Medical Policy

 

Subject: Ramucirumab (Cyramza®)
Document #: DRUG.00067 Publish Date:    08/02/2018
Status: Revised Last Review Date:    07/26/2018

Description/Scope

This document addresses the indications and criteria for use of ramucirumab (Cyramza, Eli Lilly and Company, Indianapolis, IN), a fully human monoclonal antibody and angiogenesis inhibitor that blocks the activation of vascular endothelial growth factor (VEGF) receptor-2.

Position Statement

Medically Necessary:

I.  Esophageal, Gastric, and Gastroesophageal Junction Adenocarcinoma

Ramucirumab is considered medically necessary as a single agent or in combination with paclitaxel for the treatment of individuals with advanced (non-resectable) or metastatic esophageal, gastric, or gastroesophageal junction adenocarcinoma with disease progression that occurs during or after fluoropyrimidine- or platinum-containing chemotherapy.

II.  Non-Small Cell Lung Cancer (NSCLC)

Ramucirumab is considered medically necessary in combination with docetaxel for the treatment of individuals with metastatic NSCLC when either of the following criteria is met:

  1. Individual does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor mutation, and the disease has progressed on or after platinum-containing chemotherapy; or
  2. Individual has an EGFR or ALK genomic tumor mutation and both of the following criteria are met:
    1. Disease has progressed on a U.S. Food & Drug Administration (FDA)-approved therapy (for example, afatinib, crizotinib, erlotinib, or gefitinib) for these mutations prior to receiving ramucirumab; and
    2. Disease has progressed on or after platinum-containing chemotherapy.

III.  Colorectal Cancer

Ramucirumab is considered medically necessary in combination with irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) for the treatment of individuals with metastatic colorectal cancer (mCRC) with disease progression that occurs during or after bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing chemotherapy.

IV.  Urothelial Cancer

Ramucirumab is considered medically necessary in combination with docetaxel for the treatment of locally advanced, unresectable or metastatic urothelial cancer originating from the bladder, urethra, ureter, or renal pelvis when the following criteria are met:

  1. Individual is 18 years of age or older; and
  2. Has a current Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and
  3. Disease has progressed after platinum-containing chemotherapy (cisplatin or carboplatin); and
  4. Has received treatment with no more than one immune checkpoint inhibitor (such as, atezolizumab, avelumab, durvalumab, nivolumab or pembrolizumab); and
  5. Has received treatment with no more than one prior systemic chemotherapy regimen in the relapsed or metastatic setting; and
  6. Has received no prior systemic taxane therapy in any setting (that is, neoadjuvant, adjuvant, or metastatic).

Investigational and Not Medically Necessary

Ramucirumab is considered investigational and not medically necessary when the criteria are not met and for all other indications, including but not limited to:

Rationale

Gastric and Gastroesophageal Junction Adenocarcinoma

On April 14, 2014, the FDA approved ramucirumab for use as a single agent in individuals with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy. On November 5, 2014, the FDA expanded approval of ramucirumab for use in combination with paclitaxel for the treatment of individuals with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy. 

The safety and efficacy of ramucirumab was evaluated in a multicenter, double-blind, randomized clinical study (phase III, REGARD trial) (Fuchs, 2014) of individuals (n=355) with locally advanced or metastatic gastric (75%) or gastroesophageal junction adenocarcinoma (25%) who were previously treated with fluoropyrimidine- or platinum-containing chemotherapy. Subjects were required to have disease progression that occurred during treatment or within 4 months after the last dose of chemotherapy, or within 6 months after the last dose of adjuvant therapy. All subjects were randomized (2:1) to receive either single agent ramucirumab (n=238) (8 mg/kg over a 60-minute infusion occurring every 2 weeks) and best supportive care (BSC) or placebo (n=117) and BSC (placebo infusion administered every 2 weeks). The primary outcome measure was overall survival (OS). The median OS for the ramucirumab group was 5.2 months compared with 3.8 months for the placebo group (hazard ratio [HR]=0.78; 95% confidence interval [CI], 0.60-0.998; p=0.047). These results indicate that the risk of death was significantly reduced by 22% in the treatment group compared with placebo. Since quality of life (QOL) outcomes were not measured, the clinical significance of this magnitude of treatment effect is not known. However, based on the OS data, the study authors concluded that ramucirumab had significant and positive treatment effects in individuals previously treated with fluoropyrimidine- or platinum-containing chemotherapy.

