small-Cell Lung Cancer

Kenmotsu and colleagues (2022) stated that previous studies have shown the potentials of anti-angiogenesis inhibitors in extensive-stage SCLC. In a single-center, phase-Ib clinical trial, these researchers determined the recommended dose of ramucirumab in combination with irinotecan plus cisplatin for extensive-stage SCLC. Chemo-naïve patients with extensive-stage SCLC were enrolled and received ramucirumab (day 1 and 15) with irinotecan (60 mg/m2, day 1, 8, and 15) plus cisplatin (60 mg/m2, day 1) every 4 weeks for 4 cycles, followed by bi-weekly maintenance ramucirumab. The recommended ramucirumab dose (10 or 8 mg/kg) was determined using a traditional 3 + 3 design, and the number of patients treated at the recommended dose was set at 10 to evaluate drug efficacy and tolerability. The first 3 patients that received irinotecan plus cisplatin with ramucirumab 10 mg/kg did not experience DLTs; thus, the recommended dose of ramucirumab was set at 10 mg/kg, and 10 patients received this dose. The ORR was 100 % (95 % CI: 69 % to 100 %), with a median PFS of 7.2 months (95 % CI: 5.3 to 9.0) and median OS of 22.4 months (95 % CI: 12.1 to not reached). Grade 3 neutropenia and hypertension were observed in 4 and 2 patients, respectively. No ramucirumab-related deaths were noted; hypertension and bleeding events were observed in 5 and 6 patients, respectively. The authors concluded that this study showed the satisfactory tolerability and efficacy of ramucirumab at 10 mg/kg in combination with irinotecan plus cisplatin in chemo-naïve patients with extensive-stage SCLC. These preliminary findings need to be validated by well-designed studies.

Combined Ramucirumab and Sorafenib for Hepatocellular Carcinoma

Taha et al (2022) noted that sorafenib is the standardized treatment for HCC. One strategy to improve HCC therapy is to combine agents that target key signaling pathways. These researchers examined the effect of combining sorafenib with either bevacizumab (anti-VEGF), panitumumab (anti-EGFR) or ramucirumab (anti-VEGFR2) on HepG2 cancer cell line with the objective of improving effectiveness and possibility of therapeutic dose reduction of sorafenib. HepG2 cancer cell line was treated with sorafenib alone or in combination with either bevacizumab, panitumumab or ramucirumab. Cell proliferation; apoptosis and cell cycle distribution; gene expression of VEGFR2, EGFR, MMP-9 and CASPASE3; the protein levels of pVEGFR2 and pSTAT3 and the protein expression of CASPASE3, EGFR and VEGFR2 were determined. Combined treatments of sorafenib with ramucirumab or panitumumab resulted in a significant decrease in sorafenib IC50. Sorafenib combination with ramucirumab or bevacizumab resulted in a significant arrest in pre-G and G0/G1 cell cycle phases, significantly induced apoptosis and increased the relative expression of CASPASE3 and decreased the anti-proliferative and angiogenesis markers´ MMP-9 and pVEGFR2 or VEGFR2 in HepG2 cells. A significant decrease in the levels of pSTAT3 was only detected in case of sorafenib-ramucirumab combination. The combined treatment of sorafenib with panitumumab induced a significant arrest in pre-G and G2/M cell cycle phases and significantly decreased the relative expression of EGFR and MMP-9. Sorafenib-ramucirumab combination showed enhanced apoptosis, inhibited proliferation and angiogenesis in HepG2 cancer cells. The authors concluded that these findings suggested that ramucirumab could be a useful adjunctive therapy for improvement of sorafenib effectiveness in the suppression of HCC. Moreover, these researchers stated that further confirmation of the enhanced activity of ramucirumab-sorafenib combination should be tested in Huh-7 HCC cell lines and normal cell lines.

