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Clinical trial efficacy: REACH‑2

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.

SELECT IMPORTANT SAFETY INFORMATION

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.

CYRAMZA® (ramucirumab) significantly reduced the risk of death1

REACH‑2 OS: Median—Months (95% CI)1

Major outcome measure
  • The percentage of deaths at the time of analysis was 75% (147 patients) and 78% (74 patients) in the CYRAMZA and placebo treatment arms, respectively1

REACH-2 CYRAMZA OS analysis based on prespecified patient subgroups3

  • This was a prespecified exploratory analysis of the major outcome measure. The analysis was not adjusted for multiplicity or powered to detect the effect of CYRAMZA between subgroups. Therefore, no conclusions of statistical or clinical significance can be drawn.3

REACH Trial Outcomes

Median OS, the major efficacy outcome measure for the ITT population in the REACH trial, did not meet statistical significance.9

9.2 months with CYRAMZA + BSC (n=283; 95% CI: 8.1, 10.6) vs 7.6 months with placebo + BSC (n=282; 95% CI: 6.0, 9.3); HR=0.87 (95% CI: 0.72, 1.05)9

  • The percentage of deaths at the time of analysis was 77.0% (218 patients) and 79.4% (224 patients) in the CYRAMZA and placebo treatment arms, respectively12

The analyses for the AFP subgroups (≥400 ng/mL and <400 ng/mL) were prespecified and exploratory without controlling for type 1 error. Observations made from these analyses cannot be considered statistically significant.

Median OS in the prespecified subgroup of patients with AFP ≥400 ng/mL showed an improvement in OS9: 7.8 months with CYRAMZA + BSC (n=119; 95% CI: 5.8, 9.3) vs 4.2 months with placebo + BSC (n=131; 95% CI: 3.7, 4.8); HR=0.67 (95% CI: 0.51, 0.90)9

  • The percentage of deaths at the time of analysis was 83.2% (99 patients) and 88.5 % (116 patients) in the CYRAMZA and placebo treatment arms, respectively12

Median OS in the prespecified subgroup of patients with AFP <400 ng/mL showed no improvement in OS9: 10.1 months with CYRAMZA + BSC (n=160; 95% CI: 8.7, 12.3) vs placebo + BSC (n=150; 95% CI: 9.9, 13.1); HR=1.09 (95% CI: 0.84, 1.43)9

  • The percentage of deaths at the time of analysis was 72.5% (116 patients) and 72% (108 patients) in the CYRAMZA and placebo treatment arms, respectively12

More than 500 AFP-High patients were studied in the REACH Program, adding to the body of evidence in these difficult-to-treat patients.1,5,9

TODO

The REACH Program pooled analysis was prespecified and exploratory without controlling for type 1 error. Observations made from this analysis cannot be considered statistically significant.

OS in the pooled analysis of AFP-High patients was consistent with results from REACH-2

REACH Program Pooled OS: Median-Months (95% CI)10

REACH-2 Major Outcome Measure: Median OS with CYRAMZA (n=197) was 8.5 months (95% CI: 7.0, 10.6) vs 7.3 months (95% CI: 5.4, 9.1) with placebo (n=95) (HR=0.71 [95% CI: 0.53, 0.95];P=0.0201

CYRAMZA significantly reduced the risk of disease progression or death1

REACH‑2 PFS: Median—Months (95% CI)1,4

Supportive outcome measure
  • The percentage of events at the time of analysis was 87% (172 patients) and 91% (86 patients) in the CYRAMZA and placebo treatment arms, respectively1
  • 26 of 172 events in CYRAMZA-treated patients and 9 of 86 events in placebo-treated patients were deaths1

REACH‑2 ORR: Percentage of Patients (95% CI)

Disease control rate

SELECT IMPORTANT SAFETY INFORMATION

The labeling for CYRAMZA contains warnings and precautions for hemorrhage and GI hemorrhage, including severe and sometimes fatal events; gastrointestinal (GI) perforations, a potentially fatal event; impaired wound healing; arterial thromboembolic events (ATEs), including serious and sometimes fatal events; hypertension; infusion-related reactions (IRR), including severe and sometimes fatal events; worsening of pre-existing hepatic impairment; posterior reversible encephalopathy syndrome (PRES), including fatal events; proteinuria including nephrotic syndrome; thyroid dysfunction; and embryo-fetal toxicity. CYRAMZA should be permanently discontinued in patients who experience severe bleeding, a GI perforation, an ATE, uncontrolled hypertension, severe IRR, PRES, or urine protein >3 grams/24 h or nephrotic syndrome.