The second pivotal trial of ramucirumab was a multicenter, double-blind, randomized clinical study (phase III, RAINBOW trial) (Wilke, 2014) in which subjects (n=665) were randomized to receive either ramucirumab (8 mg/kg) plus paclitaxel (80 mg/m2) (n=330) or placebo plus paclitaxel (80 mg/m2) (n=335). Subjects were adults with advanced gastric or gastroesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy. The primary outcome measure was OS, and secondary outcomes were progression-free survival (PFS) and the objective response rate. The median OS for the treatment group was 9.6 months (95% CI, 8.5-10.8) compared with 7.4 months for the placebo group (95% CI, 6.3-8.4) (HR=0.81; 95% CI, 0.68-0.96; p=0.017). The median PFS for the treatment group was 4.4 months (95% CI, 4.2-5.3) compared with 2.9 months for the placebo group (95% CI, 2.8-3.0) (HR=0.64; 95% CI, 0.54-0.75; p<0.001). The objective response rate for the treatment group was 28% (95% CI, 23-33) compared with 16% for the placebo group (95% CI, 13-22). The most commonly observed adverse events (grade 3 or higher) for those treated with ramucirumab combined with paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most frequently reported treatment-emergent adverse event was neutropenia, which had a higher all-grade incidence in the ramucirumab plus paclitaxel group (54.4%) than the placebo plus paclitaxel group (31.0%). Based on the OS data, the study investigators concluded that ramucirumab plus paclitaxel had significant and positive treatment effects in individuals with advanced gastric cancer or gastroesophageal junction adenocarcinoma previously treated with fluoropyrimidine- or platinum-containing chemotherapy.

Al-Batran and colleagues (2016) subsequently reported an analysis of quality of life (QoL) and performance status outcomes for participants in the phase III RAINBOW trial. Participant-reported outcomes were assessed using the European Organization for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30) and the EuroQoL 5 dimensions health status questionnaire (EQ-5D-3L) at baseline and 6-week intervals. Performance status was assessed at baseline and day 1 of every cycle. The time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥ 10 points (on a 100-point scale) and TtD in performance status was defined as first worsening to ≥ 2. A total of 650 of 665 (98%) randomized participants provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) provided data from ≥ 1 post-baseline time point. Baseline scores were similar in both treatment arms for the 15 QLQ-C30 scales and the EQ-5D instrument. The participants treated with ramucirumab plus paclitaxel demonstrated a similar or longer TtD in the functioning and worsening of symptoms compared with participants treated with placebo plus paclitaxel. Ramucirumab plus paclitaxel was associated with improved outcomes in 14 of the 15 symptom scales compared with placebo plus paclitaxel, although statistical significance was only reached in two of the symptoms scales (that is, emotional function and nausea and vomiting). Diarrhea was the only QoL symptom with a non-favorable HR in the ramucirumab plus paclitaxel group. The analysis of QLC-C30 TtD data demonstrated that treatment with ramucirumab and paclitaxel was associated with a delay in TtD in performance status to ≥ 2 (HR=0.798; p=0.0941). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. Based on these results, the authors suggest that second-line treatment with ramucirumab and paclitaxel prolongs survival and maintains QoL, lengthens the TtD of symptoms and functions, and slows performance status deterioration in individuals with metastatic gastric or gastroesophageal junction adenocarcinoma.

Fuchs and colleagues (2017) pooled data from the REGARD and RAINBOW clinical trials to identify baseline prognostic factors for survival in individuals with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction cancer. From the 1020 randomized participants, 953 (93%) without any missing covariates were included in the analysis. The authors identified 12 independent prognostic factors for poor survival: peritoneal metastases; Eastern Cooperative Oncology Group (ECOG) performance score 1; the presence of a primary tumor; time to progression since prior therapy < 6 months; poor/unknown tumor differentiation; abnormally low blood levels of albumin, sodium, and/or lymphocytes; and abnormally high blood levels of neutrophils, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and/or lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (that is, median OS by risk in months): high risk, 3.4; moderate risk, 6.4; medium risk, 9.9; and low risk, 14.5; Harrell's C-index=0.66; 95% CI, 0.64-0.68). The addition of quality of life to the model identified patient-reported appetite loss as an independent prognostic factor. The authors suggest these prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies for use of ramucirumab in the treatment of advanced gastric or gastroesophageal junction cancer.

Esophageal Adenocarcinoma

Esophageal cancer is the sixth most common cause of cancer deaths worldwide with adenocarcinoma more common in North America and Western European countries. Esophageal adenocarcinoma originates most often in the lower third of the esophagus, and may involve the esophagogastric junction (EGJ). The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guideline (CPG for esophageal and EGJ cancers (V2.2018) includes a category 2A recommendation for use of ramucirumab as a single agent or in combination with paclitaxel as preferred second-line or subsequent therapy for metastatic or locally advanced esophageal adenocarcinoma. The NCCN based this category 2A recommendation on uniform consensus and consideration of a subset analysis of individuals with EGJ in the studies detailed in the section above (Fuchs, 2014; Wilke, 2014) who were randomized to receive ramucirumab plus paclitaxel or ramucirumab for metastatic or locally advanced EGJ. To date, the safety and efficacy of ramucirumab for use in the treatment of esophageal adenocarcinoma has not been evaluated in a randomized controlled trial.