Gastric and Esophageal Cancer

In an international, randomized, multi-center, placebo-controlled, phase III clinical trial (the REGARD trial), Fuchs et al (2014) examined if ramucirumab prolonged survival in patients with advanced gastric cancer.  These researchers carried out this phase III trial between October 6, 2009 and January 26, 2012 at 119 centers in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa.  Patients aged 24 to 87 years with advanced gastric or gastro-esophageal (GE) junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1) to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks.  The study sponsor, participants, and investigators were masked to treatment assignment.  The primary end-point was overall survival (OS).  Analysis was by intention-to-treat.  A total of 355 patients were assigned to receive ramucirumab (n = 238) or placebo (n = 117).  Median OS was 5.2 months (inter-quartile range [IQR] 2.3 to 9.9) in patients in the ramucirumab group and 3.8 months (1.7 to 7.1) in those in the placebo group (hazard ratio [HR] 0.776, 95 % confidence intervals [CI]: 0.603 to 0.998; p = 0.047).  The survival benefit with ramucirumab remained unchanged after multi-variable adjustment for other prognostic factors (multi-variable HR 0.774, CI: 0.605 to 0.991; p = 0.042).  Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16 %] versus 9 [8 %]), whereas rates of other adverse events were mostly similar between groups (223 [94 %] versus 101 [88 %]).  Five (2 %) deaths in the ramucirumab group and 2 (2 %) in the placebo group were considered to be related to study drug.  The authors concluded that ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or GE junction adenocarcinoma progressing after first-line chemotherapy.  They stated that these findings validated VEGFR-2 signaling as an important therapeutic target in advanced gastric cancer.

On April 21, 2014, the Food and Drug Administration (FDA) approved ramucirumab (Cyramza) to treat patients with advanced gastric cancer or gastro-esophageal junction adenocarcinoma.  Ramucirumab is intended for patients with unresectable cancer or metastatic cancer after being treated with a fluoropyrimidine- or platinum-containing therapy.  The safety and effectiveness of ramucirumab were evaluated in a clinical trial of 355 participants with unresectable or metastatic gastric or gastro-esophageal (EG) junction cancer; 2/3 of trial participants received ramucirumab while the remaining participants received a placebo (the REGARD Trial).  Results from a second clinical trial that evaluated the effectiveness of ramucirumab plus paclitaxel versus paclitaxel alone also showed an improvement in OS.  Common side effects experienced by ramucirumab-treated participants during clinical testing include diarrhea and hypertension.  The recommended ramucirumab dose and schedule is 8 mg/kg administered as a 60-minute intravenous infusion every 2 weeks.

Hepatocellular Carcinoma

On May 10, 2019, the Food and Drug Administration approved ramucirumab as a single agent for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥ 400 ng/mL and have been previously treated with sorafenib. Approval was based on REACH‑2 (Zhu 2019; NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in 292 patients with advanced HCC with AFP ≥ 400 ng/mL who had disease progression on or after sorafenib or who were intolerant. Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. The trial’s primary endpoint was overall survival (OS). The estimated median OS was 8.5 months (7.0, 10.6) for patients receiving ramucirumab and 7.3 months (5.4, 9.1) for those receiving placebo (HR 0.71; 95% CI: 0.53, 0.95; p=0.020). The most common adverse reactions observed in patients with HCC receiving single-agent ramucirumab (≥ 15% and ≥ 2% higher incidence than placebo) were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities (≥ 30% and a ≥ 2% higher incidence than placebo) were hypoalbuminemia, hyponatremia, and thrombocytopenia.

Zhu et al (2019) stated patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations have poor prognosis. The authors aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and alpha-fetoprotein concentrations of 400 ng/mL or higher. REACH-2 was a randomized, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centers in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, alpha-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. The authors also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with alpha-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (inter-quartile range [IQR] 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatremia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure). The authors concluded that REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and alpha-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To the authors’ knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma.

