| Coverage Policy Manual | |
| Policy #: | 2017016 |
| Category: | Pharmacy |
| Initiated: | May 2017 |
| Last Review: | May 2023 |
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| Ramucirumab (e.g., Cyramza™) | |
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| Description: |
Ramucirumab is a fully human monoclonal antibody, that binds to VEGFR2 on the extracellular domainof endothelial cells. This inhibits activation of VEGFR2, which causes cell proliferation and migration of human endothelial cells to be inhibited. (Clinical Pharmacology, 2017).
Regulatory Status
Ramucirumab (e.g., Cyramza™) was initially approved by the FDA in April 2014 as monotherapy for advanced or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma; approval was expanded in late 2014 for the treatment of GEJ adenocarcinoma in combination with paclitaxel and for metastatic non-small cell lung cancer (NSCLC) in combination with docetaxel, and then again in April 2015 for the treatment of metastatic colorectal cancer (mCRC) in combination with FOLFIRI. (U.S. Food and Drug Administration2014 & 2015).
Ramucirumab (e.g., Cyramza™) received FDA approval July 2019 for the treatment of advanced or unresectable hepatocellular carcinoma as subsequent treatment for progressive disease after sorafenib treatment, in individuals with serum α–fetoprotein (AFP) concentrations of ≥ 400 ng/mL. The approval is based on the REACH (Zhu 2015) and REACH 2 (Zhu 2019) studies. The REACH study, which did not result in improved overall survival (OS) compared to placebo, included individuals with any AFP level. However, subgroup analysis around baseline AFP level prompted the REACH 2 study which included only individuals with baseline AFP of ≥ 400 ng/mL. In this study, the primary endpoint of improved median overall survival was statistically significant
In April 2014 the FDA included a “black box warning” in the labeling indicating that Ramucirumab (e.g., Cyramza™) increased the risk of hemorrhage and GI hemorrhage including severe, sometimes fatal events. In April 2015 they expanded “black box warning’ to include an increase of risk of GI perforation and impaired wound healing that was due to antibodies inhibiting the VEGF pathway.
On May 29, 2020 the Food and Drug Administration approved Ramucirumab (e.g., Cyramza) for first-line treatment of individuals with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Effective January 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of the following listed indications:
Colorectal Cancer
Esophageal and Esophagogastric Junction Cancers
Gastric Cancer
Non-Small Cell Lung Cancer
Hepatocellular Carcinoma
Rectal Cancer
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Gastric Cancer
Non-Small Cell Lung Cancer
Colorectal Cancer
Hepatocellular Carcinoma
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any indication or circumstance other than those outlined above, does not meet member benefit certificate primary coverage criteria that there be evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any indication or circumstance other than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective May 2021 through December 31, 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
FDA labeled
Off – Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Gastric Cancer
Non-Small Cell Lung Cancer
EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – Ramucirumab in Combination with Erlotinib
Disease Progression On or After Platinum-based Chemotherapy – Ramucirumab in Combination with Docetaxel
Colorectal Cancer
Hepatocellular Carcinoma
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2019 to April 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
FDA labeled
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy in combination with docetaxel.
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
3. Colorectal Cancer, in combination with FOLFIRI (flurouracil, leucovorin, and irinotecan), for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluropyrimidine.
4. Hepatocellular Carcinoma, as a single agent for the treatment of hepatocellular carcinoma for those patients who have an alpha fetoprotein (AFP) of >400 ng/mL and have been treated with sorafenib.
Off – Label
For those members subject to Arkansas state law (Act 270) requiring coverage of drugs that are deemed to be safe and effective for a specific cancer by the National Comprehensive Cancer Network (NCCN), the use of ramucirumab for NCCN Category 1 and 2a recommendations in accordance with Coverage Policy #2000030 meet member benefit certificate primary coverage criteria.