NSCLC

On December 11, 2014, the FDA approved ramucirumab for use in combination with docetaxel in the treatment of individuals with metastatic NSCLC who experience disease progression on or after platinum-based chemotherapy. The FDA also approved ramucirumab for the treatment of individuals with EGFR or ALK genomic tumor mutations, who experience disease progression on FDA-approved therapy specific for these mutations.

The safety and efficacy of ramucirumab in the treatment of NSCLC was evaluated in a randomized, double-blind study (phase III, REVEL trial) (n=1253) of individuals with squamous or non-squamous NSCLC who progressed during or after first-line platinum-based therapy for locally advanced or metastatic disease (Garon, 2014). Participants were randomized to either ramucirumab (10 mg/kg) plus docetaxel (75 mg/m2) every 21 days, or placebo plus docetaxel (75 mg/m2) every 21 days. Participants received a median of 4.5 doses of ramucirumab with a median duration of 3.5 months. A total of 195 of 627 participants (31%) received ramucirumab for at least 6 months. The primary outcome measure was OS; secondary outcomes included PFS and the objective response rate. Study investigators reported a significant improvement in OS of 10.5 months in the ramucirumab plus docetaxel group compared with 9.1 months in the placebo plus docetaxel group (HR=0.86; 95% CI, 0.75-0.98; p=0.024). Similarly, the median PFS was significantly improved in the ramucirumab plus docetaxel group compared with the placebo plus docetaxel group (4.5 months vs. 3.0 months, respectively; HR=0.76; 95% CI, 0.68-0.86; p<0.001).

The most common serious adverse events observed with ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). More than 70% of participants had grade 3 or higher adverse events in both groups (79% for ramucirumab plus docetaxel vs. 71% for docetaxel alone). Adverse events of significance with ramucirumab plus docetaxel therapy included risk for severe hemorrhage, grade 3 to 4 gastrointestinal bleeding, gastrointestinal perforation or fistula, impaired wound healing, and poorly controlled hypertension. Treatment with ramucirumab plus docetaxel resulted in significantly greater number of participants discontinuing treatment (9%) compared with the placebo group (5%). In individuals older than 65 years, there were 18 (8%) deaths during treatment or within 30 days of ending treatment with ramucirumab plus docetaxel compared with 9 (4%) deaths for placebo plus docetaxel. In individuals younger than age 65, there were 13 (3%) deaths during treatment or within 30 days of ending treatment with ramucirumab plus docetaxel compared with 26 (6%) deaths for placebo plus docetaxel.

Colorectal Cancer

On April 24, 2015, the FDA approved ramucirumab for use in combination with irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) in the treatment of individuals with metastatic colorectal cancer whose disease has progressed during or after bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing chemotherapy. The safety and efficacy of ramucirumab for this use was evaluated in a randomised, double-blind, multinational trial (phase III, RAISE trial) of individuals with metastatic colorectal cancer that progressed during or within 6 months of discontinuation of bevacizumab-, oxaliplatin-, and fluoropyrimidine-based combination chemotherapy (Tabernero, 2015).

A total of 1072 participants were randomized to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab. The median age of the study population was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1. Both study groups repeated treatment every 2 weeks; the treatment arm received 8 mg/kg of IV infused ramucirumab every 2 weeks until disease progression or unacceptable toxicity. The primary efficacy endpoint was reported as a statistically significant improvement observed in OS in those participants who received FOLFIRI plus ramucirumab compared to those who received FOLFIRI plus placebo (HR=0.85; 95% CI, 0.73, 0.98; p=0.023, stratified log-rank test). The median OS was 13.3 and 11.7 months for participants in the FOLFIRI plus ramucirumab compared to those in the FOLFIRI plus placebo arms, respectively. The median PFS was 5.7 months in participants in the FOLFIRI plus ramucirumab arm versus 4.5 months in those in the FOLFIRI plus placebo arm (HR=0.79; 95% CI, 0.70, 0.90; p<0.001). Rates of discontinuation of therapy were 11.5% in the ramucirumab arm and 4.5% in the placebo arm. Thyroid dysfunction (hypothyroidism) was reported in 2.6% of participants. The most common grade 3 or worse adverse events were neutropenia, hypertension, diarrhea, and fatigue.

The current NCCN CPG for colon (V2.2018) and rectal cancer (V1.2018) state there is no data to suggest activity of FOLFIRI plus ramucirumab in an individual who has progressed on FOLFIRI plus bevacizumab, or vice-versa. In addition, ramucirumab has only shown activity in colorectal cancer when given in conjunction with FOLFIRI in FOLFIRI-naive individuals.