Non-Small Cell Lung Cancer

In a randomized, double-blind, multi-center, phase III clinical trial, Garon et al (2014) evaluated the safety and effectiveness of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV NSCLC after platinum-based therapy.  In this trial (REVEL), these investigators enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen.  Patients were randomly allocated (1:1) with a centralized, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes versus no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, withdrawal, or death.  The primary end-point was OS in all patients allocated to treatment.  These researchers assessed adverse events according to treatment received.  Between December 3, 2010, and January 24, 2013, these investigators screened 1,825 patients, of whom 1,253 patients were randomly allocated to treatment.  Median OS was 10.5 months (inter-quartile range [IQR] 5.1 to 21.2) for 628 patients allocated ramucirumab plus docetaxel and 9.1 months (4.2 to 18.0) for 625 patients who received placebo plus docetaxel (HR 0.86, 95 % CI: 0.75 to 0.98; p = 0.023).  Median progression-free survival (PFS) was 4.5 months (IQR 2.3 to 8.3) for the ramucirumab group compared with 3.0 months (1.4 to 6.9) for the control group (0.76, 0.68 to 0.86; p < 0.0001).  These researchers noted treatment-emergent adverse events in 613 (98 %) of 627 patients in the ramucirumab safety population and 594 (95 %) of 618 patients in the control safety population.  The most common grade 3 or worse adverse events were neutropenia (306 patients [49 %] in the ramucirumab group versus 246 [40 %] in the control group), febrile neutropenia (100 [16 %] versus 62 [10 %]), fatigue (88 [14 %] versus 65 [10 %]), leucopenia (86 [14 %] versus 77 [12 %]), and hypertension (35 [6 %] versus 13 [2 %]).  The numbers of deaths from adverse events (31 [5 %] versus 35 [6 %]) and grade 3 or worse pulmonary hemorrhage (8 [1 %] versus 8 [1 %]) did not differ between groups.  Toxicities were manageable with appropriate dose reductions and supportive care.  The authors concluded that ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.

On December 12, 2014, the FDA expanded the approved use of ramucirumab (Cyramza) to treat patients with metastatic NSCLC. Ramucirumab in combination with docetaxel, was approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. The labeling states that patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab.

The approval of ramucirumab plus docetaxel for metastatic NSCLC is based on a clinical study of 1,253 patients with previously treated and progressive lung cancer. Subjects were randomly assigned to receive ramucirumab plus docetaxel or a placebo plus docetaxel. Treatment was given until disease progression or development of intolerable side effects. The trial was designed to measure OS, the length of time a participant lived before death. Results showed that 50 % of the participants treated with ramucirumab plus docetaxel survived an average of 10.5 months from the start of treatment, compared to an average of 9.1 months from the start of treatment for 50 % of the participants who received placebo plus docetaxel.

Garon et al (2012) described the treatment rationale and study-related procedures for the a randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV NSCLC following disease progression after one prior platinum-based therapy (REVEL) study.  This international, randomized, placebo-controlled, double-blinded phase III trial examines the safety and effectiveness of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV NSCLC whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment.  The primary end-point is OS; secondary end-points include PFS, objective response rate (ORR), disease control rate (DCR), patient-reported outcomes, and assessment of safety and tolerability of ramucirumab.  Eligible patients (enrollment n = 1,242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m(2)) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m(2)) plus placebo (Arm B).  Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, non-compliance, or patient's consent withdrawal.  Safety and effectiveness will be compared between the study arms and in patient subgroups including patients with non-squamous versus squamous tumor histology and patients who received prior bevacizumab treatment.  Multiple blood and tumor tissue biomarker samples are collected during the study.  The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves OS of patients with NSCLC with progressive disease after first-line therapy, and to advance the knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis.

Other Indications

While ramucirumab for the treatment of unresectable or metastatic gastric cancer, EG junction adenocarcinoma, non-small cell lung cancer, and metastatic colorectal cancer has been approved by the FDA, its effectiveness for other types of solid tumors has yet to be established.

Krupitskaya and Wakelee (2009) stated that ramucirumab was well-tolerated on weekly and fortnightly schedules in phase I clinical trials in patients with advanced cancers; mechanism-related dose-limiting toxicities were hypertension and deep venous thrombosis.  Stable disease was also observed in several patients treated on either schedule, and several patients on the weekly schedule exhibited partial responses.  At the time of publication, ramucirumab was undergoing assessment in phase II trials as a monotherapy in hepato-cellular carcinoma (HCC), renal cell carcinoma (RCC) and ovarian cancer.  Ramucirumab was also in phase II trials in combination with dacarbazine in melanoma, with mitoxantrone/prednisone in prostate cancer, with carboplatin/paclitaxel in non-small-cell lung cancer (NSCLC) and with oxaliplatin/folinic acid/5-fluorouracil in colorectal cancer (CRC).  A phase III trial in combination with docetaxel in breast cancer (BC) was also ongoing.