Colorectal Cancer
2. Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIFI (fluorouracil, leucovorin and irinotecan) regimen in patient not previously treated with irinotecan-based therapy.
Esophageal and Esophagogastric Junction Cancers
Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic adenocarcinoma and a Karnofsky performance score >60% or ECOG performance score <2 or as a preferred second-line or subsequent therapy as a single agent or in combination with paclitaxel.
Gastric Cancer
Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and a Karnofsky performance score >60% or ECOG performance score <2 as a preferred second-line or subsequent therapy as a single agent or in combination with paclitaxel.
Hepatobiliary Cancers
Subsequent treatment as a single agent for progressive disease in patients (AFP >400ng/mL only) who:
Non-Small Cell Lung Cancer
Subsequent systemic therapy (for first progression after initial systemic therapy) in combination with docetaxel (if not already given) for recurrent, advanced or metastatic disease in patients with performance status 0-2.
Dosage and Administration:
Gastric Cancer
The recommended dose of Cyramza either as a single agent or in combination with weekly paclitaxel is 8mg/kg every 2 weeks administered as an IV infusion over 60 mins. Continue Cyramza until disease progression or unacceptable toxicity. When given in combination, administer Cyramza prior to administration of paclitaxel.
Non-Small Cell Lung Cancer
The recommended dose is 10mg/kg administered by IV infusion over 60 mins on day 1 of a 21-day cycle prior to docetaxel infusion. Continue Cyramza until progression or unacceptable toxicity.
Colorectal Cancer
The recommended dose is 8 mg/kg every 2 weeks administered by IV over 60 mins prior toFOLFIRI administration. Continue Cyramza until progression or unacceptable toxicity.
Hepatocellular Carcinoma
The recommended dosage is 8 mg/kg every 2 weeks administered by IV over 60 mins. If first infusion is tolerated, all subsequent infusions may be administered over 30 mins. Continue until disease progression or unacceptable toxicity.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
FDA labeled
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy in combination with docetaxel.
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
3. Colorectal Cancer, for the treatment of metastatic colorectal cancer with:
4. Hepatocellular Carcinoma, as a single agent for the treatment of hepatocellular carcinoma for those patients who have an alpha fetoprotein (AFP) of >400 ng/mL and have been treated with sorafenib.
Off – Label
For those members subject to Arkansas state law (Act 270) requiring coverage of drugs that are deemed to be safe and effective for a specific cancer by the National Comprehensive Cancer Network (NCCN), the use of ramucirumab for NCCN Category 1 and 2a recommendations in accordance with Coverage Policy #2000030 meet member benefit certificate primary coverage criteria.
Colorectal Cancer
2. Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIFI (fluorouracil, leucovorin and irinotecan) regimen in patient not previously treated with irinotecan-based therapy.
Esophageal and Esophagogastric Junction Cancers
Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic adenocarcinoma and a Karnofsky performance score >60% or ECOG performance score <2 or as a preferred second-line or subsequent therapy as a single agent or in combination with paclitaxel.
Gastric Cancer
Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and a Karnofsky performance score >60% or ECOG performance score <2 as a preferred second-line or subsequent therapy as a single agent or in combination with paclitaxel.
Hepatobiliary Cancers
Subsequent treatment as a single agent for progressive disease in patients (AFP >400ng/mL only) who:
Non-Small Cell Lung Cancer
Subsequent systemic therapy (for first progression after initial systemic therapy) in combination with docetaxel (if not already given) for recurrent, advanced or metastatic disease in patients with performance status 0-2.
Dosage and Administration:
Gastric Cancer
The recommended dose of Cyramza either as a single agent or in combination with weekly paclitaxel is 8mg/kg every 2 weeks administered as an IV infusion over 60 mins. Continue Cyramza until disease progression or unacceptable toxicity. When given in combination, administer Cyramza prior to administration of paclitaxel.