Locally Advanced or Metastatic Urothelial Carcinoma

The off-label use of ramucirumab in combination with docetaxel has been studied in individuals with platinum-refractory advanced or metastatic urothelial carcinoma. Petrylak and colleagues (2017) conducted a multicenter, randomized, double-blind, phase III trial (RANGE; NCT02426125) in which eligible participants had a confirmed diagnosis of advanced or metastatic urothelial carcinoma originating in the bladder, urethra, ureter, or renal pelvis and disease progression after platinum-containing chemotherapy. Participants aged 18 years or older with an ECOG performance status of 0 or 1 were permitted prior treatment with one immune checkpoint inhibitor. Key exclusion criteria included more than one previous systemic chemotherapy in the relapsed or metastatic setting (previous systemic therapy in the perioperative setting was not judged a previous line) and previous systemic taxane therapy. A total of 530 eligible participants were randomized to receive intravenous ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). The primary endpoint was investigator-assessed PFS (until first radiographic documentation of objective progression) or death from any cause as analyzed by intention-to-treat analysis in the first 437 randomized participants. Participants treated with ramucirumab plus docetaxel experienced longer PFS compared with placebo plus docetaxel (median 4.07 months [95% CI, 2.96-4.47] vs. 2.76 months [2.60-2.96], respectively; HR=0.757, 95% CI, 0.607-0.943; p=0.0118). Blinded independent central analysis found consistent results, with median PFS of 4.04 months (95% CI, 2.96-4.30) and 2.46 months (95% CI, 1.45-2.83), respectively (stratified HR=0.672; 95% CI, 0.536-0.842; p=0.0005). An objective response was achieved by 53 of 216 ramucirumab plus docetaxel-treated participants (24.5%; 95% CI, 18.8-30.3) and 31 of 221 placebo plus docetaxel-treated participants (14.0%; 95% CI, 9.4-18.6). Objective responses by blinded independent central analysis were achieved by 48 (22.2%; 95% CI, 16.7-27.8) of 216 participants allocated ramucirumab and 28 (12.7%; 95% CI, 8.3-17.1) of 221 assigned placebo. Of the participants who previously received an immune checkpoint inhibitor, 5 of 14 (36%) allocated to ramucirumab plus docetaxel and 2 of 19 (11%) assigned placebo achieved an objective response to treatment. The frequency of grade 3 or worse adverse events was similar in both groups (156 of 258 [60%], ramucirumab plus docetaxel arm vs. 163 of 265 [62%], placebo plus docetaxel arm). A total of 63 of 258 (24%) ramucirumab plus docetaxel participants and 54 of 265 (20%) placebo plus docetaxel participants experienced a serious treatment-related adverse event. Thirty-eight of 258 (15%) participants in the ramucirumab plus docetaxel arm and 43 of 265 (16%) participants in the placebo plus docetaxel arm died on treatment or within 30 days of discontinuation, of which 8 (3%) and 5 (2%) deaths, respectively, were determined to be treatment-related. Sepsis was the most common adverse event leading to death on treatment, with one fatal event of neutropenic sepsis reported in a participant in the ramucirumab arm. Enrollment of participants previously treated with an immune checkpoint inhibitor was limited; data may show some additional benefit when used with checkpoint inhibitors. At the time of the primary PFS analysis, the overall median follow-up in the intention-to-treat population was limited to 5 months. Additional survival data are anticipated pending study maturation.

To date, the FDA has not approved ramucirumab for use in the treatment of bladder cancer. Additionally, the current NCCN CPG for bladder cancer (V4.2018) does not address the use of ramucirumab in the treatment of urothelial cancer. The reported outcomes of the phase III RANGE study (Petrylak, 2017) suggest the use of  ramucirumab in combination with docetaxel may provide improved progression-free survival in select individuals with platinum-refractory advanced or metastatic urothelial carcinoma.

Other Proposed Uses of Ramucirumab

Ongoing clinical trials are identified in the ClinicalTrials.gov database investigating the use of ramucirumab for other conditions including, but not limited to, single-agent therapy for advanced, pretreated biliary cancer, advanced pancreatic cancer, first-line therapy in combination with FOLFOX for advanced esophageal, EGJ, or gastric adenocarcinoma (Yoon, 2016), first-line therapy in combination with pemetrexed and platinum for the treatment of advanced/metastatic (stage IV) nonsquamous NSCLC (Doebele, 2015), combination therapy with nab-paclitaxel for previously treated advanced gastric cancer (Bando, 2018), metastatic docetaxel-pretreated castration-resistant prostate cancer (Hussain, 2015), metastatic melanoma (Carvajal, 2014), combination therapy with erlotinib in previously untreated EGFR-mutant metastatic NSCLC (Reck, 2017), and other advanced malignant solid tumors (Chiorean, 2015). At this time, the published data consists of preliminary results from ongoing phase I and phase II trials (NIH, 2018). The evidence in the peer-reviewed published medical literature is insufficient to draw reasonable conclusions regarding the clinical safety and effectiveness of ramucirumab to improve net health outcomes for any of these non-FDA approved indications.