The most common adverse reactions (all Grades) observed in single agent CYRAMZA-treated HCC patients at a rate of ≥15% 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%). The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%).

REACH Trial Design

The phase III REACH trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with advanced HCC after prior sorafenib therapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures included PFS and ORR. The ITT population of patients was ECOG PS 0 or 1, with BCLC stage B (and no longer amenable to locoregional therapy) or C disease, and Child-Pugh A liver disease. Patients were stratified by geographic region and etiology of liver disease. Patient subgroup analysis was prespecified by baseline serum level of AFP ≥400 ng/mL. Patients were randomized 1:1 to CYRAMZA 8 mg/kg + BSC (n=283) or placebo + BSC (n=282) every 2 weeks (on days 1 and 15) of each 28-day cycle until disease progression, unacceptable toxicity, or death.9

The Major Outcome Measure for the ITT population within the REACH trial did not meet statistical significance.9


REACH‑2 Trial Design

The phase III REACH‑2 trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with advanced HCC after prior sorafenib therapy and high baseline serum AFP levels ≥400 ng/mL.1 Major efficacy outcome measure was OS. Supportive efficacy outcome measures included PFS and ORR. All patients were ECOG PS 0 or 1, with BCLC stage B (and no longer amenable to locoregional therapy) or C disease, and Child-Pugh A liver disease. Patients were stratified by geographic region, macrovascular invasion, and ECOG PS. Patients were randomized 2:1 to CYRAMZA 8 mg/kg + BSC (n=197) or placebo + BSC (n=95) every 2 weeks (on days 1 and 15) of each 28-day cycle.1,5,6

For your patients with AFP ≥400 ng/mL: CYRAMZA1

The first and only biomarker-driven therapy approved for AFP-High patients with advanced HCC1,5,7

National Comprehensive Cancer Network® (NCCN®)

Ramucirumab

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

*Patients who have unresectable disease and are not transplant candidates; are inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only; have metastatic disease or extensive liver tumor burden.8

The Category 1 recommendation is based on data reflecting use on or after sorafenib.8

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.

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See the adverse reactions profile of CYRAMZA

AFP=alpha-fetoprotein; BCLC=Barcelona Clinic Liver Cancer; BSC=best supportive care; CI=confidence interval; CR=complete response; DCR=disease control rate; ECOG=Eastern Cooperative Oncology Group; HCC=hepatocellular carcinoma; HR=hazard ratio; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PR=partial response; PS=performance status; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.

References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 2. Data on File, Lilly USA, LLC, DOF-RB-US-0050. 3. Data on File, Lilly USA, LLC, DOF-RB-US-0067. 4. Data on File, Lilly USA, LLC, DOF-RB-US-0066. 5. Zhu AX, Kang Y-K, Yen C-J, et al; for REACH‑2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH‑2): a randomised, double-blind, placebo-controlled, phase 3 trial [published online January 18, 2019]. Lancet Oncol. doi:10.1016/S1470-2045(18)30937-9. 6. Zhu AX, Kang Y-K, Yen C-J, et al. REACH‑2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as secondline treatment in patients with advanced hepatocellular carcinoma and elevated baseline alpha-fetoprotein following first-line sorafenib. J Clin Oncol. 2018; 36(suppl; abstr 4003). 7. Llovet JM, Montal R, Sia D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599-616. 8. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V.4.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed June 19, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 9. Zhu AX, Park JO, Ryoo B-Y, et al; REACH Trial Investigators. Ramucirumab versus placebo as second line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859-870. 10. Data on File, Lilly USA, LLC, DOF-RB-US-0052. 11. Zhu AX, Finn RS, Galle PR, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: pooled efficacy and safety across two global randomized phase 3 studies (REACH-2 and REACH). Poster presented at: ESMO 20th World Congress on Gastrointestinal Cancer; June 20-23, 2018; Barcelona, Spain. 12. Zhu AX et al. J Clin Oncol. 33, 2015 (suppl 3; abstr 232).

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 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.
Important Safety Information for Cyramza® (ramucirumab)
Warnings and Precautions

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)

  • 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)

  • 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 29MAY2020