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A CONTINUUM OF CARE

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Clinical Case Presentations

The Importance of Delaying Progression to Gain Control Thumb
Raise Trial

RAISE trial Design

PEER VIDEOS

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DAVID ROSS CAMIDGE, MD, PhD, PRESENTS A CHALLENGING CLINICAL CASE OF AGGRESSIVE mNSCLC

REVIEW FULL CLINICAL PRESENTATION:

51-YEAR-OLD FEMALE WITH STAGE IV ADENOCARCINOMA OF THE LUNG WITH AGGRESSIVE DISEASE*†

David Ross Camidge, MD, PhD
Director of Thoracic Oncology,
University of Colorado Cancer Center

Why adding CYRAMZA may be appropriate for this patient:

  • She has a good performance status, with an ECOG PS of 1
  • This young woman wants to delay tumor growth and is willing to do what is necessary to actively treat her aggressive disease
  • She understands the risks associated with therapy, but she has had disease progression on initial platinum-based chemotherapy and is determined to continue treatment
  • There are no contraindications for antiangiogenic therapy

Patient Information

History of Present Illness:

  • A 51-year-old Caucasian female presents with a painless lump in her left deltoid and no other signs or symptoms
  • X-ray reveals a 5-cm soft tissue mass
  • Biopsy reveals a TTF-1 positive adenocarcinoma with a G12C KRAS mutation
  • Staging investigations (CT chest/abdomen/pelvis and MRI brain) reveal the intra-muscular mass in the left deltoid, together with subcutaneous deposits in the back and thigh, a 5-cm right lower lobe spiculated mass, bilateral bulky mediastinal lymphadenopathy and a 4-cm right adrenal mass (T2aN3M1b)
  • PD-L1 staining using the 22C3 antibody reveals a proportion score of 0%

Past Medical History:

  • Ex-smoker (10 pack years, quit 10 years previously)
  • No significant past medical history
  • Taking no medications

Social History:

  • She is a single mother and has a supportive friend who comes with her to most appointments
  • She supports her 2 children (aged 8 and 12, two boys)
  • She owns a small cleaning service

Treatment

Initial Treatment:

  • She commences platinum-based treatment with pemetrexed but has clinical progression (enlarging deltoid lesion) soon after completing the second cycle
  • Repeat imaging confirms widespread progression with new and enlarging lesions, including a significant increase in her soft tissue and lymph node disease, collapse of her right lower lobe, and new liver lesions
  • Her deltoid mass receives additional treatment resulting in improved pain control, but still requiring opiates

Physical Exam/Review of Both Symptoms and Labs at Progression:

  • Despite her symptoms she still has good performance status (ECOG PS 1)
  • Tumor was PD-L1 negative by immunohistochemistry (TPS <1%)
  • Patient has a persistent but largely stable left deltoid mass and is taking an opioid to control her pain
  • She has some sense of pressure behind her sternum and some of her subcutaneous deposits are becoming painful

Response Assessment/Follow-Up Imaging:

  • Imaging shows 4 lesions within the liver, the largest at 1.5 cm, a 5.5-cm right adrenal mass, a 4.5-cm right lower lobe mass with surrounding lobar collapse and bilateral mediastinal lymph nodes, the largest with a short axis of 2.5 cm
  • Subcutaneous nodules are now present in 4 separate places, the largest at 9 mm
  • The deltoid mass has had minor shrinkage and is 3.5 cm
  • Her CEA (elevated at baseline) has doubled during her time on chemotherapy

Patient Attitude/Characteristics:

  • Her goal is to live as long as possible for her children and she is determined to do whatever she can to actively treat her cancer
  • She is concerned with regard to her disease, which is progressing after only two cycles, and the fact that she can feel and see several deposits under her skin and feel the sense of pressure in her chest
  • She feels it critical that the next treatment helps her cancer shrink and does something to slow her progression, and ultimately help her live longer

Why CYRAMZA

Treatment Plan:

  • Biomarker-driven therapies (including anti-PD-L1) were considered
  • After reviewing her treatment options, ramucirumab 10 mg/kg and docetaxel 75 mg/m2 IV every three weeks were commenced

Why adding CYRAMZA may be appropriate for this patient:

  • She has a good performance status, with an ECOG PS of 1
  • This young woman wants to delay tumor growth and is willing to do what is necessary to actively treat her aggressive disease
  • She understands the risks associated with therapy, but she has had disease progression on initial platinum-based chemotherapy and is determined to continue treatment
  • There are no contraindications for antiangiogenic therapy

Clinical Case Presentation By:
David Ross Camidge, MD, PhD
Professor, Division of Medical Oncology,
Joyce Zeff Chair in Lung Cancer Research,
Director of Thoracic Oncology,
University of Colorado Cancer Center

REVEL Trial Design (N=1253)1

The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was overall survival (OS). Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 to receive either CYRAMZA 10 mg/kg (n=628) or placebo (n=625), in combination with docetaxel at 75 mg/m2 every 21 days.

ITT Population

Primary measure—OS: Median OS with CYRAMZA plus docetaxel was 10.5 months (95% CI: 9.5, 11.2) vs 9.1 months (95% CI: 8.4, 10.0) with placebo plus docetaxel (hazard ratio 0.86 [95% CI: 0.75, 0.98]; P=0.024).1

Supportive measure—PFS: Median PFS§ with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001).11

Supportive measure—ORR: ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001).1

REVEL Exploratory Analyses2,3

The REVEL trial was not powered for subgroup analyses, nor were any such analyses error-controlled. The primary platinum-refractory population (n=360/N=1253) was a pre-specified subgroup in the REVEL trial; however, the subgroup of patients with limited time on initial platinum-based therapy (8 or 12 weeks; n=200/N=1253 and n=448/N=1253, respectively) was not pre-specified. Each subgroup analysis presented was exploratory. Kaplan-Meier estimates and Cox regression analyses of OS and PFS were performed for all subgroups. The Cochran-Mantel-Haenszel test assessed differences in ORR between treatment groups. Safety analyses were performed on both subsets of patients from the safety population, defined as all patients who had received at least one dose of study drug.

