CYRAMZA patient who wants to stay a step ahead of their cancer

CYRAMZA + erlotinib helped patients with EGFR mut+ mNSCLC reach more than 19 months median PFS¹

Adding CYRAMZA to erlotinib increased median PFS by 7 months — Progression-free survival (PFS) was a major outcome measure of the RELAY trial. The following PFS results for epidermal growth factor receptor gene mutant (EGFR mut+) metastatic non-small cell lung cancer (mNSCLC) patients are presented in a Kaplan-Meier curve. With CYRAMZA plus erlotinib in the intent-to-treat (ITT) population (n equals 224), median PFS was 19.4 months with a 95 percent confidence interval of 15.4 to 21.6 months. With placebo plus erlotinib in the ITT population (n equals 225), median PFS was 12.4 months with a 95 percent confidence interval of 11.0 to 13.5 months. The hazard ratio was 0.59 with a 95 percent confidence interval of 0.46 to 0.76 and a P value less than 0.0001.

The percentage of events at the time of analysis was 55% (122 patients) and 70% (158 patients) in the CYRAMZA + erlotinib and placebo + erlotinib treatment arms, respectively¹
4 of 122 events in CYRAMZA-treated patients and 1 of 158 events in placebo-treated patients were deaths¹
The major efficacy outcome measure was PFS as assessed by the investigator RECIST v1.1¹

28.1% of patients treated with CYRAMZA + erlotinib and 49.3% of those treated with placebo + erlotinib had their disease progress at 1 year²

The RELAY trial evaluated the efficacy and safety of CYRAMZA + erlotinib vs placebo + erlotinib in previously untreated patients with EGFR mut+ mNSCLC. Major outcome measure was PFS. Supportive outcome measures included OS, ORR, and DoR. Patients were stratified by EGFR mutation status (exon 21 vs exon 19), geographic region (East Asia vs other), gender, and local EGFR testing method (therascreen^® and cobas^® vs other PCR and sequencing-based methods). All patients were required to have ECOG PS 0 or 1. Patients were randomized 1:1 to receive CYRAMZA 10 mg/kg (n=224) or placebo (n=225) every 2 weeks + erlotinib 150 mg/day.^1,3

ORR=CR+PR; ORR does not include SD.^3.

For patients on CYRAMZA + erlotinib who had a response, the median DoR was 18.0 months with CYRAMZA + erlotinib vs 11.1 months with placebo + erlotinib^1,3

RELAY ITT DoR graph — Duration of a response (DoR) was a supportive outcome measure of the RELAY trial. The following results are presented.

With CYRAMZA plus erlotinib (n equals 171), median DoR was 18.0 months with a 95 percent confidence interval of 13.9 to 19.8 months. With placebo plus erlotinib (n equals 168), median DoR was 11.1 months with a 95 percent confidence interval of 9.7 to 12.3 months. The unstratified hazard ratio was 0.62 with a 95 percent confidence interval of 0.48 to 0.81.

The percentage of events at the time of analysis was 59% (101 patients) and 76% (128 patients) in the CYRAMZA + erlotinib and placebo + erlotinib treatment arms, respectively³

DoR was a prespecified secondary efficacy endpoint. DoR was not powered or controlled for type 1 error, and treatment differences observed cannot be regarded as statistically significant.

SELECT IMPORTANT SAFETY INFORMATION

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.

Supportive Outcome Measure: Interim OS¹

HR=0.83 [95% CI: 0.53, 1.30]

CYRAMZA + erlotinib [n=224] vs Placebo + erlotinib [n=225]

The interim OS data at the time of data cutoff for the primary analysis were immature^1,3
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 occurred¹
A final OS analysis is planned when ≥300 events have occurred³

Overall response rate (ORR) was a supportive outcome measure of the RELAY trial. The following ORR results for epidermal growth factor receptor gene mutant (EGFR mut+) metastatic non-small cell lung cancer (mNSCLC) patients are presented. With CYRAMZA plus erlotinib in the intent-to-treat (ITT) population (n equals 224), ORR was 76 percent of patients with a 95 percent confidence interval of 71 to 82 percent. With placebo plus erlotinib in the ITT population (n equals 225), ORR was 75 percent with a 95 percent confidence interval of 69 to 80 percent. ORR was a prespecified secondary efficacy endpoint. ORR was not powered or controlled for type 1 error, and treatment differences observed cannot be regarded as statistically significant.
ORR was defined as CR + PR. ORR does not include stable disease³
Disease progression and tumor response were assessed by investigators in accordance with RECIST v1.1³

ORR was a prespecified secondary efficacy endpoint. ORR was not powered or controlled for type 1 error, and treatment differences observed cannot be regarded as statistically significant.

