1.1 Gastric Cancer

CYRAMZA®, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

1.2 Non-Small Cell Lung Cancer

CYRAMZA, in combination with erlotinib, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

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.

1.3 Colorectal Cancer

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.

1.4 Hepatocellular Carcinoma

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.

2.1 Premedication

• Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride) [see Warnings and Precautions (5.6)].
• For patients who have experienced a Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each CYRAMZA infusion [see Dosage and Administration (2.6)].

2.2 Recommended Dosage for Gastric Cancer

• The recommended dosage of CYRAMZA, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
• When given in combination with paclitaxel, administer CYRAMZA prior to administration of paclitaxel.
• Refer to the prescribing information for paclitaxel for dosage information.

2.3 Recommended Dosage for Non-Small Cell Lung Cancer

EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations – CYRAMZA in Combination with Erlotinib

• The recommended dosage of CYRAMZA is 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
• Refer to the prescribing information for erlotinib for dosage information.

Disease Progression On Or After Platinum-based Chemotherapy – CYRAMZA in Combination with Docetaxel

• The recommended dosage of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
• Refer to the prescribing information for docetaxel for dosage information.

2.4 Recommended Dosage for Colorectal Cancer

• The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.
• Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information.

2.5 Recommended Dosage for Hepatocellular Carcinoma

• The recommended dosage of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent CYRAMZA infusions may be administered over 30 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity.

2.6 Dosage Modifications for Adverse Reactions

Reduce dose, withhold dose, or discontinue CYRAMZA to manage adverse reactions as described in Table 1.

2.7 Preparation and Administration

5.1 Hemorrhage

CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5% [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.6)].

5.2 Gastrointestinal Perforations

CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2% [see Adverse Reactions (6.1)].

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation [see Dosage and Administration (2.6)].

5.3 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 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 [see Dosage and Administration (2.6)].

5.4 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 six clinical studies 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% [see Adverse Reactions (6.1)].

Permanently discontinue CYRAMZA in patients who experience an ATE [see Dosage and Administration (2.6)].

5.5 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% [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.6)].

5.6 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 six clinical studies 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% [see Adverse Reactions (6.1)].

Premedicate prior to each CYRAMZA infusion [see Dosage and Administration (2.1)]. 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 [see Dosage and Administration (2.6)].

5.7 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%) [see Adverse Reactions (6.1)].

5.8 Posterior Reversible Encephalopathy Syndrome

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

Confirm the diagnosis of PRES with magnetic resonance imaging and 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 [see Dosage and Administration (2.6)].

5.9 Proteinuria Including Nephrotic Syndrome

Across six clinical studies 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% [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.6)].

5.10 Thyroid Dysfunction

Across six clinical studies 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 [see Adverse Reactions (6.1)]. Monitor thyroid function during treatment with CYRAMZA.

5.11 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 [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section reflect exposure to CYRAMZA in 2137 patients from six studies: REGARD, RAINBOW, RAISE, REVEL, REACH-2, and RELAY.

6.2 Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CYRAMZA. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and lymphatic system: Thrombotic microangiopathy
• Neoplasms benign, malignant and unspecified: Hemangioma
• Respiratory, thoracic, and mediastinal: Dysphonia
• Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 563 CYRAMZA-treated patients in REGARD and RAINBOW, 205 (36%) were 65 and over, while 41 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 221 patients who received CYRAMZA with erlotinib in RELAY, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Overall, no clinically meaningful differences in effectiveness were observed between these patients and younger patients. 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%).

Of the 1253 patients in REVEL, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA with docetaxel in REVEL, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of REVEL, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years and over was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received CYRAMZA with FOLFIRI in RAISE, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 197 patients who received CYRAMZA in REACH-2, 95 (48%) were 65 years and over, while 37 (19%) were 75 years and over. Overall, no differences in efficacy were observed between these subjects and younger subjects.

8.6 Hepatic Impairment

No dose adjustment is recommended for patients with mild (total bilirubin within ULN and aspartate aminotransferase [AST] >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single agent CYRAMZA [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

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 inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.

12.3 Pharmacokinetics

The pharmacokinetics (PK) of ramucirumab were studied in patients with various cancers over a dose range of 6-12 mg/kg administered every two or three weeks. The PK characteristics of ramucirumab are similar for patients across cancer types based on a population PK analysis. Ramucirumab systemic exposure increased dose proportionally at doses of 8 mg/kg and above and steady state concentrations were achieved at approximately 12 weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity.

Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.

13.2 Animal Toxicology and/or Pharmacology

Adverse effects in the kidney (glomerulonephritis) occurred in monkeys at doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent).

A single dose of ramucirumab resulting in an exposure approximately 10 times the human exposure at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.

