On May 29, 2020, ramucirumab was approved for use in combination with erlotinib for first-line treatment of metastatic non–small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 (L858R) substitution mutation.^1,2

Supporting Efficacy Data

Approval was based on findings from the multinational, double-blind, placebo-controlled phase III RELAY trial (ClinicalTrials.gov identifier NCT02411448).^2,3 In the trial, 499 patients with previously untreated metastatic NSCLC with tumors having EGFR exon 19 deletion or exon 21 (L858R) mutation were randomly assigned to receive ramucirumab at 10 mg/kg (n = 224) or placebo (n = 225) every 2 weeks via intravenous (IV) infusion in combination with oral erlotinib at 150 mg once daily until disease progression or unacceptable toxicity. Randomization was stratified by geographic region (East Asia vs other), sex, EGFR mutation (exon 19 deletion vs exon 21 [L858R] mutation), and local EGFR testing method (therascreen and cobas vs other polymerase chain reaction and sequencing-based methods).

Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion criteria included bilirubin greater than the upper limit of normal, central nervous system metastases, and clinically active interstitial lung disease.

The major efficacy outcome measure was investigator-assessed, progression-free survival using Response Evaluation Criteria in Solid Tumors, version 1.1. Median progression-free survival was 19.4 months (95% confidence interval [CI] = 15.4–21.6 months) with ramucirumab/erlotinib vs 12.4 months (95% CI = 11.0––13.5 months) with placebo/erlotinib (hazard ratio [HR] = 0.59, 95% CI = 0.46––0.76, P < .0001). Results were similar on blinded independent radiologic review. The benefit of ramucirumab/erlotinib was consistent across prespecified stratification factors.

Overall response rates were 76% vs 75%, with a median response duration of 18.0 months (95% CI = 13.9––19.8 months) vs 11.1 months (95% CI = 9.7––12.3 months). At the time of the final analysis of progression-free survival, overall survival data were not mature (26% of planned events for final analysis); the hazard ratio for ramuciru-mab/erlotinib vs placebo/erlotinib was 0.83 (95% CI = 0.53––1.30).

How It Works

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 blocks ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in animal models.

How It Is Used

The recommended dosage of ramucirumab for metastatic -NSCLC in combination with erlotinib is 10 mg/kg every 2 weeks via IV infusion over 60 minutes. If the first infusion is tolerated, subsequent infusions may be given over 30 minutes. Ramucirumab treatment should continue until disease progression or unacceptable toxicity. The recommended dosage of erlotinib in combination with ramucirumab in the current indication is 150 mg once daily, with treatment continuing until disease progression or unacceptable toxicity.

Prior to each ramucirumab infusion, all patients should be premedicated with an IV histamine-1 receptor antagonist (eg, diphenhydramine hydrochloride). Patients who have a grade 1 or 2 infusion-related reaction should be premedicated with a histamine-1 antagonist, dexamethasone (or equivalent), and acetaminophen prior to each infusion. The infusion rate should be reduced by 50% for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 infusion-related reactions.

Ramucirumab prescribing information provides instructions for dosage modification or discontinuation of treatment for adverse reactions including hemorrhage, gastrointestinal perforation, wound-healing complications, arterial thromboembolic events, hypertension, infusion-related reactions, posterior reversible encephalopathy syndrome, and proteinuria.

Safety Profile

In the RELAY trial, the median duration of exposure to ramucirumab was 11 months, with 41% of patients receiving treatment for at least 12 months.

The most common adverse events of any grade in patients receiving ramucirumab/erlotinib at a rate of at least 20% and at least 2% higher vs placebo/erlotinib were infections (81% vs 76%), hypertension (45% vs 12%), stomatitis (42% vs 36%), proteinuria (34% vs 8%), alopecia (34% vs 20%), epistaxis (34% vs 12%), and peripheral edema (23% vs 4%). The most common grade 3 or 4 adverse events with ramucirumab/erlotinib included hypertension (24% vs 5%), infections (17% vs 7%), and diarrhea (7% vs 1%). The most common laboratory abnormalities of any grade occurring at a rate of at least 30% and at least 2% higher vs placebo/erlotinib were increased alanine aminotransferase (74% [11% at least grade 3] vs 60% [13% at least grade 3]), increased aspartate aminotransferase (71% [6%] vs 47% [4%]), anemia (42% [5%] vs 25% [2%]), thrombocytopenia (41% [3%] vs 12% [3%]), and neutropenia (33% [7%] vs 21% [4%]).

The most common serious adverse events in the ramucirumab/erlotinib group were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% (vs no patients in the placebo/erlotinib group). Adverse events led to discontinuation of both ramucirumab and erlotinib in 13% of patients, with the most common causes being increased alanine aminotransferase (1.4%) and paronychia (1.4%). The most common adverse events leading to discontinuation of ramucirumab were proteinuria (8.6%) and hyperbilirubinemia (6%). Fatal adverse events included infection in three patients and pulmonary hemorrhage in one patient.

Ramucirumab has warnings/precautions for hemorrhage and gastrointestinal hemorrhage, gastrointestinal perforations, impaired wound healing, arterial thromboembolic events, hypertension, infusion-related reactions, worsening of preexisting hepatic impairment, posterior reversible encephalopathy syndrome, proteinuria, thyroid dysfunction,and embryofetal toxicity.

Ramucirumab should be withheld for 28 days prior to elective surgery and not given for at least 2 weeks following a major surgical procedure and until adequate wound healing; the safety of resumption after resolution of wound-healing complications has not been established. Blood pressure should be monitored and hypertension treated. Patients should be monitored for proteinuria and thyroid function during treatment. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves ramucirumab plus erlotinib for first-line metastatic NSCLC. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ramucirumab-plus-erlotinib-first-line-metastatic-nsclc. Accessed June 10, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Cyramza (ramucirumab) injection. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125477s034lbl.pdf. Accessed June 10, 2020.

3. Nakagawa K, et al: Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY). Lancet Oncol 20:1655-1669, 2019.