Non-Small Cell Lung Cancer
The recommended dose is 10mg/kg administered by IV infusion over 60 mins on day 1 of a 21-day cycle prior to docetaxel infusion. Continue Cyramza until progression or unacceptable toxicity.
Colorectal Cancer
The recommended dose is 8 mg/kg every 2 weeks administered by IV over 60 mins prior toFOLFIRI administration. Continue Cyramza until progression or unacceptable toxicity.
Hepatocellular Carcinoma
The recommended dosage is 8 mg/kg every 2 weeks administered by IV over 60 mins. If first infusion is tolerated, all subsequent infusions may be administered over 30 mins. Continue until disease progression or unacceptable toxicity.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective May 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
FDA labeled
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
3. Colorectal Cancer, for the treatment of metastatic colorectal cancer
Off – Label
Dosage and Administration:
Gastric Cancer
Non-Small Cell Lung Cancer
Colorectal Cancer
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective May 2018 to April 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
FDA labeled
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
3. Colorectal Cancer, for the treatment of metastatic colorectal cancer
Off – Label
2. Esophageal and Esophagogastric Junction Cancers
3. Gastric Cancer
4. Non-Small Cell Lung Cancer
5. Rectal Cancer
Dosing:
Gastric Cancer
Non-Small Cell Lung Cancer
Colorectal Cancer
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Coverage Prior to May 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
Ramucirumab meets primary coverage criteria and is covered for treatment for the following listed
indications:
FDA labeled (2017)
1. Gastric Cancer, for the treatment of advanced gastric or gastro-esophageal junction
adenocarcinoma,
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
3. Colorectal Cancer, for the treatment of metastatic colorectal cancer
Off-label (2017)
2. Esophageal and Esophagogastric Junction Cancers
3. Gastric Cancer
4. Rectal Cancer
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of less than 10mg/kg ever 2 weeks
Ramucirumab is given as an IV infusion over 60 minutes.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Gastric Cancer
Fuchs et al (2014) published the results of the phase III REGARD trial which was a multinational, randomized, double-blind, multicenter study of Ramucirumab plus best supportive care (BSC) versus placebo plus BSC. 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy were randomized 2:1 between the two treatment arms of those receiving Ramucirumab plus BSC (n=238) and those receiving Placebo plus BSC (n=117) intravenously every 2 weeks. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy or within 6 months after the last dose of adjuvant therapy. Patients were also required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Median overall survival was 5.2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3.8 months (1·7-7·1) in those in the placebo group (hazard ratio. The authors concluded that Ramucirumab has survival benefits in patients with advanced gastric or GEF adenocarcinoma progressing after first-line chemotherapy.
Al-Batran et al (2016) published the results of a phase III RAINBOW trial that was a multinational, randomized, double-blind study of Ramucirumab plus paclitaxel versus placebo plus paclitaxel. 665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum- and fluoropyrimidine-containing chemotherapy were randomized 1:1 between the two treatment arms of those receiving Ramucirumab plus paclitaxel (n=330) and those receiving Placebo plus paclitaxel (n=335) intravenously. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1. The major efficacy outcome measure was overall survival (OS) and the supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). Median OS was 9.6 months in the Ramucirumab plus paclitaxel group versus 7.4 months in the Placebo plus paclitaxel group. PFS in the Ramucirumab plus paclitaxel group was 4.4 months versus 2.9 months in the Placebo plus paclitaxel group. ORR in the Ramucirumab plus paclitaxel group was 28% months versus 16% in the Placebo plus paclitaxel group. The authors concluded that addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient quality-of-life with delayed symptom worsening and functional status deterioration in patients with previously treated advanced gastric/GEJ adenocarcinoma.