Aprile et al (2013) noted that ramucirumab is emerging as a novel anti-angiogenic agent.  Starting with pre-clinical data and early clinical results, these researchers discussed the development of the novel compound across multiple cancers (including gastro-intestinal malignancies, BC, lung carcinoma, and genitourinary tumors), and presented available data from randomized phase II and phase III trials.  REGARD was the first phase III study to report on the efficacy of single-agent ramucirumab in patients with refractory metastatic gastric cancer.

In a phase II study, Zhu and colleagues (2013) evaluated the safety and effectiveness of ramucirumab as first-line therapy in patients with advanced HCC and explored potential circulating biomarkers.  Adults with advanced HCC and no prior systemic treatment received ramucirumab 8 mg/kg every 2 weeks until disease progression or limiting toxicity.  The primary end-point was PFS; secondary end-points included ORR and OS.  Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients.  A total of 42 patients received ramucirumab.  Median PFS was 4.0 months [95 % CI: 2.6 to 5.7], ORR was 9.5 % (95 % CI: 2.7 to 22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95 % CI: 6.1 to 19.7).  For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95 % CI: 0.5 to 9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95 % CI: 6.1 to 23.5) for patients with Child-Pugh A cirrhosis.  Treatment-related grade greater than or equal to 3 toxicities included hypertension (14 %), gastro-intestinal hemorrhage and infusion-related reactions (7 % each), and fatigue (5 %).  There was 1 treatment-related death (gastro-intestinal hemorrhage).  After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2.  The authors concluded that ramucirumab monotherapy may confer anti-cancer activity in advanced HCC with an acceptable safety profile.  Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and soluble VEGFR-2 that are consistent with those seen with other anti-VEGF agents.

Wadhwa et al (2014) stated that ramucirumab is being investigated in many malignancies including gastric cancer.  The phase III trial in patients with advanced breast cancer failed to improve the primary end-point.

In a single-arm, phase II clinical trial, Garcia et al (2014) examined the safety and effectiveness of ramucirumab in patients with tyrosine kinase inhibitors (TKIs)-resistant/intolerant metastatic RCC (mRCC).  Patients received ramucirumab 8 mg/kg every 2 weeks until they developed disease progression or intolerable toxicity.  The primary end-point was the best ORR; additional end-points included the DCR, PFS, the median duration of OS, and safety.  A total of 39 patients with RCC received ramucirumab monotherapy.  Prior TKI therapy included sunitinib (59 % of patients), sunitinib and sorafenib (30.8 % of patients), and sorafenib (10.3 % of patients).  The ORR was 5.1 % (95 % CI: 0.6 % to 17.3 %).  The 12-week DCR was 64.1 % (95 % CI: 47.2 % to 78.8 %).  The median PFS was 7.1 months (95 % CI: 4.1 to 9.7 months), and the median OS was 24.8 months (95 % CI: 18.9 to 32.6 months).  Grade 3 or higher adverse events that occurred in greater than or equal to 5 % of patients included grade 3 hypertension (7.7 %) and proteinuria (5.1 %).  There was 1 on-study death from multi-organ failure.  The authors concluded that although the study did not meet its primary end-point of greater than or equal to 15 % ORR, ramucirumab was associated with evidence of anti-tumor activity in patients with TKI-resistant/intolerant mRCC.  Ramucirumab was safe and well-tolerated.

In a randomized, double-blind, placebo-controlled, multi-national, phase III clinical trial, Mackey et al (2015) evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer.  In this study, a total of 1,144 patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a 2-to-1 ratio to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg or docetaxel 75 mg/m2 plus placebo once every 3 weeks.  Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region.  An independent data monitoring committee oversaw the trial.  The primary end-point was investigator-assessed PFS.  Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (HR, 0.88; p = 0.077).  Median OS was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; p = 0.915).  Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis.  The authors concluded that addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

