AVASTIN REFERENCE GUIDE

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1 AVASTIN REFERENCE GUIDE Indications Avastin, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. Avastin, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Avastin, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer. Avastin, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma. Avastin is indicated for the treatment of recurrent glioblastoma in adults. Avastin, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non squamous non small cell lung cancer. Avastin, in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatinbased chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. Boxed WARNINGS Gastrointestinal (GI) perforation Discontinue for gastrointestinal perforation Surgery and wound healing complications Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed Discontinue in patients with wound healing complications requiring medical intervention Hemorrhage Severe or fatal hemorrhage have occurred Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis Discontinue for Grade 3-4 hemorrhage

2 Dosing per pivotal Phase III trial protocols Avastin dosing in approved indications 1 Avastin is administered as a solution for intravenous (IV) infusion at the following doses and schedules Dosing Tumor Type Dose/Schedule Tumor Type Dose/Schedule MCRC IFL* (First-line Study 2107) MCRC FOLFOX4 (Second-line Study E3200) 5 mg/kg IV every 2 weeks 10 mg/kg IV every 2 weeks CC cisplatin/paclitaxel or topotecan/paclitaxel # proc** 15 mg/kg IV every 3 weeks 10 mg/kg IV every 2 weeks if used in combination with weekly paclitaxel, PLD, or weekly topotecan or 15 mg/kg IV every 3 weeks if used in combination with topotecan every 3 weeks MCRC fluoropyrimidine-based chemotherapy in patients who had progressed on a first-line Avastincontaining regimen (First- through second-line TML study ) First-line NSCLC PC II mrcc IFN 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks 15 mg/kg IV every 3 weeks 10 mg/kg IV every 2 weeks IV=intravenous. * 5 mg/kg IV dose evaluated in first-line metastatic colorectal cancer (MCRC) in combination with 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL). 10 mg/kg IV dose evaluated in second-line, Avastin-naive MCRC patients in combination with 5-FU/LV/ oxaliplatin (FOLFOX4). 1,2 5 mg/kg IV every 2 weeks and 7.5 mg/kg IV every 3 weeks doses evaluated, in combination with fluoropyrimidine and either irinotecan- or oxaliplatin-containing chemotherapy, in MCRC patients who had progressed on a first-line Avastin-containing regimen. TML=Treatment through Multiple Lines (first and second line). 15 mg/kg IV dose evaluated in first-line locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) in combination with paclitaxel/carboplatin (PC). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone until disease progression or unacceptable toxicity mg/kg IV dose evaluated in metastatic renal cell carcinoma (mrcc) in combination with interferon alfa (IFN). AVOREN protocol allowed for IFN dose escalation (attaining a dose of 9 million international units [MIU] within the first 2 weeks), reduction, or discontinuation. IFN was discontinued after 52 weeks or earlier. 1,3 2 In the majority of approved indications (NSCLC, second-line MCRC in combination with FOLFOX4 [Study E3200], mrcc, CC, and proc), Avastin is consistently dosed at the weekly equivalent of 5 mg/kg 1 In first-line MCRC in combination with IFL (Study 2107) and when Avastin is continued in patients who had progressed on a first-line Avastin-containing regimen in combination with fluoropyrimidine-based chemotherapy (the TML study ), Avastin is dosed at the weekly equivalent of 2.5 mg/kg 1 Across all indications, study results were achieved with Avastin given at the approved dose until disease progression or unacceptable toxicity 1,3-8 psoc GBM 15 mg/kg IV every 3 weeks for 6 and up to 8 cycles if used in combination with carboplatin and paclitaxel, followed by Avastin 15 mg/kg IV every 3 weeks as a single agent as maintenance or 15 mg/kg IV every 3 weeks for 6 and up to 10 cycles if used in combination with carboplatin and gemcitabine, followed by Avastin 15 mg/kg IV every 3 weeks as a single agent as maintenance 10 mg/kg IV every 2 weeks # 15 mg/kg IV dose evaluated in persistent, recurrent, or metastatic cervical cancer (CC) in combination with either cisplatin/paclitaxel or topotecan/paclitaxel. Treatment was given until disease progression or unacceptable toxicity. ** 10 mg/kg IV dose evaluated in platinum-resistant recurrent epithelial ovarian, fallopian tube or proc in combination with weekly paclitaxel, pegylated liposomal doxorubicin (PLD), or weekly topotecan; or 15 mg/kg IV dose evaluated in combination with topotecan administered every 3 weeks. Treatment was given until disease progression or unacceptable toxicity. 15 mg/kg IV dose evaluated in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psoc) every 3 weeks when administered in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent as maintenance until disease progression. Alternatively, Avastin can be administered as a 15 mg/kg dose every 3 weeks when given in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent as maintenance until disease progression or unacceptable toxicity. 10 mg/kg IV evaluated in glioblastoma (GBM) every 2 weeks in combination with lomustine plus radiotherapy. Treatment was given until disease progression or unacceptable toxicity. Important treatment considerations Women of childbearing potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to the first dose of Avastin Long-term effects of Avastin exposure on fertility are unknown Patients should also use effective contraception during treatment and for 6 months following the last dose of Avastin Nursing mothers should be advised to discontinue nursing during treatment and for 6 months following their last dose of treatment