Aggressive Disease Subgroup

OS: Median OS with CYRAMZA plus docetaxel was 8.3 months (95% CI: 6.6, 9.8) vs 6.3 months (95% CI: 5.1, 8.0) with placebo plus docetaxel (unstratified HR 0.86 [95% CI: 0.68, 1.08]).3

PFS: Median PFS# with CYRAMZA plus docetaxel was 4.0 months (95% CI: 2.9, 4.4) vs 2.5 months (95% CI: 1.6, 2.8) with placebo plus docetaxel (unstratified HR 0.71 [95% CI: 0.57, 0.88]).3

ORR: ORR with CYRAMZA plus docetaxel was 23% (95% CI: 17, 29) vs 13% (95% CI: 8, 18) with placebo plus docetaxel.3

This is a hypothetical patient case based on the author’s clinical experience with CYRAMZA in combination with docetaxel for mNSCLC.

*This clinical case presentation has been sponsored by Eli Lilly and Company.

Aggressive disease is defined by those patients who were primary refractory to platinum-based therapy or who experienced limited time on initial platinum-based therapy (8 or 12 weeks).3

The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively.1

§The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively.1

Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.4

ORR=complete + partial response; does not include stable disease.

The percentage of deaths at the time of analysis in the CYRAMZA plus docetaxel arm was 75% (134 patients) and 77% (141 patients) in the placebo plus docetaxel arm.3

#The percentage of events at the time of analysis in the CYRAMZA plus docetaxel arm was 88% (156 patients) and 92% (168 patients) in the placebo plus docetaxel arm.3

CEA=carcinoembryonic antigen; CT=computerized tomography; ECOG=Eastern Cooperative Oncology Group; KRAS=Kirsten rat sarcoma viral oncogene homolog; mNSCLC=metastaHtic non-small cell lung cancer; MRI=magnetic resonance imaging; PD-L1=programmed death-ligand 1; PS=performance status; TPS=tumor proportion score; TTF-1=thyroid transcription factor 1.

SELECT IMPORTANT SAFETY INFORMATION

  • The labeling for CYRAMZA contains a Boxed Warning for: hemorrhage, including severe and sometimes fatal events; gastrointestinal (GI) perforation, a potentially fatal event; and impaired wound healing. CYRAMZA should be permanently discontinued in patients who experience severe bleeding or a GI perforation. CYRAMZA should be withheld prior to surgery and discontinued if a patient develops wound healing complications. CYRAMZA contains additional Warnings and Precautions for arterial thromboembolic events, which are sometimes fatal; hypertension; infusion-related reactions; clinical deterioration in patients with Child-Pugh B or C cirrhosis; reversible posterior leukoencephalopathy syndrome; proteinuria including nephrotic syndrome; thyroid dysfunction; and embryofetal toxicity. The most commonly reported adverse reactions (all grades; grade 3/4) occurring in 5% of patients receiving CYRAMZA plus docetaxel and 2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%). The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017. 2. Data on file. Eli Lilly and Company.ONC20170210a. 3. Reck M, Paz-Ares L, Bidoli P, et al. Exploratory subgroup analysis of patients refractory to first-line chemotherapy from REVEL, a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Poster presented at: Annual Meeting of American Society of Clinical Oncology; June 3-7, 2016; Chicago, IL. Abstract 9079. 4. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

CYRAMZA® (ramucirumab), 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.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions

Hemorrhage

  • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)

  • Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

  • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs)

  • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs 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. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations

  • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

  • Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

  • 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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

  • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

  • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction

  • Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

  • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal 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 at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions

  • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in 5% of patients receiving CYRAMZA plus docetaxel and 2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
  • The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
  • In patients 65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
  • Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).
  • For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade 3 pulmonary hemorrhage for placebo plus 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 plus docetaxel compared to 12% overall incidence and 2% for grade 3 pulmonary hemorrhage for placebo plus docetaxel.
  • Clinically relevant adverse reactions reported in 1% and <5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

  • No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Use in Specific Populations

  • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.
  • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.
  • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see full Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing.

RB-L HCP ISI 17SEP2015

INDICATION AND IMPORTANT SAFETY INFORMATION

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INDICATION AND IMPORTANT SAFETY INFORMATION

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IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions

Hemorrhage

  • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)

  • Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

  • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs)

  • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs 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. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations

  • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

  • Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

  • 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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

  • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

  • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction

  • Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

  • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal 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 at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions

  • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in 5% of patients receiving CYRAMZA plus docetaxel and 2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
  • The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
  • In patients 65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
  • Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).
  • For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade 3 pulmonary hemorrhage for placebo plus 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 plus docetaxel compared to 12% overall incidence and 2% for grade 3 pulmonary hemorrhage for placebo plus docetaxel.
  • Clinically relevant adverse reactions reported in 1% and <5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

  • No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Use in Specific Populations

  • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.
  • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.
  • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see full Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing.

RB-L HCP ISI 17SEP2015

INDICATIONS

Advanced gastric or GEJ adenocarcinoma

CYRAMZA® (ramucirumab) 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.