14.1 Gastric Cancer

REGARD

The efficacy of CYRAMZA was evaluated in REGARD (NCT00917384), a multinational, randomized, double-blind, multicenter study in patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the GEJ) who previously received platinum- or fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients were randomized (2:1) to receive either an intravenous infusion of CYRAMZA 8 mg/kg or placebo every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ). The major efficacy outcome measure was overall survival (OS). An additional efficacy outcome measure was progression-free survival (PFS).

A total of 355 patients were randomized, 238 to the CYRAMZA-treatment group and 117 to the placebo-treatment group. Baseline demographic and disease characteristics were similar between treatment arms. The median age was 60 years (range 24-87); 70% were men; 77% were White, 16% Asian; 28% had ECOG PS 0 and 72% had ECOG PS 1; 91% had measurable disease; 75% had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). Patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo.

Efficacy results are shown in Table 10 and Figure 1.

Table 10: Efficacy Results in REGARD

Abbreviations: BSC = best supportive care; CI = confidence interval
a 65 of 199 events in CYRAMZA-treated patients and 31 of 108 events in placebo-treated patients were deaths.
	CYRAMZA + BSC N=238	Placebo + BSC N=117
Overall Survival
Number of deaths (%)	179 (75%)	99 (85%)
Median – months (95% CI)	5.2 (4.4, 5.7)	3.8 (2.8, 4.7)
Hazard Ratio (95% CI)	0.78 (0.60, 0.998)
Stratified Log-rank p-value	0.047
Progression-free Survival
Number of events (%)a	199 (84%)	108 (92%)
Median – months (95% CI)	2.1 (1.5, 2.7)	1.3 (1.3, 1.4)
Hazard Ratio (95% CI)	0.48 (0.38, 0.62)
Stratified Log-rank p-value	<0.001

Figure 1: Kaplan-Meier Curves for Overall Survival in REGARD

RAINBOW

The efficacy of CYRAMZA was evaluated in RAINBOW (NCT01170663), a multinational, randomized, double-blind study in patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the GEJ) who previously received platinum- and fluoropyrimidine-containing chemotherapy. 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. Patients were randomized (1:1) to receive either CYRAMZA 8 mg/kg or placebo as an intravenous infusion every 2 weeks (on Days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 by intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. Prior to administration of each dose of paclitaxel, patients were required to have adequate hematopoietic and hepatic function. The paclitaxel dose was permanently reduced, in increments of 10 mg/m2, for a maximum of two dose reductions for Grade 4 hematologic toxicity or Grade 3 paclitaxel-related non-hematologic toxicity. Randomization was stratified by geographic region, time to progression from the start of first-line therapy (<6 months versus ≥6 months), and disease measurability. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and overall response rate (ORR).

A total of 665 patients were randomized, 330 to the CYRAMZA-treatment group and 335 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 61 years (range: 24-84); 71% were men; 61% were White, 35% Asian; 39% had ECOG PS 0 and 61% had ECOG PS 1; 78% had measurable disease; 79% had gastric cancer; and 21% had adenocarcinoma of the GEJ. Two-thirds of the patients experienced disease progression while on first-line therapy (67%) and 25% of patients received an anthracycline in combination with platinum/fluoropyrimidine combination therapy.

Efficacy results are shown in Table 11 and Figure 2.

Table 11: Efficacy Results in RAINBOW

Abbreviations: CI = confidence interval, CMH = Cochran-Mantel-Haenszel
a 56 of 279 events in CYRAMZA-treated patients and 55 of 296 events in placebo-treated patients were deaths.
b 2 complete responses in CYRAMZA-treated patients and 1 complete response in placebo-treated patients.
	CYRAMZA + Paclitaxel N=330	Placebo + Paclitaxel N=335
Overall Survival
Number of deaths (%)	256 (78%)	260 (78%)
Median – months (95% CI)	9.6 (8.5, 10.8)	7.4 (6.3, 8.4)
Hazard Ratio (95% CI)	0.81 (0.68, 0.96)
Stratified Log-rank p-value	0.017
Progression-free Survival
Number of events (%)a	279 (85%)	296 (88%)
Median – months (95% CI)	4.4 (4.2, 5.3)	2.9 (2.8, 3.0)
Hazard Ratio (95% CI)	0.64 (0.54, 0.75)
Stratified Log-rank p-value	<0.001
Overall Response Rateb
Rate – percent (95% CI)	28% (23, 33)	16% (13, 20)
Stratified CMH p-value	<0.001