Non-Small Cell Lung Cancer (NSCLC)
Garon et al (2014) published the results of the REVEL trial which was a multicentre, double-blind, randomized phase 3 trial of CYRAMZA plus docetaxel versus placebo plus docetaxel. 1253 patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease were randomized 1:1 between the two treatment arms of Ramucirumab plus docetaxel (N=628) and Placebo plus docetaxel (N=625). The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. Patients were also required to have ECOG PS 0 or 1. Median overall survival was 10.5 months for 628 patients allocated ramucirumab plus docetaxel and 9.1 months for 625 patients who received placebo plus docetaxel. Median progression-free survival was 4.5 months for the ramucirumab group compared with 3.0 months for the control group. The authors concluded that Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.
Metastatic Colorectal Cancer (mCRC)
Tabernero et al (2015) published the results of the RAISE trial which was a multinational, randomized, double-blind, study of Ramucirumab plus FOLFIRI versus placebo plus FOLFIRI, in patients with mCRC, who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. 1072 patients were 1:1 randomized to receive either Ramucirumab plus FOLFIRI (n=536) or Placebo plus FOLFIRI (n=536) intravenously every 2 weeks. The major efficacy outcome measure was overall survival (OS) and the supportive efficacy outcome measure was progression-free survival (PFS). Median OS was 13.3 months for patients in the ramucirumab group versus 11.7 months for the placebo group. PFS was 5.7 months in the ramucirumab group versus 4.5 months in the placebo group. The authors concluded that Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma.
2019 Update
A literature search conducted through April 2019 did not reveal any new information that would prompt a change in the coverage statement.
November 2019
Hepatocellular Carcinoma
Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. In REACH-2 the aim was to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher (Zhu AX, Kang YK, Yen CJ, et al. 2019).
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, α-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. 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. Individual patient data was also pooled from REACH-2 with data from REACH ( NCT01140347) for patients with α-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. This trial is registered with ClinicalTrials.gov, number NCT02435433.
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 (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).
REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile.
2020 Update
The REVEL study demonstrated improved efficacy with ramucirumab plus docetaxel versus placebo plus docetaxel for previously treated advanced/metastatic non-small-cell lung cancer (NSCLC) without further detriment to patient quality of life, symptoms, or functioning. This post hoc analysis explored the association between baseline Lung Cancer Symptom Scale (LCSS) Average Symptom Burden Index (ASBI) and efficacy.
Baseline ASBI scores were the average of the 6 LCSS symptom components. Low and high symptom burden (LSB ≤ median, HSB > median) were analyzed across and by treatment arms for effects on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) using the Kaplan-Meier method and Cox proportional hazards model.
Baseline LCSS compliance was approximately 78% in both REVEL treatment arms. Patients with LSB versus HSB had fewer poor prognostic factors. The HSB patient population significantly overlapped with previously identified aggressive disease subgroups (rapidly progressing disease or refractory to first-line treatment). Patients with LSB versus HSB had significantly improved OS (P < 0.0001), PFS (P < 0.0001), and ORR (P = 0.0003) regardless of treatment, with superior ORR and PFS but not OS in the ramucirumab plus docetaxel arm. Patients with HSB treated with ramucirumab plus docetaxel versus docetaxel had improved OS (median, 7.39 vs. 5.95 months; HR 0.749 [95% CI 0.610-0.920]; P = 0.0308), PFS (median, 4.01 vs. 2.63 months; HR 0.749 [0.619-0.907]; P = 0.0202), and ORR (18% vs. 11%; P = 0.0458). Of patients with rapidly progressing disease, 57% (92/162) also had HSB.
Baseline ASBI may be an independent prognostic factor in this large second-line cohort of patients with advanced NSCLC. The preservation of improved PFS and OS in the HSB cohort suggests that the addition of ramucirumab to docetaxel provides benefit in patients with greater symptom burden, consistent with previous data on REVEL patients with aggressive disease. (Pérol M, et al., 2019).
2021 Update
In a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centers in 13 countries the safety and efficacy of Ramucirumab was studied. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. Eligible patients were randomly assigned in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.
Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. (Nakagawa K, Garon EB, Seto T, 2019)
2022 Update
RELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC).
Eligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments.
The safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care.
This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient's ability to benefit from treatment. (Nadal E, Horinouchi H, Shih JY, et.al., 2022)
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
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Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H.(2016) 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 Apr;27(4):673-9. doi: 10.1093/annonc/mdv625. Epub 2016 Jan 7. Eli Lilly and Company(2017) Cyramza® [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017 Elsevier.(2018) Ramucirumab [Internet]. Tampa (FL): Elsevier. c2018- [cited 2018 May 01]. Available from: http://www.clinicalpharmacology.com Fuchs CS, Tomasek J, Yong CJ et al, REGARD Trial Investigators.(2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. doi: 10.1016/S0140-6736(13)61719-5. Epub 2013 Oct 3. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K et al.(2014) 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 multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2. Nadal E, Horinouchi H, Shih JY, Nakagawa K, Reck M, Garon EB, Wei YF, Kollmeier J, Frimodt-Moller B, Barrett E, Lipkovich O, Visseren-Grul C, Novello S.(2022) RELAY, Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients with Untreated, Epidermal Growth Factor Receptor Mutation-Positive, Metastatic Non-Small-Cell Lung Cancer: Safety Profile and Manageability. Drug Saf. 2022 Jan;45(1):45-64. doi: 10.1007/s40264-021-01127-2. Epub 2021 Dec 20. PMID: 34928484; PMCID: PMC8763844. Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M(2019) RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. doi: 10.1016/S1470-2045(19)30634-5. Epub 2019 Oct 4. PMID: 31591063. National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Ramucirumab. Available at https://www.nccn.org. Accessed April 28, 2023. NCCN Clinical Practice Guidelines in Oncology™. © 2019 National Comprehensive Cancer Network, Inc.(2019) Esophageal and Esophagogastric Junction Cancers. V2.2019. Revised May 29, 2019. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on Nov 6, 2019. NCCN Clinical Practice Guidelines in Oncology™. © 2019 National Comprehensive Cancer Network, Inc.(2019) Gastric Cancer. V2.2019. Revised June 03, 2019. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on Nov 6, 2019. NCCN Clinical Practice Guidelines in Oncology™. © 2019 National Comprehensive Cancer Network, Inc.(2019) Hepatocellular Carcinoma. V3.2019. Revised August 1, 2019. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on Nov 6, 2019. NCCN Clinical Practice Guidelines in Oncology™. © 2019 National Comprehensive Cancer Network, Inc.(2019) Non-Small Cell Lung Cancer. V7.2019. Revised August 30, 2019. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on Nov 6, 2019. NCCN Clinical Practice Guidelines in Oncology™. © 2019 National Comprehensive Cancer Network, Inc.(2019) Small Cell Lung Cancer. V1.2020. Revised October 10, 2019 For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on Nov 6, 2019. NCCN(2018) NCCN Compendia. https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=5. Accessed March 31, 2017. Pérol M, Winfree KB, Cuyun Carter G, Lin Cui Z, Bowman L, Garon EB.(2019) Association of baseline symptom burden with efficacy outcomes: Exploratory analysis from the randomized phase III REVEL study in advanced non-small-cell lung cancer. Lung Cancer. 2019;131:6–13. Ramucirumab. National Comprehensive Cancer Network (NCCN). NCCN Drugs and Biologics Compendium: Tabernero J, Yoshino T, Cohn AL, RAISE Study Investigators.(2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with mCRC that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12. Zhu AX, Kang YK, Yen CJ, et al.(2019) Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased a-fetoprotein concentrations (REACH-2):a randomised, double-blind, placebo controlled, phase 3 trial. Lancet Oncol, 2019 Feb;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9. Epub 2019 Jan 18. Zhu AX, Park JO, Ryoo BY, et al.(2015) Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH) Lancet Oncol. 2015; 16(7):859-870 |
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