3 Duration of Avastin therapy in pivotal trials In pivotal Phase III MCRC trials, Avastin has demonstrated survival benefits in the first line and when continued beyond first progression 1,4 TML study* results were achieved with Avastin given at the approved dose until second disease progression or unacceptable toxicity To realize the clinical benefit of Avastin, patients in clinical trials were treated until disease progression or unacceptable toxicity Patient starts with Avastin Administer as indicated Monitor and manage adverse events Continue Avastin until - Cancer grows or spreads - Unacceptable adverse events Disease progression Patient continues with Avastin Administer Avastin Monitor and manage Continue Avastin Second disease progression or unacceptable toxicity First-line advanced nsnsclc 1,9 Number of Patients (n) Avastin + PC PC alone n=437 n=422 98% 99% 90% 91% 79% 73% 73% 65% 66% 52% 60% 44% 1 Cycle n=387 n=402 2 Cycles Avastin + PC n=338 n=323 n=314 n=286 n=284 3 Cycles 4 Cycles DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY n=230 5 Cycles Avastin + PC (n=429) PC alone (n=440) n=258 n=194 6 Cycles Duration Avastin treatment may be continued when chemotherapy is switched Patients completing treatment (%) *TML=Treatment through Multiple Lines (first and second line). Across all indications, study results were achieved with Avastin given at the approved dose until disease progression or unacceptable toxicity 1,3-8 nsnsclc=non-squamous non-small cell lung cancer. Per protocol, patients had to be progression free and without unacceptable toxicity to receive each cycle of treatment, based on investigator assessment (not independently verified), and patients progression free after 6 cycles of Avastin plus PC were eligible to receive Avastin alone. 9 Cycle information was not collected for EPP (Expanded Participation Project) patients. Therefore, these patients were not included in this analysis. 9 Indications Avastin, in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. 4

4 Dosing and duration in recurrent ovarian cancer 1 Start with Avastin at first recurrence and stay with Avastin until disease progression or unacceptable toxicity Patients start with Avastin and chemotherapy Administer as indicated Monitor and manage adverse events Continue Avastin until either - Disease progression - Unacceptable toxicity For patients with platinum-sensitive ovarian cancer, Avastin monotherapy may be continued after completion of combination therapy treatment cycles Disease progression Chemotherapies included carboplatin and gemcitabine, carboplatin and paclitaxel, paclitaxel, PLD, or topotecan. or unacceptable toxicity: Avastin dosing has been established across 3 large Phase III trials with various chemotherapy regimens Platinum-sensitive ovarian cancer 1 15 mg/kg IV every 3 weeks for 6 and up to 10 cycles if used in combination with carboplatin and gemcitabine 15 mg/kg IV every 3 weeks for 6 and up to 8 cycles if used in combination with carboplatin and paclitaxel Platinum-resistant ovarian cancer 1 10 mg/kg IV every 2 weeks if used in combination with weekly paclitaxel, PLD, or weekly topotecan* or 15 mg/kg IV every 3 weeks if used in combination with topotecan every 3 weeks Followed by maintenance: Avastin 15 mg/kg IV every 3 weeks as a single agent until disease progression or unacceptable toxicity *Weekly topotecan given days 1, 8, and 15 every 4 weeks. For patients with platinum-sensitive ovarian cancer, Avastin monotherapy may be continued after completion of combination therapy treatment cycles Boxed WARNINGS 6 Gastrointestinal (GI) perforation Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy The incidence of GI perforation ranged from 0.3% to 3% across clinical studies 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 Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed Discontinue in patients with wound healing complications 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. In clinical studies, the incidence of grade 3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7% Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis ( 1/2 tsp of red blood) in patients who develop grade 3-4 hemorrhage roc dosing

