Clinical trial design: REGARD

• 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 with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; 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. In 2137 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 - CYRAMZA^® 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 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA^® after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events (ATEs) - Serious, sometimes fatal, ATEs, including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. In 2137 patients with various cancers treated with CYRAMZA^®, the incidence of all Grade ATE was 1-3%. 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, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA^®, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%. In 221 patients with NSCLC receiving CYRAMZA^® in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA^® and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA^® and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.

• 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 (IRR) - including severe and life-threatening IRR, occurred in CYRAMZA^® clinical trials. 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. In 2137 patients with various cancers treated with CYRAMZA^® in which premedication was recommended or required, the incidence of all Grade IRR ranged from <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%).

Posterior Reversible Encephalopathy Syndrome (PRES) - (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients with various cancers treated with CYRAMZA^®. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.

• Permanently discontinue CYRAMZA^® in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome - In 2137 patients with various cancers treated with CYRAMZA^®, the incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%.

• Monitor for proteinuria. 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 - In 2137 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 - CYRAMZA^® can cause fetal harm when administered to pregnant women. 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.

Adverse Reactions

REGARD:

• The most common adverse reactions (all Grades) observed in single agent CYRAMZA^®-treated gastric cancer patients at a rate of ≥5% and ≥2% higher than placebo were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).
• 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%.

RAINBOW:

• The most common adverse reactions (all grades) observed in patients treated with CYRAMZA^® with paclitaxel at a rate of ≥5% and ≥2% higher than placebo with paclitaxel were fatigue/asthenia (57% vs 44%), neutropenia (54% vs 31%), diarrhea (32% vs 23%), epistaxis (31% vs 7%), hypertension (25% vs 6%), peripheral edema (25% vs 14%), stomatitis (20% vs 7%), proteinuria (17% vs 6%), thrombocytopenia (13% vs 6%), hypoalbuminemia (11% vs 5%), and gastrointestinal hemorrhage events (10% vs 6%).
• The most common serious adverse reactions with 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.

REVEL:

• The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA^® with docetaxel at a rate of ≥5% and ≥2% higher than placebo with docetaxel were neutropenia (55% vs 46%), fatigue/asthenia (55% vs 50%), stomatitis/mucosal inflammation (37% vs 19%), epistaxis (19% vs 7%), febrile neutropenia (16% vs 10%), peripheral edema (16% vs 9%), thrombocytopenia (13% vs 5%), lacrimation increased (13% vs 5%), and hypertension (11% vs 5%).
• The most common serious adverse reactions with 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%).

RELAY:

• The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA^® with erlotinib at a rate of ≥5% and ≥2% higher than placebo with erlotinib were infections (81% vs 76%), diarrhea (70% vs 71%), hypertension (45% vs 12%), stomatitis (42% vs 36%), alopecia (34% vs 20%), epistaxis (34% vs 12%), proteinuria (34% vs 8%), peripheral edema (23% vs 4%), headache (15% vs 7%), gastrointestinal hemorrhage (10% vs 3%), gingival bleeding (9% vs 1%), and pulmonary hemorrhage (7% vs 2%).
• The most common serious adverse reactions with CYRAMZA^® with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA^®-treated patients versus 0 patients who received placebo.
• Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA^® with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA^® were proteinuria (8.6%) and hyperbilirubinemia (6%).
• Of the 221 patients who received CYRAMZA^® with erlotinib, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA^® with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%), and weight loss (19% versus 6%).

RAISE:

• The most common adverse reactions (all Grades) observed in patients treated with CYRAMZA^® with FOLFIRI at a rate of ≥5% and ≥2% higher than placebo with FOLFIRI were diarrhea (60% vs 51%), neutropenia (59% vs 46%), decreased appetite (37% vs 27%), epistaxis (33% vs 15%), stomatitis (31% vs 21%), thrombocytopenia (28% vs 14%), hypertension (26% vs 9%), peripheral edema (20% vs 9%), proteinuria (17% vs 5%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%), gastrointestinal hemorrhage events (12% vs 7%), and hypoalbuminemia (6% vs 2%). 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.

REACH-2:

• The most common adverse reactions (all Grades) observed in single agent CYRAMZA^®-treated HCC patients at a rate of ≥10% and ≥2% higher than placebo were fatigue (36% vs 20%), peripheral edema (25% vs 14%), hypertension (25% vs 13%), abdominal pain (25% vs 16%), decreased appetite (23% vs 20%), proteinuria (20% vs 4%), nausea (19% vs 12%), ascites (18% vs 7%), headache (14% vs 5%), epistaxis (14% vs 3%), insomnia (11% vs 6%), pyrexia (10% vs 3%), vomiting (10% vs 7%), and back pain (10% vs 7%).
• 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.

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RB-P HCP ISI 14SEP2022