Advanced Hepatocellular Cancer

Zhu and colleagues (2015) evaluated the efficacy and safety of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. In this multicenter, randomised, double-blind, phase III, placebo-controlled trial (REACH), eligible participants included those aged 18 years or older with Barcelona Clinic Liver Cancer stage C or stage B hepatocellular carcinoma refractory or not amenable to locoregional therapy, Child-Pugh A liver disease, ECOG performance status of 0 or 1, previous treatment with sorafenib (stopped because of progression or intolerance), and adequate hematological and biochemical parameters. Participants were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) (n=283) or placebo (n=282) every 2 weeks plus best supportive care until disease progression, unacceptable toxicity, or death. The primary endpoint was OS in the intention-to-treat population. The median OS for the ramucirumab group was 9.2 months (95% CI, 8.0-10.6) versus 7.6 months (6.0-9.3) for the placebo group (HR=0.87; 95% CI, 0.72-1.05; p=0.14). Grade 3 or greater adverse events occurring in 5% or more of participants in either treatment group were ascites (13 [5%] of 277 ramucirumab-treated participants vs. 11 [4%] of 276 placebo-treated participants), hypertension (34 [12%] vs. 10 [4%]), asthenia (14 [5%] vs. 5 [2%]), malignant neoplasm progression (18 [6%] vs. 11 [4%]), increased AST concentration (15 [5%] vs. 23 [8%]), thrombocytopenia (13 [5%] vs. 1 [< 1%]), hyperbilirubinemia (3 [1%] vs. 13 [5%]), and increased blood bilirubin (5 [2%] vs. 14 [5%]). Based on these results, the investigators concluded that second-line treatment with ramucirumab did not significantly improve OS compared to placebo in individuals with advanced hepatocellular carcinoma.

Metastatic Renal Cell Cancer

Ramucirumab has been studied as second-line therapy in a phase II, single-arm trial of individuals (n=39) with metastatic renal cell cancer with disease progression on or intolerance to tyrosine kinase inhibitor (TKI) therapy (Garcia, 2014). Ramucirumab was associated with evidence of antitumor activity; however, the study did not meet the primary endpoint of ≥ 15% best “objective response rate” (ORR 5.1%; 95% CI, 0.6%-17.3%).

Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

In a phase II trial, individuals (n=60) with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer following ≥ 1 platinum-based chemotherapeutic regimen received ramucirumab at 2-week intervals. Antitumor activity was observed; however, the predetermined efficacy endpoints were not met, as the best overall response was reported as “partial” in 5% (3 of 60 participants), 56.7% (34 of 60 participants) had stable disease, and 33.3% (20 of 60 participants) had progressive disease (Penson, 2014).

Unresectable, Locally Recurrent or Metastatic Breast Cancer

Mackey and colleagues (2015) reported on the results of a randomized, placebo-controlled trial (phase III, ROSE/TRIO-12) evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in the treatment of individuals with unresectable, locally recurrent or metastatic breast cancer. A total of 1144 participants 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 plus ramucirumab or docetaxel plus placebo once every 3 weeks. Participants received treatment until disease progression, unacceptable toxicity, or other withdrawal criteria. The primary endpoint was investigator-assessed PFS. The median PFS in the ramucirumab plus docetaxel group was 9.5 months, compared with 8.2 months in participants who received placebo plus docetaxel (HR=0.88; p=0.077). The median OS was 27.3 months in ramucirumab plus docetaxel group, compared with 27.2 months in participants who received placebo plus docetaxel (HR=1.01; p=0.915). Significantly higher rates of toxicities were observed in participants receiving ramucirumab, including fatigue, febrile neutropenia, hypertension, palmar-plantar erythrodysesthesia syndrome, and stomatitis. The investigators concluded that the addition of ramucirumab to docetaxel did not significantly improve PFS and OS in individuals with HER2-negative advanced breast cancer.

Yardley and colleagues (2016) evaluated the safety and efficacy of ramucirumab with eribulin mesylate versus eribulin mesylate alone as third- to fifth-line therapy in locally recurrent or metastatic breast cancer previously treated with anthracycline and taxane therapy. In this multicenter, randomized, open-label, phase II trial, participants aged 18 years or older with two to four previous chemotherapy regimens for locally recurrent or metastatic breast cancer, previous anthracycline and taxane treatment, and ECOG performance status of 0 or 1 received ramucirumab with eribulin mesylate or eribulin mesylate alone in 21-day cycles. Participants were randomized according to previous antiangiogenic therapy and triple-negative status. The primary endpoint was PFS in the intention-to-treat population. A total of 141 participants were randomized to ramucirumab with eribulin mesylate (n=71) or eribulin mesylate alone (n=70). Median PFS for ramucirumab with eribulin mesylate was 4.4 months (95% CI, 3.1-6.7) compared with 4.1 months (95% CI, 3.2-5.6) for eribulin mesylate (HR=0.83; 95% CI, 0.56-1.23; p=0.35). Median OS in participants who received ramucirumab with eribulin mesylate was 13.5 months (95% CI, 10.4-17.9) compared with 11.5 months (95% CI, 9.0-17.3) in those who received eribulin mesylate alone (HR=0.91; 95% CI, 0.59-1.41; p=0.68); objective response rate was 21% (13 of 62 participants) for combination therapy and 28% (17 of 60 participants) for eribulin mesylate alone. Treatment was discontinued in near equal numbers of participants in both groups (ramucirumab with eribulin mesylate [n=71] vs. eribulin mesylate alone [n=70]). Overall, there were more adverse events reported in the ramucirumab with eribulin mesylate group (p<0.05) than in the eribulin mesylate group. Treatment emergent adverse events (any grade) reported more frequently in the ramucirumab with eribulin mesylate group were headache (27 [39%] vs. 10 [15%]) and pyrexia (14 [20%] vs. 5 [8%]). Hypertension and bleeding were the most frequently reported (p<0.05) serious adverse events in the ramucirumab with eribulin mesylate compared to eribulin mesylate alone (9 of 69 [13%] vs. 1 of 65 [2%] and 13 of 69 [19%] vs. 3 of 65 [5%], respectively). The investigators concluded that ramucirumab combined with eribulin mesylate did not significantly improve PFS, OS or objective response rate as third-to fifth-line therapy in individuals with advanced metastatic breast cancer.

