Genentech BioOncology Nurse Educational Series

Avastin (bevacizumab)

Metastatic Colorectal Cancer (mCRC)

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy.

Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer in combination with carboplatin and paclitaxel.

Metastatic Renal Cell Carcinoma (mRCC)

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Boxed WARNINGS and additional important safety information

• Gastrointestinal (GI) perforation: Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

• Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

• Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

• Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

• The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

• The most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

• The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

• Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

• The most common grade 3-5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

Please see full Prescribing Information, including Boxed WARNINGS for additional safety information.

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Herceptin (trastuzumab)

Adjuvant indications

Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer:

• As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel

• With docetaxel and carboplatin

• As a single agent following multi-modality anthracycline-based therapy

* ER/PR-negative, tumor size >2 cm, age <35 years, or histological and/or nuclear grade 2 or 3.

Metastatic indications

Herceptin is indicated:

• In combination with paclitaxel for the first line treatment of HER2-overexpressing metastatic breast cancer

• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Boxed WARNINGS and Additional Important Safety Information

Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Please see the Herceptin full prescribing information including Boxed WARNINGS and additional important safety information.

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Rituxan (rituximab)

INDICATIONS AND IMPORTANT SAFETY INFORMATION

RITUXAN^® (Rituximab) is indicated for the treatment of patients with:

• Relapsed or refractory, low grade or follicular, CD20 positive, B cell NHL as a single agent

  • Weekly x4
  • Weekly x8
  • Bulky disease
  • Retreatment

• Previously untreated follicular, CD20 positive, B cell NHL in combination with CVP chemotherapy

• Non-progressing (including stable disease), low grade, CD20 positive, B cell NHL, as a single agent, after first line CVP chemotherapy

• Previously untreated diffuse large B cell, CD20 positive NHL in combination with CHOP or other anthracycline based chemotherapy regimens

• Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)

RITUXAN is not recommended for use in patients with severe, active infections.

BOXED WARNINGS

• RITUXAN administration can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML)

Warnings and Precautions

• RITUXAN can also result in serious, including fatal, adverse reactions. These include hepatitis B reactivation with fulminant hepatitis and hepatic failure resulting in death; other infections, including bacterial, fungal, new or reactivated viral infections; cardiovascular events; severe, including fatal, renal toxicity; and abdominal pain, bowel obstruction and perforation, in some cases leading to death

Additional Important Safety Information

• The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias, including lymphopenia

• The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia

• In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment

For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

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Tarceva (erlotinib)

Indication and Use in maintenance and second-line Advanced NSCLC

Tarceva monotherapy is indicated for

• the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

• the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Results from two, multicenter, placebo-controlled, randomized, Phase III trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Tarceva with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting.

Indication and Use in first-line Advanced Pancreatic Cancer

Tarceva in combination with gemcitabine is indicated for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Important Safety Information

There have been reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. Tarceva therapy should be interrupted for acute onset of new or progressive, unexplained pulmonary symptoms such as dyspnea, cough, and fever. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as needed.

Cases of hepatic failure, hepatorenal syndrome, acute renal failure (all including fatalities), and renal insufficiency have been reported during use of Tarceva. Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe. Patients should be closely monitored during therapy with Tarceva.

Gastrointestinal perforation (including fatalities) has been reported in patients receiving Tarceva. Permanently discontinue Tarceva in patients who develop gastrointestinal perforation.

Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal. Interrupt or discontinue Tarceva treatment if the patient develops severe bullous, blistering or exfoliating conditions.

In the pancreatic cancer trial, other serious adverse reactions associated with Tarceva plus gemcitabine and which may have included fatalities, were myocardial infarction/ischemia, cerebrovascular accident and microangiopathic hemolytic anemia with thrombocytopenia. Corneal perforation and ulceration have been reported during use of Tarceva. Interrupt or discontinue Tarceva therapy if patients present with acute/worsening ocular disorders such as eye pain.

International Normalized Ratio (INR) elevation and infrequent reports of bleeding events, including gastrointestinal and non-gastrointestinal bleeding, have been reported in clinical studies. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR.

Tarceva is pregnancy category D. When receiving Tarceva therapy, women should be advised to avoid pregnancy or breastfeeding.

The most common adverse reactions in patients with NSCLC receiving single-agent Tarceva 150 mg were rash and diarrhea. In the 2nd/3rd line study, severe rash and diarrhea (9% & 6% NCI-CTC Grades 3/4, respectively) were reported. Rash and diarrhea each resulted in dose reductions (6% and 1%, respectively) and discontinuation in 1% of Tarceva-treated patients. In the maintenance study, severe rash and diarrhea (6.0% & 1.8% NCI-CTC Grades 3/4, respectively) were reported. Rash and diarrhea resulted in dose reductions or interruption (5.1% and 2.8%, respectively) and discontinuation (1.2% and 0.5%, respectively) of Tarceva-treated patients.

The most common adverse reactions in patients with pancreatic cancer receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. Severe rash and diarrhea (5% and 5% NCI-CTC Grades 3/4, respectively) were reported. Rash and diarrhea each resulted in dose reductions in 2% of patients, and discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine.

Please see the Tarceva full prescribing information for complete safety information.

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XELODA (capecitabine)

Indications

XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent XELODA in the adjuvant treatment of Dukes' C colon cancer.

XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

XELODA monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

Important Safety Information

Contraindications and Warnings

• XELODA is contraindicated in patients who have a known hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.

