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REVEL trial overview

REVEL: A pivotal phase III trial in patients with mNSCLC (nonsquamous or squamous histologies) with disease progression on or after platinum-based therapy (N=1253)1

REVEL Trial Design1,2

A large, multinational, randomized, double-blind, placebo-controlled trial in patients with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease1

REVEL trial chart

*Stratification factors: Geographic region, ECOG PS, prior maintenance therapy, and gender.1
†24 patients at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks.1

Major Efficacy Outcome Measure: Overall Survival (OS)

Supportive Efficacy Outcome Measures: Progression-Free Survival (PFS), Overall Response Rate (ORR)

  • Patients received treatment until disease progression, unacceptable toxicity, withdrawal, or death3

Approximately 1 in 6 patients in the REVEL trial had rapidly progressing disease‡4

REVEL: Post Hoc Exploratory Subgroup Analysis in Patients with Rapidly Progressing Disease‡ on Initial Platinum-based Therapy4

REVEL subgroup chart

REVEL Exploratory Analyses3-5:
The REVEL trial was not adequately powered or error-controlled for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were post hoc and exploratory.

SELECT IMPORTANT SAFETY INFORMATION

GASTROINTESTINAL PERFORATIONS

  • CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.
  • Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

REVEL population highlights (N=1253)1

REVEL population highlights chart
  • Patients who discontinued combination therapy because of an adverse event attributed to either CYRAMZA or docetaxel were permitted to continue monotherapy with the other treatment component until disease progression or intolerable toxicity1
  • Tumor EGFR status was unknown for the majority of patients (65%). Where tumor EGFR status was known (n=445), 7.5% were positive for EGFR mutation (n=33)1
  • No data were collected regarding tumor ALK rearrangement status1

Demographics and baseline characteristics were similar between the ITT population and rapid progression‡ subgroup1,3,4,6

ITT Population: Demographics and Baseline Characteristics3,7

REVEL population highlights chart

§Data not available for 1 patient in the CYRAMZA plus docetaxel group.1,3
ǁData not available for 1 patient in each group.1,3

Demographics and Baseline Characteristics: Patients with Rapidly Progressing Disease‡ ≤12 Weeks (n=209)4

Demographics and baseline chart

‡Rapidly progressing disease is defined as time to progression within 9 or 12 weeks after starting initial platinum-based treatment.4

ALK=anaplastic lymphoma kinase; CR=complete response; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; ITT=intent-to-treat; IV=intravenous; mNSCLC=metastatic non-small cell lung cancer; ORR=overall response rate; OS=overall survival; PD=progressive disease; PFS=progression-free survival; PR=partial response; PS=performance status; SD=stable disease.

References:   1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.  2. Supplement to: Garon EB, Ciuleanu T-E, 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 multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.  3. Garon EB, Ciuleanu T-E, 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 multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.  4. Reck M, Shepherd F, Pérol M, et al. Effects of second-line ramucirumab after rapid time to progression on first-line therapy: subgroup analysis of REVEL in advanced non-small cell lung cancer. Oral presentation presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan.  5. Data on File, Lilly USA, LLC, DOF-RB-US-0006.  6. Data on file. Eli Lilly and Company. ONC20170503b.  7. Data on file. Eli Lilly and Company. ONC20170511A.

INDICATIONS and IMPORTANT SAFETY INFORMATION
Indications
  • CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
  • CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.
  • CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
  • CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha-fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.
Important Safety Information for Cyramza® (ramucirumab)
Warnings and Precautions

Hemorrhage

  • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage occurred between 13-44%. Grade 3-5 hemorrhage incidence ranged from 2-5%.
  • Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.
  • Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from REVEL; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.
  • Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.

Gastrointestinal Perforations

  • CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.
  • Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

  • Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2 antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.
  • Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 28 days following a major surgical procedure and until the wound is fully healed. Discontinue CYRAMZA in patients who develop wound healing complications that require medical intervention.

Arterial Thromboembolic Events

  • Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 2-3%. Grade 3-5 ATE incidence was 1-2%.
  • Permanently discontinue CYRAMZA in patients who experience an ATE.

Hypertension

  • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension occurred between 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%.
  • Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions

  • Infusion-related reactions (IRR), including severe and life threatening IRR, occurred in CYRAMZA clinical trials. The majority of IRR across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRR included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR occurred between <1-9%. Grade 3-5 IRR incidence was <1%.
  • Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRR.

Worsening of Pre-existing Hepatic Impairment

  • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.
  • Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%).

Reversible Posterior Leukoencephalopathy Syndrome

  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in <0.1% of 1916 patients enrolled in five clinical studies with CYRAMZA.
  • Confirm the diagnosis of RPLS with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

  • Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-20%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%.
  • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction

  • Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA.