5 Dose modification guidance 1 Dose modifications for specific adverse reactions No dose reductions for Avastin are recommended Adverse Reaction Severity Dose Modification Adverse Reaction Severity Dose Modification Gastrointestinal Perforation and Fistulae Wound Healing Complications Gastrointestinal perforation, any grade Tracheoesophageal fistula, any grade Fistula, Grade 4 Fistula formation involving any internal organ Wound healing complications requiring medical intervention Necrotizing fasciitis Posterior Reversible Encephalopathy Syndrome (PRES) Renal Toxicity and Proteinuria Any Nephrotic syndrome Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome Severe infusion reaction Withhold Avastin until proteinuria less than 2 grams per 24 hours Hemorrhage Thromboembolic Events Hypertension Grade 3 or 4 Recent history of hemoptysis of 1/2 teaspoon (2.5 ml) or more Arterial thromboembolism, severe Venous thromboembolism, Grade 4 Hypertensive crisis Hypertensive encephalopathy Hypertension, severe Withhold Avastin Withhold Avastin if not controlled with medical management; resume once controlled Infusion Reaction Congestive Heart Failure Clinically significant Mild, clinically insignificant Any Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve Decrease infusion rate Dose modifications 8

6 Preparation for administration 1 Administration Administer as an intravenous infusion 10 First infusion: Administer infusion over 90 minutes Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated Administer all subsequent infusions over 30 minutes if second infusion over 60 minutes is tolerated. Preparation Use appropriate aseptic technique Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration Withdraw necessary amount of Avastin and dilute in a total volume of 100 ml of 0.9% Sodium Chloride Injection, USP. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION Discard any unused portion left in a vial, as the product contains no preservatives Store diluted Avastin solution at 2 8 C (36 46 F) for up to 8 hours No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been observed Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included: Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer) Arterial thromboembolic events (grade 3, 5%, highest in patients with GBM) Renal injury and proteinuria Grade 3 4 proteinuria ranged from 0.7% to 7% in clinical studies Nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included: Venous thromboembolism (grade 3, 11% seen in GOG-0240) Hypertension (grade 3 4, 5% 18%) Posterior reversible encephalopathy syndrome (PRES) (<0.5%) Congestive heart failure (CHF) (1%) Infusion reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.2% of patients Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin Administration and infusion times 1 First dose IF TOLERATED Second dose IF TOLERATED Subsequent doses 90 minutes 60 minutes 30 minutes DO NOT ADMINISTER AS AN IV PUSH OR BOLUS DO NOT INITIATE AVASTIN UNTIL AT LEAST 28 DAYS FOLLOWING SURGERY AND UNTIL THE SURGICAL WOUND IS FULLY HEALED In clinical studies, infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Infusion reactions in clinical trials and in postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, NCI-CTC Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis Decrease the rate of infusion for mild, clinically insignificant infusion reactions Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution Discontinue in patients who develop a severe infusion reaction and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen) NCI-CTC=National Cancer Institute Common Toxicity Criteria. Administration

7 Study 2107*: Phase III trial of Avastin plus IFL in first-line MCRC The only available biologic with an FDA-approved label that includes prospectively demonstrated OS in a Phase III first-line MCRC trial 1,5,9 Percentage Surviving Number at risk: Avastin + IFL Placebo + IFL Avastin + IFL (n=402) Placebo + IFL (n=411) Median OS: 20.3 vs 15.6 months (HR=0.66 [95% CI, ], P<0.001) OS (Months) Avastin plus IFL: First-line Study 2107 grade 3 4 adverse events ( 2% higher incidence in the Avastin arm) 1 NCI-CTC grade 3 4 events Avastin + IFL (n=392) % of Patients Placebo + IFL (n=396) Asthenia 10 7 Pain 8 5 Hypertension 12 2 Deep vein thrombosis 9 5 Intra-abdominal thrombosis 3 1 Syncope 3 1 Diarrhea Abdominal pain 8 5 Constipation 4 2 Leukopenia Neutropenia MCRC first-line data At 1 year, 74% of Avastin-treated patients were alive vs 63% of those receiving placebo plus IFL 5 At 2 years, 45% of Avastin-treated patients were alive vs 30% of those receiving placebo plus IFL 9 Avastin + IFL (n=402) Placebo + IFL (n=411) HR P value PFS, months 1, (median) 6.2 (median) 0.54 (95% CI, ) 9 < ORR (RECIST criteria, %) 1, NR <0.01 OS=overall survival; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival; ORR=overall response rate; RECIST=Response Evaluation Criteria in Solid Tumors; NR=not reported. * Study 2107 was a randomized, double-blind, active-controlled trial evaluating Avastin 5 mg/kg IV every two weeks plus IFL until disease progression or unacceptable toxicity vs placebo plus IFL as first-line treatment of MCRC (N=813). 1,5 12