• XELODA is contraindicated in patients with severe renal impairment. Patients with mild or moderate renal impairment at baseline should be carefully monitored for adverse events. Patients with moderate renal impairment at baseline require a reduced starting dose.

• XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated.

  If an adverse event of grade 2, 3, or 4 occurs (eg, diarrhea), administration of XELODA should be immediately interrupted until the adverse event resolves or decreases in intensity to grade 1. Following a grade 2 reoccurrence of the adverse event or occurrence of any other grade 3 or 4 adverse event, subsequent doses of XELODA should be decreased. Please consult XELODA Prescribing Information (DOSAGE AND ADMINISTRATION) for recommended dose modifications for management of adverse events

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA. Men should use birth control while taking XELODA. Women should not nurse when receiving XELODA therapy.

Precautions

• The addition of leucovorin to XELODA is not recommended. There was no apparent advantage in response rate by adding leucovorin to XELODA; however, toxicity was increased.

• Cardiotoxicity has been observed with XELODA, including myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse events may be more common in patients with a prior history of coronary artery disease.

• Care should be exercised when XELODA is coadministered with CYP2C9 substrates.

• The level of phenytoin should be carefully monitored in patients taking XELODA and the dose of phenytoin may need to be reduced.

• If drug-related grade 2 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1.

Adverse Events

In XELODA monotherapy for colon cancer in the adjuvant setting, the most common adverse events for all grades (≥10%) in patients receiving either XELODA or 5-FU/LV (%;%) were handfoot syndrome (60;9), diarrhea (47;65), nausea (34;47), stomatitis (22;60), fatigue (16;16), lethargy (16;15), vomiting (15;21), abdominal pain (14;16), asthenia (10;10), anorexia (9;11), constipation (9;11), and alopecia (6;22). Grade 3/4 adverse events (≥5%) in patients receiving either XELODA or 5-FU/LV were hand-foot syndrome (17;<1), diarrhea (12;14), stomatitis (2;14), and neutropenia (<1;5).

In XELODA monotherapy for metastatic colorectal cancer, the most common adverse events (≥10%) in patients receiving either XELODA or 5-FU/LV (%;%) were anemia (80;79), diarrhea (55;61), hand-foot syndrome (54;6), hyperbilirubinemia (48;17), nausea (43;51), fatigue/weakness (42;46), abdominal pain (35;31), dermatitis (27;26), vomiting (27;30), appetite decrease (26;31), stomatitis (25;62), pyrexia (18;21), edema (15;9), constipation (14;17), dyspnea (14;10), neutropenia (13;46), pain (12;10), back pain (10;9), headache (10;7), gastrointestinal motility disorder (10;7), oral discomfort (10;10), upper GI inflammatory disorders (8;10), peripheral sensory neuropathy (10;4), taste disturbance (6;11), and eye irritation (13;10). Grade 3/4 adverse events (≥5%) in patients receiving either XELODA or 5-FU/LV were hyperbilirubinemia (23;6), hand-foot syndrome (17;1), diarrhea (15;12), abdominal pain (10;5), vomiting (5;5), ileus (5;3), stomatitis (3;15), and neutropenia (3;21).

In XELODA monotherapy for metastatic breast cancer, the most common adverse events (≥10%) in patients receiving XELODA (%) were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), fatigue (41), dermatitis (37), vomiting (37), neutropenia (26), stomatitis (24), thrombocytopenia (24), anorexia (23), hyperbilirubinemia (22), paresthesia (21), abdominal pain (20), constipation (15), eye irritation (15), and pyrexia (12). Grade 3/4 adverse events (≥5%) in patients receiving XELODA were lymphopenia (59), diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia (11), fatigue (8), stomatitis (7), and dehydration (5).

In XELODA combination therapy (XELODA plus docetaxel) for breast cancer, the most common adverse events (≥10%) in patients receiving either XELODA plus docetaxel or docetaxel alone (%;%) were lymphocytopenia (99;98), leukopenia (91;88), neutropenia/granulocytopenia (86;87), anemia (80;83), diarrhea (67;48), stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), alopecia (41;42), thrombocytopenia (41;23), vomiting (35;24), edema (33;34), abdominal pain (30;24), pyrexia (28;34), asthenia (26;25), fatigue (22;27), constipation (20;18), hyperbilirubinemia (20;6), neutropenic fever (16;21), taste disturbance (16;14), weakness (16;11), arthralgia (15;24), headache (15;15), myalgia (15;25), dyspnea (14;16), dyspepsia (14;8), nail disorder (14;15), anorexia (13;11), cough (13;22), pain in limb (13;13), back pain (12;11), dizziness (12;8), lacrimation increase (12;7), paresthesia (12;16), sore throat (12;11), appetite decrease (10;5), dehydration (10;7), bone pain (8;10), dermatitis (8;11), insomnia (8;10), and peripheral neuropathy (6;10). Grade 3/4 adverse events (≥5%) in patients receiving XELODA plus docetaxel or docetaxel alone (%;%) were lymphocytopenia (89;84), leukopenia (61;75), neutropenia/granulocytopenia (69;76), hand-foot syndrome (24;1), stomatitis (18;5), neutropenic fever (16;21), diarrhea (15;6), anemia (10;6), hyperbilirubinemia (9;4), nausea (7;2), alopecia (6;7), vomiting (5;2), asthenia (5;6), and fatigue (4;6).

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