In a phase II clinical trial, Penson et al (2014) investigated the effectiveness of ramucirumab in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.  Primary end-points were PFS at 6 months (PFS-6) and confirmed ORR.  Women who received greater than or equal to 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of less than 12 months with measurable disease were eligible.  Patients received 8 mg/kg ramucirumab intravenously every 2 weeks.  A total of 60 patients were treated; 1 patient remained on study as of September 2013.  The median age was 62 years (range of 27 to 80), and median number of prior regimens was 3.  Forty-five (75 %) patients had platinum refractory/resistant disease; 39 patients (65.0 %) had serous tumors.  PFS-6 was 25.0 % (n = 15/60, 95 % CI: 14.7 to 37.9 %).  Best overall response was: partial response (PR) 5.0 % (n = 3/60), stable disease (SD) 56.7 % (n = 34/60), and progressive disease 33.3 % (n = 20/60).  The most common treatment-emergent adverse events possibly related to study drug were headache (65.0 %; 10.0 % Grade greater than or equal to 3), fatigue (56.7 %; 3.3 % Grade greater than or equal to 3), diarrhea (28.3 %; 1.7 % Grade greater than or equal to 3), hypertension (25.0 %; 3.3 % Grade greater than or equal to 3), and nausea (20.0 %; no Grade greater than or equal to 3).  Two patients experienced intestinal perforations (3.3 % Grade greater than or equal to 3).  Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2.  The authors concluded that although anti-tumor activity was observed, the pre-determined efficacy end-points were not met.

Chondrosarcoma

Jones and colleagues (2017) noted that chondrosarcoma is the most common bone sarcoma in adults.  Conventional chondrosarcoma, the commonest histological subtype, is largely resistant to anthracycline-based chemotherapy.  There have been anecdotal reports of durable clinical benefit with anti-angiogenic agents in this disease.  These investigators carried out a retrospective search of patients treated at 3 sarcoma referral centers to identify patients with advanced chondrosarcoma treated with anti-angiogenic agents.  They evaluated the safety and effectiveness of anti-angiogenic agents in advanced chondrosarcoma.  A total of 10 patients were identified; 7 with conventional, 1 each with clear cell, extra-skeletal mesenchymal chondrosarcoma and extra-skeletal myxoid chondrosarcoma.  The median PFS for patients with conventional and clear cell sarcoma was 22.6 months.  Median OS has not been met.  Anti-angiogenic therapy was well-tolerated in this series of patients.  The authors concluded that the findings of this retrospective study suggested that anti-angiogenic therapy can provide prolonged clinical benefit in advanced chondrosarcoma patients.  Moreover, they stated that further prospective trials are needed to precisely define the role of this class of agent in advanced chondrosarcoma (ramucirumab was one of the keywords of this trial).

Gastric Neuroendocrine Carcinoma

Koizumi and co-workers (2018) reported on the case of a 84-year old man who underwent total gastrectomy with D1 plus lymph node dissection in December 2015, with a diagnosis of Stage III B neuroendocrine carcinoma (NEC) of the stomach.  An abdominal computed tomography (CT) revealed swollen para-aortic lymph nodes and left adrenal grand in May 2016.  Since his serum level of CA19-9 was elevated, he was thus diagnosed as having recurrence, and was started chemotherapy with ramucirumab (RAM).  After introduction of the chemotherapy, his serum level of CA19-9 was decreased gradually and metastatic foci were also decreased in size.  Although the patient required relatively longer administration interval according to the severity of general fatigue, he continued the chemotherapy without severe adverse effects until he rejected further treatment in January 2017, and satisfactory therapeutic result was acquired.  While the prognosis of gastric NEC is reported to be very poor, no definitive therapeutic guideline is available at present. The authors stated that especially in elderly patients, considerable attention should be paid to the selection of chemotherapeutic agents because of their own adverse effects.  In the present case, RAM could be administered safely, and it appeared that RAM might become a useful therapeutic option for gastric NEC even in elderly patients.  These preliminary findings need to be further investigated.

Matsubara and colleagues (2018) noted that extra-pulmonary NEC is a rare disease, and there is no standard chemotherapy.  These investigators reported on the case of a 73-year old man who was diagnosed with advanced gastric NEC.  He received chemotherapy of irinotecan plus cisplatin, and amrubicin monotherapy.  After failure of 2nd-line chemotherapy, he received RAM plus paclitaxel; this treatment was chosen because VEGF 2 was strongly expressed in the tumor endothelial cells.  After 2 cycles, his NEC had markedly reduced in size, and he continued with this treatment for over 8 months.  In this case, the combination of an anti-angiogenic inhibitor and a cytotoxic agent was highly effective for gastric NEC.  This was a single-case study; and its findings were confounded by the combined use of RAM and paclitaxel.