Figure 2: Kaplan-Meier Curves for Overall Survival in RAINBOW

14.2 Non-Small Cell Lung Cancer

RELAY

The efficacy of CYRAMZA in combination with erlotinib was evaluated in RELAY (NCT02411448), a multinational, randomized, double-blind, placebo-controlled, multicenter study in patients with previously untreated metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations. Patients in RELAY were required to have measurable disease, ECOG PS of 0 or 1, no central nervous system (CNS) metastases, and no known EGFR T790M mutations at baseline. Patients were randomized (1:1) to receive either CYRAMZA 10 mg/kg or placebo every 2 weeks as an intravenous infusion, in combination with erlotinib 150 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by geographic region (East Asia versus other), gender, EGFR mutation (exon 19 deletion versus exon 21 [L858R] substitution mutation), and local EGFR testing method (therascreen® and cobas® versus other polymerase chain reaction [PCR] and sequencing-based methods). The major efficacy outcome measure was PFS as assessed by the investigator (RECIST v1.1). Additional efficacy outcome measures included OS, ORR, and duration of response (DoR).

A total of 449 patients were randomized, 224 to the CYRAMZA-treatment group and 225 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 65 years (range 23-89); 63% of patients were female; 77% were Asian and 22% were White; 52% had ECOG PS 0; 61% were never smokers; 54% had exon 19 mutation deletions, and 45% had exon 21 (L858R) substitution mutations.

Efficacy results are shown in Table 12 and Figure 3.

Table 12: Efficacy Results in RELAY

Abbreviations: ITT = Intent-to-treat patients, CI = confidence interval, NR = not reached
a 4 of 122 events in CYRAMZA-treated patients and 1 of 158 events in placebo-treated patients were deaths.
	CYRAMZA + Erlotinib N=224	Placebo + Erlotinib N=225
Progression-free Survival
Number of events (%)a	122 (55%)	158 (70%)
Median – months (95% CI)	19.4 (15.4, 21.6)	12.4 (11.0, 13.5)
Hazard Ratio (95% CI)	0.59 (0.46, 0.76)
Stratified Log-rank p-value	<0.0001

Figure 3: Kaplan-Meier Curves for Progression-Free Survival by Investigator Assessment in RELAY

PFS assessment based on a blinded independent radiologic review was similar to the investigator assessment. The treatment effect for PFS was consistent across pre-specified stratification factors. The ORR was 76% (95% CI: 71, 82) in the CYRAMZA in combination with erlotinib arm and 75% (95% CI: 69, 80) in the placebo in combination with erlotinib arm, with median DoR 18.0 months (95% CI: 13.9, 19.8) and 11.1 months (95% CI: 9.7, 12.3), in each arm respectively.

At the time of the final analysis of PFS, OS data were not mature as only 26% of planned events for the final analysis had occurred (HR=0.83, 95% CI: 0.53, 1.30).

REVEL

The efficacy of CYRAMZA was evaluated in REVEL (NCT01168973), a multinational, randomized, double-blind study in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients in REVEL were also required to have ECOG PS 0 or 1. Patients were randomized (1:1) to receive either CYRAMZA at 10 mg/kg or placebo by intravenous infusion, in combination with docetaxel at 75 mg/m2, every 21 days. Sites in East Asia administered a reduced dose of docetaxel at 60 mg/m2 every 21 days. Patients who discontinued combination therapy because of an adverse reaction attributed to either CYRAMZA/placebo or docetaxel were permitted to continue monotherapy with the other treatment component until disease progression or intolerable toxicity. Randomization was stratified by geographic region, sex, prior maintenance therapy, and ECOG PS. The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS and ORR.

A total of 1253 patients were randomized, 628 to the CYRAMZA-treatment group and 625 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 62 years (range 21-86); 67% were men; 82% were White and 13% were Asian; 32% had ECOG PS 0; 73% had nonsquamous histology and 26% had squamous histology. In addition to platinum chemotherapy (99%), the most common prior therapies were pemetrexed (38%), gemcitabine (25%), taxane (24%), and bevacizumab (14%). Twenty-two percent of patients received prior maintenance therapy. Tumor EGFR status was unknown for the majority of patients (65%). Where tumor EGFR status was known (n=445), 7.4% were positive for EGFR mutation (n=33). No data were collected regarding tumor ALK rearrangement status.

Overall response rate (complete response + partial response) was 23% (95% CI: 20, 26) for CYRAMZA with docetaxel and 14% (95% CI: 11, 17) for placebo with docetaxel, p-value of <0.001. Efficacy results are shown in Table 13 and Figure 4.