Vahdat and colleagues (2017) evaluated the safety and efficacy of ramucirumab in combination with capecitabine in a phase II trial of individuals previously treated for unresectable, locally advanced or metastatic breast cancer. Participants were randomly assigned to receive capecitabine alone or in combination with ramucirumab or an investigational agent (icrucumab). The primary endpoint was PFS; secondary endpoints included OS, tumor response, safety, and pharmacokinetics. The median PFS was 22.1 weeks on ramucirumab with capecitabine compared to 19.0 weeks on capecitabine alone (HR=0.691, p=0 .1315), Median OS was 67.4 weeks on ramucirumab with capecitabine and 71.6 weeks on capecitabine alone (HR=1.833, p=0 .0283). There was no statistically significant difference in PFS in the ramucirumab with capecitabine versus capecitabine alone. Treatment-related adverse events occurred more frequently (by ≥ 10%) with ramucirumab plus capecitabine than capecitabine alone, including constipation, decreased appetite, headache, epistaxis, and hypertension. In this targeted study population, combination therapy of ramucirumab with capecitabine for unresectable, locally advanced or metastatic breast cancer did not improve PFS.

Background/Overview

Ramucirumab is a fully human monoclonal antibody and angiogenesis inhibitor, also described as a VEGF receptor-2 antagonist that targets the VEGF-receptors to inhibit blood vessel structure, growth, and migration, thereby impeding sufficient blood flow necessary for tumor growth and survival.

Esophageal, Gastric, and Gastroesophageal Junction Adenocarcinoma

Gastric and esophageal cancers are rare. The National Cancer Institute (NCI) estimates 26,240 new cases and 10,800 deaths from gastric cancer in the United States in 2018. For esophageal cancer, the NCI estimates 17,290 new cases and 15,850 deaths will occur in 2018. Gastroesophageal junction adenocarcinoma, a form of cancer that is located in the region where the esophagus joins the stomach, is also rare, but equally lethal. Five-year survival rates for both cancers are relatively low; 17% for esophageal cancer and 28% for gastric cancer (Buas and Vaughan, 2013; Howlader, 2014). Treatments are aimed at extending OS, while also providing palliative and supportive care.

Colorectal Cancer

Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum. The term colorectal cancer does not include anal cancer. According to the NCI, there will be an estimated 97,220 new cases of colon cancer and 43,030 new cases of rectal cancer diagnosed in 2018. It is expected that 50,630 persons will die from colon and rectal cancer combined in 2018.

NSCLC

Lung cancer is the leading cause of death from cancer in the United States and worldwide, with advanced NSCLC representing the majority of these cases (Garon, 2014). The NCI estimates 234,030 new cases and 154,050 deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2018. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for individuals with local, regional, and distant-stage disease, respectively.

Urothelial Carcinoma

Urothelial carcinoma is the most common type of bladder cancer. The NCI estimates approximately 81,190 new cases (incidence about four times higher in men than in women) and 16,870 deaths from bladder cancer (about 12,240 in men and 4630 in women) in the United States in 2018.

FDA Product Information (PI) Label for Ramucirumab

Adverse Events and Warnings

A Black Box warning on the FDA PI Label for ramucirumab (Cyramza PI, 2017) states the following:

Warning: Hemorrhage, Gastrointestinal Perforation, and Impaired Wound Healing

Additional Warnings and Precautions from the FDA PI Label for ramucirumab (Cyramza, 2017) include:

Definitions

Adenocarcinoma: A type of carcinoma (cancerous tumor) derived from glandular tissue, which can occur at various sites (lung, esophagus, cervix, intestinal tract, etc.).

Angiogenesis: Formation of new blood vessels from pre-existing vessels.

European Organization for Research and Treatment of Cancer Quality of Life (QoL) questionnaire (EORTC QLQ-C30): A self-administered cancer-specific QoL instrument that assesses global health status, functioning, symptoms, and toxicities.