Embryo-Fetal Toxicity

  • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

Lactation

  • Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.
Most Common Adverse Reactions—CYRAMZA Administered as a Single Agent (REGARD)
  • The most commonly reported adverse reactions (all Grades; Grade 3-4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in REGARD were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).
  • The most common serious adverse reactions with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
  • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in REGARD were: neutropenia (4.7%), epistaxis (4.7%), rash (4.2%), intestinal obstruction (2.1%), and arterial thromboembolic events (1.7%).
  • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and IRR. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in REGARD was 0.8% and the rate of IRR was 0.4%.
Most Common Adverse Reactions— CYRAMZA Administered in Combination with Paclitaxel (RAINBOW)
  • The most commonly reported adverse reactions (all Grades; Grade ≥3) occurring in ≥5% of patients receiving CYRAMZA with paclitaxel and ≥2% higher than placebo with paclitaxel in RAINBOW were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).
  • The most common serious adverse reactions in patients who received CYRAMZA with paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients who received CYRAMZA with paclitaxel received granulocyte colony-stimulating factors.
  • Adverse reactions resulting in discontinuation of any component of the CYRAMZA with paclitaxel combination in ≥2% of patients in RAINBOW were neutropenia (4%) and thrombocytopenia (3%).
  • Clinically relevant adverse reactions reported in ≥1% and <5% of patients receiving CYRAMZA with paclitaxel were sepsis (3.1%), including 5 fatal events, and gastrointestinal perforations (1.2%), including 1 fatal event.
Most Common Adverse Reactions— CYRAMZA Administered in Combination with Docetaxel (REVEL)
  • The most commonly reported adverse reactions (all Grades; Grade 3-4) occurring in ≥5% of patients receiving CYRAMZA with docetaxel and ≥2% higher than placebo with docetaxel in REVEL were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
  • The most common serious adverse reactions in patients who received CYRAMZA with docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA with docetaxel-treated patients versus 37% in patients who received placebo with docetaxel.
  • Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA with docetaxel-treated patients (9%) than in placebo with docetaxel-treated patients (5%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were IRR (0.5%) and epistaxis (0.3%).
  • For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to 6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of Grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA with docetaxel compared to 12% overall incidence and 2% for Grade ≥3 pulmonary hemorrhage for placebo with docetaxel.
  • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA with docetaxel-treated patients in REVEL were hyponatremia (4.8%) and proteinuria (3.3%).
Most Common Adverse Reactions— CYRAMZA Administered in Combination with FOLFIRI (RAISE)
  • The most commonly reported adverse reactions (all Grades; Grade ≥3) occurring in ≥5% of patients receiving CYRAMZA with FOLFIRI and ≥2% higher than placebo with FOLFIRI in RAISE were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs <1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; <1% vs 0%), proteinuria (17% vs 5%; 3% vs <1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs <1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), and hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA with FOLFIRI received granulocyte colony-stimulating factors.
  • The most common serious adverse reactions with CYRAMZA with FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
  • Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA with FOLFIRI-treated patients (29%) than in placebo with FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA with FOLFIRI as compared to placebo with FOLFIRI were neutropenia (12.5% vs 5.3%) and thrombocytopenia (4.2% vs 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
  • Clinically relevant adverse reaction reported in ≥1% and <5% of patients receiving CYRAMZA with FOLFIRI was gastrointestinal perforation (1.7%) including 4 fatal events.
  • Thyroid-stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA with FOLFIRI-treated patients and 109 placebo with FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA with FOLFIRI compared with 4 (4%) patients treated with placebo with FOLFIRI.
Most Common Adverse Reactions— CYRAMZA Administered as a Single Agent (REACH‑2)
  • The most commonly reported adverse reactions (all Grades; Grade ≥3) occurring in ≥10% of patients receiving CYRAMZA and ≥2% higher than placebo in REACH-2 were fatigue (36% vs 20%; 5% vs 3%), peripheral edema (25% vs 14%; 2% vs 0%), hypertension (25% vs 13%; 13% vs 5%), abdominal pain (25% vs 16%; 2% vs 2%), decreased appetite (23% vs 20%; 2% vs 1%), proteinuria (20% vs 4%; 2% vs 0%), nausea (19% vs 12%; 0% vs 0%), ascites (18% vs 7%; 4% vs 1%), headache (14% vs 5%; 0% vs 1%), epistaxis (14% vs 3%; <1% vs 0%), insomnia (11% vs 6%; 0% vs 1%), pyrexia (10% vs 3%; 0% vs 0%), vomiting (10% vs 7%; 0% vs 0%), and back pain (10% vs 7%; <1% vs 1%). The most common laboratory abnormalities (all Grades; Grade ≥3) occurring in ≥15% of patients receiving CYRAMZA and ≥2% higher than placebo were thrombocytopenia (46% vs 15%; 8% vs 1%), hypoalbuminemia (33% vs 16%; <1% vs 0%), hyponatremia (32% vs 25%; 16% vs 5%), neutropenia (24% vs 12%; 8% vs 3%), and hypocalcemia (16% vs 5%; 2% vs 0%).
  • The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%).
  • Treatment discontinuations due to adverse reactions occurred in 18% of CYRAMZA-treated patients, with proteinuria being the most frequent (2%).
  • Clinically relevant adverse reactions reported in ≥1% and <10% of CYRAMZA-treated patients in REACH-2 were IRR (9%), hepatic encephalopathy (5%) including 1 fatal event, and hepatorenal syndrome (2%) including 1 fatal event.

Please click for full Prescribing Information for CYRAMZA.

RB-P HCP ISI 08AUG2019

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