Disease Control (DC)^* was 95% in the CYRAMZA + erlotinib arm and 96% in the placebo + erlotinib arm.³

Prespecified Supportive Outcome Measure: DC^3*

CYRAMZA + erlotinib (n=213/224)
95% (95% CI: 92, 98)
CR=1% (n=3)
PR=75% (n=168)
SD=19% (n=42)

Placebo + erlotinib (n=215/225)
96% (95% CI: 93, 98)
CR=1% (n=2)
PR=74% (n=166)
SD=21% (n=47)

^* DC was defined as CR + PR + SD.

DC was a prespecified secondary efficacy endpoint. This endpoint was not powered or controlled for type 1 error, and treatment differences observed cannot be regarded as statistically significant.

SELECT IMPORTANT SAFETY INFORMATION

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.
In RELAY, median PFS was consistent across the ITT and subgroup populations of exon 21 (L858R) substitution and exon 19 deletion³

The RELAY trial included a prespecified subgroup analysis assessing the progression-free survival (PFS) in patients with exon 21 substitution.

The results were as follows, CYRAMZA plus erlotinib (n equals 99), median PFS was 19.4 months with a 95 percent confidence interval of 14.1 to 21.9 months, and placebo plus erlotinib (n equals 105), median PFS was 11.2 months with a 95 percent confidence interval of 9.6 to 13.8 months. The unstratified hazard ratio was 0.62 with a 95 percent confidence interval of 0.44 to 0.87.
The percentage of events at the time of analysis was 58.6% (58 patients) and 70.5% (74 patients) in the CYRAMZA + erlotinib and placebo + erlotinib treatment arms, respectively³
2 of 58 events in CYRAMZA-treated patients and 1 of 74 events in the placebo-treated patients were deaths⁴

The RELAY trial was not adequately powered or error controlled for subgroup analysis. Treatment differences observed in this subgroup cannot be regarded as statistically significant.

The RELAY trial included a prespecified subgroup analysis assessing the progression-free survival (PFS) in patients with exon 19 deletion.

The results were as follows, CYRAMZA plus erlotinib (n equals 123), median PFS was 19.6 months with a 95 percent confidence interval of 15.1 to 22.2 months, and placebo plus erlotinib (n equals 120), median PFS was 12.5 months with a 95 percent confidence interval of 11.1 to 15.3 months. The unstratified hazard ratio was 0.65 with a 95 percent confidence interval of 0.47 to 0.90.
The percentage of events at the time of analysis was 52.0% (64 patients) and 70.0% (84 patients) in the CYRAMZA + erlotinib and placebo + erlotinib treatment arms, respectively³
2 of 64 events in CYRAMZA-treated patients and 0 of 84 events in the placebo-treated patients were deaths⁴

The RELAY trial was not adequately powered or error controlled for subgroup analysis. Treatment differences observed in this subgroup cannot be regarded as statistically significant.

SELECT IMPORTANT SAFETY INFORMATION

Infusion-Related Reactions (IRR)

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.

Prespecified subgroup analyses of PFS⁵

RELAY Forest Plot prespecified subgroup analyses of PFS table — The RELAY trial included several prespecified patient subgroup analyses of progression-free survival (PFS). The following results are presented in a Forest plot.

Overall, events were reported in 122 of 224 patients in the CYRAMZA plus erlotinib arm, and in 158 of 225 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib arm was favored. The hazard ratio was 0.640 with a 95 percent confidence interval 0.505 to 0.812.

In the male subgroup, events were reported in 43 of 83 patients in the CYRAMZA plus erlotinib arm, and in 64 of 83 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.505 with a 95 percent confidence interval 0.342 to 0.747. In the female subgroup, events were reported in 79 of 141 patients in the CYRAMZA plus erlotinib arm, and in 94 of 142 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.731 with a 95 percent confidence interval 0.541 to 0.988.