Fluoropyrimidine: A type of antimetabolite used to treat cancer. Examples include capecitabine, floxuridine, and fluorouracil (5-FU).

Hemorrhage: Heavy bleeding.

Immune checkpoint inhibitor: A type of drug that blocks certain proteins made by some types of immune system cells, such as T cells, and some cancer cells. When these proteins are blocked, the “brakes” on the immune system are released and T cells are able to kill cancer cells better. Examples of checkpoint proteins found on T cells or cancer cells include programmed death (PD)-1, PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen (CTLA)-4/B7-1/B7-2 (NCI, 2018).

Line of therapy:

Metastatic: A cancer that has spread from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor that has spread beyond the local lymph nodes.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Unresectable: Unable to be removed with surgery.

Vascular endothelial growth factor (VEGF): A substance made by cells that stimulate the formation of new blood vessels.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

 

J9308

Injection, ramucirumab, 5 mg [Cyramza]

 

 

 

 

ICD-10 Diagnosis

 

C15.3-C15.9

Malignant neoplasm of esophagus

C16.0-C16.9

Malignant neoplasm of stomach

C18.0-C20

Malignant neoplasm of colon, rectosigmoid junction, rectum

C34.00-C34.92

Malignant neoplasm of bronchus and lung

C65.1-C65.9

Malignant neoplasm of renal pelvis

C66.1-C66.9

Malignant neoplasm of ureter

C67.0-C67.9

Malignant neoplasm of bladder

C68.0

Malignant neoplasm of urethra

C78.00-C78.02

Secondary malignant neoplasm of lung

C78.5

Secondary malignant neoplasm of large intestine and rectum

C78.89

Secondary malignant neoplasm of other digestive organs

Z85.01

Personal history of malignant neoplasm of esophagus

Z85.028

Personal history of other malignant neoplasm of stomach

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

Z85.51

Personal history of malignant neoplasm of bladder

Z85.53-Z85.59

Personal history of malignant neoplasm of renal pelvis, ureter, other urinary tract organ

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Al-Batran SE, Van Cutsem E, Oh SC, et al. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016; 27(4):673-679.
  2. Bando H, Shimodaira H, Fujitani K, et al. A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer. Eur J Cancer. 2018; 91:86-91.
  3. Buas MF, Vaughan TL. Epidemiology and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease. Semin Radiat Oncol. 2013; 23(1):3-9.
  4. Carvajal RD, Wong MK, Thompson JA, et al. A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. Eur J Cancer. 2014; 50(12):2099-2107.
  5. Chiorean EG, Hurwitz HI, Cohen RB, et al. Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol. 2015; 26(6):1230-1237.
  6. Doebele RC, Spigel D, Tehfe M, et al. Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non-small cell lung cancer. Cancer. 2015; 121(6):883-892.
  7. Fuchs CS, Muro K, Tomasek J, et al. Prognostic factor analysis of overall survival in gastric cancer from two phase III studies of second-line ramucirumab (REGARD and RAINBOW) using pooled patient data. J Gastric Cancer. 2017; 17(2):132-144.
  8. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383(9911):31-39.
  9. Garcia JA, Hudes GR, Choueiri TK, et al. A phase 2, single-arm study of ramucirumab in patients with metastatic renal cell carcinoma with disease progression on or intolerance to tyrosine kinase inhibitor therapy. Cancer. 2014; 120(11):1647-1655.
  10. Garcia-Carbonero R, Rivera F, Maurel J, et al. An open-label phase II study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for metastatic colorectal cancer. Oncologist. 2014; 19(4):350-351.
  11. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicenter, double-blind, randomized phase 3 trial. Lancet. 2014; 384(9944): 665-673.
  12. Hussain M, Rathkopf D, Liu G, et al. A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer. Eur J Cancer. 2015; 51(13):1714-1724.
  13. Mackey JR, Ramos-Vazquez M, Lipatov O, et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015; 33(2):141-148.
  14. Penson RT, Moore KM, Fleming GF, et al. A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Gynecol Oncol. 2014; 134(3):478-485.
  15. Petrylak DP, de Wit R, Chi KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017; 390(10109):2266-2277.
  16. Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016; 34(13):1500-1509.
  17. Reck M, Garon EB, Paz-Ares L, et al. Randomized, double-blind phase Ib/III study of erlotinib with ramucirumab or placebo in previously untreated EGFR-mutant metastatic non-small-cell lung cancer (RELAY): phase Ib results. Clin Lung Cancer. 2018; 19(3):213-220.e4.
  18. Tabernero J, Yoshino T, Cohn AL, et al. 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(5):499-508. Correction: 2015; 16(6):e262.
  19. Vahdat LT, Layman R, Yardley DA, et al. Randomized phase II study of ramucirumab or icrucumab in combination with capecitabine in patients with previously treated locally advanced or metastatic breast cancer. Oncologist. 2017; 22(3):245-254.
  20. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11):1224-1235.
  21. Yardley DA, Reeves J, Dees EC, et al. Ramucirumab with eribulin versus eribulin in locally recurrent or metastatic breast cancer previously treated with anthracycline and taxane therapy: a multicenter, randomized, phase II study. Clin Breast Cancer. 2016; 16(6):471-479.
  22. Yoon HH, Bendell JC, Braiteh FS, et al. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol. 2016; 27(12):2196-2203.
  23. Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015; 16(7):859-870.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Cyramza [Product Information]. Indianapolis, IN. Eli Lilly and Company; March 2017. Available at: http://pi.lilly.com/us/cyramza-pi.pdf. Accessed on June 11, 2018.
  2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2011. Updated December 17, 2014. Available at: http://seer.cancer.gov/csr/1975_2011/. Accessed on June 11, 2018.
  3. Janmaat VT, Steyerberg EW, van der Gaast A, et al. Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer. Cochrane Database Syst Rev. 2017;(11):CD004063.
  4. National Comprehensive Cancer Network®. NCCN® Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on June 11, 2018.
  5. NCCN Clinical Practice Guidelines in Oncology®. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on June 11, 2018.
    • Bladder Cancer (V4.2018). Revised May 22, 2018.
    • Colon Cancer (V2.2018). Revised March 14, 2018.
    • Esophageal and Esophagogastric Junction Cancers (V2.2018). Revised May 22, 2018.
    • Gastric Cancer (V2.2018). Revised May 22, 2018.
    • Non-Small Cell Lung Cancer (V4.2018). Revised April 26, 2018.
    • Rectal Cancer (V1.2018). Revised March 14, 2018.
  6. Ramucirumab. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Last updated February 2, 2018. Available at: http://www.micromedexsolutions.com. Accessed on June 11, 2018.
  7. U.S. National Institutes of Health (NIH). ClinicalTrials.gov. Search: ramucirumab. Available at: https://www.clinicaltrials.gov/ct2/results?term=ramucirumab&Search=Search. Accessed on June 11, 2018.
Websites for Additional Information
  1. National Cancer Institute (NCI). A to Z List of Cancers. Available at: http://www.cancer.gov/cancertopics/types/alphalist. Accessed on June 11, 2018.
    • Bladder Cancer Treatment (PDQ®). Last modified April 12, 2018.
    • Colon Cancer Treatment (PDQ®). Last modified April 6, 2018.
    • Esophageal Cancer Treatment (PDQ®). Last modified February 6, 2018.
    • Gastric Cancer Treatment (PDQ). Last modified February 2, 2018.
    • Non-Small Lung Cancer Treatment (PDQ). Last modified March 20, 2018.
    • Rectal Cancer Treatment (PDQ®). Last modified June 7, 2018.
Index