Table 13: Efficacy Results in REVEL

Abbreviations: CI = confidence interval
a 126 of 558 events in CYRAMZA-treated patients and 109 of 583 events in placebo-treated patients were deaths.
	CYRAMZA + Docetaxel N=628	Placebo + Docetaxel N=625
Overall Survival
Number of deaths (%)	428 (68%)	456 (73%)
Median – months (95% CI)	10.5 (9.5, 11.2)	9.1 (8.4, 10.0)
Hazard Ratio (95% CI)	0.86 (0.75, 0.98)
Stratified Log-rank p-value	0.024
Progression-free Survival
Number of events (%)a	558 (89%)	583 (93%)
Median – months (95% CI)	4.5 (4.2, 5.4)	3.0 (2.8, 3.9)
Hazard Ratio (95% CI)	0.76 (0.68, 0.86)
Stratified Log-rank p-value	<0.001

Figure 4: Kaplan-Meier Curves for Overall Survival in REVEL

14.3 Colorectal Cancer

The efficacy of CYRAMZA was evaluated in RAISE (NCT01183780), a multinational, randomized, double-blind study in patients with mCRC, who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients in RAISE were required to have ECOG PS 0 or 1 and to have disease progression within 6 months of the last dose of first-line therapy. Patients were randomized (1:1) to receive either CYRAMZA at 8 mg/kg as an intravenous infusion or placebo, in combination with FOLFIRI: irinotecan 180 mg/m2 administered intravenously over 90 minutes and folinic acid 400 mg/m2 administered intravenously simultaneously over 120 minutes; followed by fluorouracil 400 mg/m2 intravenous bolus over 2 to 4 minutes; followed by fluorouracil 2400 mg/m2 administered intravenously by continuous infusion over 46 to 48 hours. Treatment cycles on both arms were repeated every 2 weeks. Patients who discontinued one or more components of treatment because of an adverse reaction were permitted to continue therapy with the other treatment component(s) until disease progression or unacceptable toxicity. Randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment (<6 months versus ≥6 months). The major efficacy outcome measure was OS. An additional efficacy outcome measure was PFS.

A total of 1072 patients were randomized, 536 to the CYRAMZA-treatment group and 536 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between treatment arms. The median age was 62 years (range 21-87); 57% were men; 76% were White and 20% were Asian; 49% had ECOG PS 0; 49% had KRAS mutant tumors; and 24% had <6 months from time to disease progression after beginning first-line treatment. The treatment effect was consistent across the pre-specified stratification factors.

Efficacy results are shown in Table 14 and Figure 5.

Figure 5: Kaplan-Meier Curves for Overall Survival in RAISE

14.4 Hepatocellular Carcinoma

The efficacy of CYRAMZA was evaluated in REACH-2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in patients with advanced HCC with AFP ≥400 ng/mL who had disease progression on or after prior sorafenib therapy or who were intolerant to sorafenib. Patients in REACH-2 were required to have ECOG PS of 0 or 1, Child-Pugh A, BCLC stage B and no longer amenable to locoregional therapy, or BCLC stage C. Patients were randomized (2:1) to receive CYRAMZA 8 mg/kg or placebo every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Randomization was stratified by geographic region, macrovascular invasion (yes versus no), and ECOG PS (0 versus 1). The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS and ORR based on investigator assessment.

A total of 292 patients were randomized, 197 to the CYRAMZA-treatment group and 95 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between the arms. The median age was 64 years (range 26-88); 80% were men; 50% were Asian; 58% had ECOG PS 0; 35% had macrovascular invasion; 72% had extrahepatic spread; 17% were sorafenib intolerant, 37% had hepatitis B, 26% had hepatitis C, 24% had significant prior alcohol use, and 64% had prior locoregional therapy.

Efficacy results are shown in Table 15 and Figure 6.

Figure 6: Kaplan-Meier Curves for Overall Survival in REACH-2

Hemorrhage

Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness [see Warnings and Precautions (5.1)].

Gastrointestinal Perforations

Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain [see Warnings and Precautions (5.2)].

Impaired Wound Healing

Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider [see Warnings and Precautions (5.3)].

Arterial Thromboembolic Events

Advise patients of an increased risk of an arterial thromboembolic event [see Warnings and Precautions (5.4)].

Hypertension

Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.5)].

Posterior Reversible Encephalopathy Syndrome

Advise patients to inform their health care provider if they develop neurological symptoms consistent with PRES (seizure, headache, nausea/vomiting, blindness, or altered consciousness) [see Warnings and Precautions (5.8)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their health care provider of a known or suspected pregnancy and to use effective contraception during CYRAMZA treatment and for 3 months after the last dose [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during CYRAMZA treatment and for 2 months after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that CYRAMZA may impair fertility [see Use in Specific Populations (8.3)].

Eli Lilly and Company, Indianapolis, IN 46285, USA

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Copyright © 2014, 2020, Eli Lilly and Company. All rights reserved.

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