In the subgroup of patients who were less than 65 years of age, events were reported in 57 of 102 patients in the CYRAMZA plus erlotinib arm, and in 92 of 114 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.534 with a 95 percent confidence interval 0.382 to 0.745. In the subgroup of patients who were 65 years of age or older, events were reported in 65 of 122 patients in the CYRAMZA plus erlotinib arm, and in 66 of 111 patients in the placebo plus erlotinib arm. The hazard ratio was 0.771 with a 95 percent confidence interval 0.547 to 1.088.

In the subgroup of patients from East Asia, events were reported in 94 of 166 patients in the CYRAMZA plus erlotinib arm, and in 124 of 170 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.636 with a 95 percent confidence interval 0.485 to 0.833 In the subgroup of patients from Other regions, events were reported in 28 of 58 patients in the CYRAMZA plus erlotinib arm, and in 34 of 55 patients in the placebo plus erlotinib arm. The hazard ratio was 0.605 with a 95 percent confidence interval 0.362 to 1.010. East Asia includes South Korea, Hong Kong, Japan, and Taiwan, and Other includes Canada, France, Germany, Italy, Romania, Spain, Turkey, the United States, and the United Kingdom.

In the Asian subgroup, events were reported in 97 of 172 patients in the CYRAMZA plus erlotinib arm, and in 127 of 174 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.638 with a 95 percent confidence interval 0.489 to 0.833. In the Caucasian subgroup, events were reported in 25 of 52 patients in the CYRAMZA plus erlotinib arm, and in 29 of 48 patients in the placebo plus erlotinib arm. The hazard ratio was 0.618 with a 95 percent confidence interval 0.357 to 1.070.

In the subgroup of patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, events were reported in 51 of 116 patients in the CYRAMZA plus erlotinib arm, and in 77 of 119 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.584 with a 95 percent confidence interval 0.409 to 0.833. In the subgroup of patients with an ECOG PS of 1, events were reported in 71 of 108 patients in the CYRAMZA plus erlotinib arm, and in 81 of 106 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.671 with a 95 percent confidence interval 0.487 to 0.925.

In the subgroup of patients who reported as ever having smoked, events were reported in 32 of 64 patients in the CYRAMZA plus erlotinib arm, and in 55 of 73 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.579 with a 95 percent confidence interval 0.373 to 0.899. In the subgroup of patients who reported as never having smoked, events were reported in 74 of 134 patients in the CYRAMZA plus erlotinib arm, and in 91 of 139 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.694 with a 95 percent confidence interval 0.510 to 0.946. In the subgroup of patients whose smoking history was unknown, events were reported in 16 of 26 patients in the CYRAMZA plus erlotinib arm, and in 12 of 13 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.237 with a 95 percent confidence interval 0.099 to 0.565.

In the subgroup with stage IV disease at diagnosis, events were reported in 111 of 195 patients in the CYRAMZA plus erlotinib arm in 135 of 189 patients, and in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.622 with a 95 percent confidence interval 0.483 to 0.801. In the subgroup with other than stage IV disease at diagnosis, events were reported in 11 of 29 patients in the CYRAMZA plus erlotinib arm, and in 21 of 34 patients in the placebo plus erlotinib arm. The hazard ratio was 0.735 with a 95 percent confidence interval 0.351 to 1.540.

In the subgroup with liver metastases at baseline, events were reported in 12 of 21 patients in the CYRAMZA plus erlotinib arm, and in 17 of 24 patients in the placebo plus erlotinib arm. The hazard ratio was 0.480 with a 95 percent confidence interval 0.226 to 1.020. In the subgroup without liver metastases at baseline, events were reported in 110 of 203 patients in the CYRAMZA plus erlotinib arm, and in 141 of 201 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.652 with a 95 percent confidence interval 0.508 to 0.838.

In the subgroup with Exon 21 (L858R) substitution, events were reported in 58 of 99 patients in the CYRAMZA plus erlotinib arm, and in 74 of 105 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.618 with a 95 percent confidence interval 0.437 to 0.874. In the subgroup with Exon 19 deletion, events were reported in 64 of 123 patients in the CYRAMZA plus erlotinib arm, and in 84 of 120 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.651 with a 95 percent confidence interval 0.469 to 0.903.