Cyramza

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

07/18/2018

Hematology/Oncology Subcommittee review. Added MN statement for use of ramucirumab in locally advanced, unresectable or metastatic urothelial carcinoma when criteria are met. Removed genitourinary cancer from the INV & NMN statement. Updated Rationale, Background, Coding, Definitions, References, and Websites for Additional Information sections.

Reviewed

05/03/2018

MPTAC review.

Reviewed

05/02/2018

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background, References, and Websites for Additional Information sections.

Reviewed

05/04/2017

MPTAC review.

Reviewed

05/03/2017

Hematology/Oncology Subcommittee review. Updated formatting in Position Statement section. Updated Rationale, Background, References, and Websites for Additional Information sections.

Revised

05/05/2016

MPTAC review.

Revised

05/04/2016

Hematology/Oncology Subcommittee review. Clarified MN statement for use in NSCLC, including the addition of examples of FDA-approved therapies “(for example, afatinib, crizotinib, erlotinib, or gefitinib)” given prior to ramucirumab in an individual who has an EGFR or ALK genomic tumor mutation. Updated Rationale, Background, Definitions, References, and Websites for Additional Information sections.

 

01/01/2016

Updated Coding section with 01/01/2016 HCPCS changes, removed C9025 deleted 12/31/2015; also removed ICD-9 codes.

Revised

05/07/2015

MPTAC review.

Revised

05/06/2015

Hematology/Oncology Subcommittee review. Updated brand name of Cyramza with registered trademark. Format changes to the medically necessary statement for NSCLC. Added esophageal adenocarcinoma to the medically necessary statement for use of ramucirumab for gastric and gastroesophageal junction adenocarcinoma when criteria are met. Added medically necessary statement for FDA approval of ramucirumab for colorectal cancer when criteria are met. Added list of conditions to the investigational and not medically necessary statement. Updated Rationale, Background, Definitions, Coding, References, and Websites for Additional Information sections.

New

11/13/2014

MPTAC review. Document reviewed on 01/06/2015.

New

11/12/2014

Hematology/Oncology Subcommittee review. Initial document development. On 12/29/2014, added medically necessary criteria for non-small cell lung cancer. Updated Rationale, Background/Overview, Coding and References sections.