Head and Neck Cancer

Lung Metastases from Gastric Cancer

In a retrospective study, Roviello and colleagues (2019) examined the activity of ramucirumab in combination with paclitaxel in patients with metastatic gastric cancer (GC) and lung metastases.  These researchers retrospectively reviewed clinical data from patients with GC treated in 2nd-line with ramucirumab and paclitaxel according to the presence or not of lung metastases.  A total of 31 patients were eligible; 5 (16.1 %) patients had lung metastases.  The median PFS was 156 days in patients without lung metastases compared with 54 days in patients with lung metastases.  The median OS also showed a trend in favor of patients without lung metastases.  The authors concluded that despite the small number of patients and the retrospective nature of the data, this analysis showed relatively poor efficacy of ramucirumab plus paclitaxel as a 2nd-line treatment in patients with lung metastases from GC.  These researchers stated that further studies are needed to evaluate novel treatments in this subset of patients.

Malignant Pleural Diseases (e.g., Mesothelioma)

Marquez-Medina and Popat (2016) stated that malignant pleural effusion (MPE) represents 15 to 35 % of pleural effusions and markedly worsens the prognosis and quality of life (QOL) of patients with cancer.  Malignant mesothelioma (MM) and lung adenocarcinoma are the most frequent primary and secondary causes, respectively, of MPE.  Effective treatments for cancer-related MPE are warranted in order to improve symptoms, reduce the number of invasive pleural procedures, and prolong patients’ life.  Since angiogenesis plays a key role in MPE development, these researchers examined the potential role of bevacizumab and other anti-angiogenic therapies in this review.  No relevant phase III clinical trials have specifically analyzed the benefit from adding bevacizumab to platinum-based chemotherapy in lung cancer-related MPE.  However, small retrospective series reported 71.4 to 93.3 % MPE control rate, a reduction in invasive procedures, and a safe profile with this combination.  Being approved for the 1st-line treatment of non-squamous advanced NSCLC, the addition of bevacizumab should be considered for patients presenting with MPE.  In MM, the addition of bevacizumab to platinum-based chemotherapy did not meet primary end-points in 2 phase II clinical trials.  However, the beneficial results on OS reported in comparison with historical cohorts and the statistically significant benefit on PFS and OS observed in the phase III MAPS trial foretell an eventual role for the combination of platinum/pemetrexed/bevacizumab as front-line systemic therapy for pleural MM.  To-date, no other anti-angiogenic drug has showed significant benefit in the treatment of patients with either MPE or MM.  However, new promising drugs such as ramucirumab or recombinant human endostar warrant further investigation.

Peritoneal Metastases from Gastric Cancer

Ishikawa and colleagues (2019) noted that ramucirumab (RAM) plus solvent-based (sb)-paclitaxel (PTX) is the standard 2nd-line chemotherapy for advanced GC (AGC).  The subset analysis of the ABSOLUTE trial, which confirmed non-inferiority of weekly nanoparticle albumin-bound (nab)-PTX to weekly sb-PTX, suggested that nab-PTX might have better efficacy than sb-PTX in patients with peritoneal metastasis.  These investigators retrospectively examined the safety and efficacy of RAM plus sb-PTX and nab-PTX in patients with peritoneal metastasis of AGC.  Patients with AGC who received RAM plus sb-PTX or nab-PTX as 2nd-line chemotherapy from June 2015 to February 2019 were included in the study; OS, PFS, response rate, and safety were assessed.  A total of 128 patients were included in this study (93 in the RAM plus sb-PTX group and 35 in the RAM plus nab-PTX group).  PFS was 4.1 months in the RAM plus sb-PTX group and 4.6 months in the RAM plus nab-PTX group (HR 0.90; 95 % CI: 0.58 to 1.41, p = 0.643).  OS was 8.9 months in the RAM plus sb-PTX group and 11.4 months in the RAM plus nab-PTX group (HR 0.95; 95 % CI : 0.56 to 1.62, p = 0.847).  A total of 62 and 31 patients had peritoneal metastasis in the RAM plus sb-PTX and the RAM plus nab-PTX groups, respectively.  RAM plus nab-PTX showed a slightly longer survival compared to RAM plus sb-PTX in patients with peritoneal metastasis (PFS 5.8 versus 3.5 months, HR 0.66; 95 % CI: 0.40 to 1.10, p = 0.109).  The authors concluded that the findings of this study suggested that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC.