In the subgroup whose epidermal growth factor receptor (EGFR) mutation status was determined by therascreen^®/cobas^®, events were reported in 46 of 96 patients in the CYRAMZA plus erlotinib arm, and in 74 of 101 patients in the placebo plus erlotinib arm. The CYRAMZA plus erlotinib group was favored. The hazard ratio was 0.397 with a 95 percent confidence interval 0.271 to 0.581 In the subgroup whose EGFR mutation status was determined by a method other than therascreen^®/cobas^®, events were reported in 76 of 128 patients in the CYRAMZA plus erlotinib arm, and in 84 of 124 patients in the placebo plus erlotinib arm. The hazard ratio was 0.837 with a 95 percent confidence interval 0.639 to 1.192. The testing method for 1 patient was missing on the case report form (CRF). Patient was stratified by other PCR and sequencing-based method in interactive web-response system (IWRS). Other trademarks are the property of their respective owners.

^† East Asia includes South Korea, Hong Kong, Japan, and Taiwan, and Other includes Canada, France, Germany, Italy, Romania, Spain, Turkey, the United States, and the United Kingdom.

^‡ Testing method for 1 patient was missing on the CRF. Patient was stratified by other PCR and sequencing-based method in IWRS.

Other trademarks are the property of their respective owners.

These analyses were not adjusted for multiplicity or powered to detect the effect of CYRAMZA + erlotinib within subgroups. Therefore, no conclusions of statistical significance can be drawn.

Consider CYRAMZA + erlotinib for your patients with EGFR mut+ mNSCLC with an exon 21 (L858R) substitution or exon 19 deletion

CI=confidence interval; CR=complete response; CRF=case report form; DoR=duration of response; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; HR=hazard ratio; ITT=intent-to-treat; IWRS=interactive web-response system; mNSCLC=metastatic non-small cell lung cancer; mut+=mutation-positive; ORR=overall response rate; OS=overall survival; PCR=polymerase chain reaction; PFS=progression-free survival; PR=partial response; PS=performance status; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.

References

CYRAMZA (ramucirumab) package insert. Indianapolis, IN: Eli Lilly and Company; 2021.
Data on File, Lilly USA, LLC, DOF-RB-US-0069.
Nakagawa K, Garon EB, Seto T, et al; for 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 [published online October 4, 2019]. Lancet Oncol. doi:10.1016/S1470-2045(19)30634-5.
Data on File, Lilly USA, LLC, DOF-RB-US-0074.
Data on File, Lilly USA, LLC, DOF-RB-US-0071.

IMPORTANT SAFETY INFORMATION

Hemorrhage - CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. 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%.

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.

Please click for full Prescribing Information for CYRAMZA.

RB-P HCP ISI 14SEP2022

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 erlotinib, is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have 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.
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.

CYRAMZA + erlotinib helped patients with EGFR mut+ mNSCLC reach more than 19 months median PFS1

28.1% of patients treated with CYRAMZA + erlotinib and 49.3% of those treated with placebo + erlotinib had their disease progress at 1 year2

For patients on CYRAMZA + erlotinib who had a response, the median DoR was 18.0 months with CYRAMZA + erlotinib vs 11.1 months with placebo + erlotinib1,3

Disease Control (DC)* was 95% in the CYRAMZA + erlotinib arm and 96% in the placebo + erlotinib arm.3

IMPORTANT SAFETY INFORMATION

Hemorrhage - CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade ≥3 hemorrhagic events. 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%.

Adverse Reactions

INDICATIONS

CYRAMZA + erlotinib helped patients with EGFR mut+ mNSCLC reach more than 19 months median PFS¹

28.1% of patients treated with CYRAMZA + erlotinib and 49.3% of those treated with placebo + erlotinib had their disease progress at 1 year²

For patients on CYRAMZA + erlotinib who had a response, the median DoR was 18.0 months with CYRAMZA + erlotinib vs 11.1 months with placebo + erlotinib^1,3

Disease Control (DC)^* was 95% in the CYRAMZA + erlotinib arm and 96% in the placebo + erlotinib arm.³