Rheumatoid Arthritis

Abdel-Maged and colleagues (2019) stated that rheumatoid arthritis (RA) is a chronic and progressive autoimmune inflammatory disease associated with irreversible joint destruction that leads to permanent motor disability and compromised QOL.  However, the main cause of RA is still unknown though stimulation of immune system and cells plays pivotal role in disease development and progression.  Ramucirumab (RAM) is the monoclonal antibody against VEGF- receptor.  These investigators examined the therapeutic effect of RAM with or without methotrexate (MTX) against adjuvant-induced arthritis in rats.  Complete Freund's adjuvant (CFA)-induced arthritic rats were treated for 3 consecutive weeks with MTX or RAM alone and MTX-RAM co-therapy.  Arthritic score, gait score, ankle diameter, paw thickness, angiogenic, inflammatory cytokines, bone erosion markers, and apoptotic markers were assessed to evaluate the anti-arthritic effect.  RAM monotherapy exhibited anti-inflammatory, anti-angiogenic and anti-apoptotic effects similar to MTX alone to treat RA in the current study.  Furthermore, RAM alone had a protective effect on bone and cartilage health better than standard anti-rheumatic agent MTX.  Interestingly, combined therapy of MTX and RAM produced significant differences in comparison with MTX or RAM monotherapy in all tested parameters.  Moreover, the current study proved that MTX-RAM co-therapy has a synergistic effect.  These preliminary findings need to be further investigated.

Soft Tissue Sarcoma

In a phase II clinical trial, Chow and colleagues (2016) evaluated PK interaction potential between ramucirumab and paclitaxel in patients with advanced malignant solid tumors including breast carcinoma, soft tissue sarcoma, and urothelial carcinoma.  This study was designed to evaluate 2-way PK drug-drug interactions between ramucirumab and paclitaxel.  A total of 24 patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m(2) was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15).  Patients could continue to receive combination therapy with ramucirumab and paclitaxel.  In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle.  Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel.  Concomitant administration of ramucirumab had no effect on PK of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab versus alone) of 1.09 (90 % CI: 0.93 to 1.29) for AUC(0-∞) and 0.97 (90 % CI: 0.83, 1.13) for maximum drug concentration (Cmax).  In addition, similar ramucirumab PK characteristics were observed with or without paclitaxel administration.  The ratios of geometric LS means of AUC(0-∞) and Cmax of ramucirumab (with paclitaxel versus alone) were 1.00 (90 % CI: 0.84 to 1.19) for AUC(0-∞) and 1.07 (90 % CI: 0.93 to 1.24) for Cmax, respectively.  The authors concluded that concomitant paclitaxel administration is unlikely to affect the PK of ramucirumab, and vice-versa.  The incidence and severity of AEs were consistent with the known safety profiles of paclitaxel and ramucirumab.

Thymic Carcinoma

Imbimbo and colleagues (2018) noted that thymic epithelial tumors are rare malignancies.  Thymic carcinoma represents about 20 % of all thymic epithelial tumors and has aggressive behavior, with a greater tendency to metastatic spread.  Thymic carcinoma is often diagnosed in advanced stages for which systemic treatment is the main therapeutic option.  The association of chemotherapy and anti-angiogenic agents in the 1st-line setting has never been investigated in this very rare cancer.  However, pre-clinical and clinical evidence has suggested that inhibition of angiogenesis could be beneficial.  The RELEVENT trial is a multi-center, open-label, single-arm, phase-II clinical trial that aimed at examining the activity and safety of ramucirumab combined with paclitaxel and carboplatin in chemotherapy-naive patients affected by thymic carcinoma or B3 thymoma with area of carcinoma.  The primary end-point of the trial is the ORR; PFS, OS, and safety are secondary end-points.  Patient-reported outcomes will be collected at each visit.  Furthermore, the mutational status of a subset of genes, polymorphisms, and selected micro-RNA expression will be evaluated.

References