8 The TML study* : Phase III trial of Avastin plus fluoropyrimidinebased chemotherapy in second-line MCRC patients who had progressed on a first-line Avastin-containing regimen The only available biologic to demonstrate significant OS when continued after a first-line Avastin-containing regimen in MCRC 1 Avastin plus fluoropyrimidine-based chemotherapy : The TML study* No new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC. 4 Percentage Surviving Median OS: 11.2 vs 9.8 months (HR=0.81 [95% CI, ], P=0.0057) Avastin + fluoropyrimidine-based chemotherapy (n=409) Fluoropyrimidine-based chemotherapy alone (n=411) MCRC data through first and second lines Number at risk: Avastin + fluoropyrimidinebased chemotherapy Fluoropyrimidinebased chemotherapy OS (Months) Avastin + fluoropyrimidine-based chemotherapy Fluoropyrimidinebased chemotherapy alone HR P value PFS, months (median) 4.0 (median) There was no significant difference in response rate (95% CI, ) < * TML=Treatment through Multiple Lines (first and second line). The TML study was a prospective, randomized, open-label, multinational, controlled, Phase III study evaluating Avastin 5 mg/kg IV every 2 weeks or Avastin 7.5 mg/kg IV every 3 weeks plus fluoropyrimidine-based chemotherapy vs fluoropyrimidine-based chemotherapy alone as second-line treatment of MCRC in patients treated with first-line Avastin-containing chemotherapy (N=820). 1 Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. After first progression, chemotherapy was switched: oxaliplatin irinotecan or irinotecan oxaliplatin. 1,4 14

9 Study E3200*: Phase III trial of Avastin plus FOLFOX4 in second-line, Avastin-naive MCRC patients Avastin is the first FDA-approved biologic with an OS benefit in second-line MCRC 1,2,9 Percentage Surviving Median OS: 13.0 vs 10.8 months (HR=0.75 [95% CI, ], P=0.001) Avastin + FOLFOX4 (n=286) FOLFOX4 alone (n=291) OS (Months) Avastin plus FOLFOX4: Second-line Study E3200 Grade 3 5 adverse events ( 2% higher incidence in the Avastin arm) 1,9 NCI-CTC grade 3 5 (nonhematologic) and grade 4 5 (hematologic) events % of Patients Avastin + FOLFOX4 (n=287) FOLFOX4 alone (n=285) Fatigue Diarrhea Sensory neuropathy 17 9 Nausea 12 5 Vomiting 11 4 Dehydration 10 5 Hypertension 9 2 Abdominal pain 8 5 Hemorrhage 5 1 Neurological other 5 3 Ileus 4 1 Headache 3 0 At 1 year, 56% of Avastin-treated patients were alive vs 43% of those receiving FOLFOX4 alone 2 At 2 years, 22% of Avastin-treated patients were alive vs 14% of those receiving FOLFOX4 alone 9 Avastin + FOLFOX4 FOLFOX4 alone HR P value PFS, months (median) 4.7 (median) 0.61 < These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study. MCRC second-line data ORR, % NR < * Study E3200 was an open-label, randomized, controlled trial evaluating Avastin 10 mg/kg IV every 2 weeks plus FOLFOX4 vs FOLFOX4 alone as second-line treatment of MCRC in Avastin-naive patients (N=829). 1,2 Avastin plus FOLFOX4: n=280; FOLFOX4 alone: n= Avastin plus FOLFOX4: n=286; FOLFOX4 alone: n=

10 Study E4599*: Phase III trial of Avastin plus PC in first-line advanced nsnsclc In Study E4599, median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, ], P=0.013) 1,10 Percentage Surviving year survival: 51% vs 44% 6 2-year survival: 23% vs 15% 6 Avastin + PC (n=434) PC alone (n=444) Number at risk: OS (Months) Avastin + PC PC alone As shown in Study E4599, Avastin plus PC has a well-documented safety profile 1 Most common grade 3 5 adverse events in first-line advanced nsnsclc patients ( 2% higher incidence in the Avastin arm) 1 NCI-CTC grade 3 5 (nonhematologic) and grade 4 5 (hematologic) events Avastin + PC (n=427) % of Patients PC alone (n=441) Neutropenia Fatigue Hypertension Infection without neutropenia 7 3 Venous thromboembolism 5 3 Febrile neutropenia 5 2 Pneumonitis/pulmonary infiltrates 5 3 Infection with grade 3 or 4 neutropenia 4 2 Hyponatremia 4 1 Headache 3 1 Proteinuria 3 0 More than half of Avastin-treated patients were alive at 1 year in Study E In an exploratory analysis across patient subgroups, the impact of Avastin on OS was less robust in the following: women, patients aged 65 years, and patients with 5% weight loss at study entry Avastin plus PC demonstrated a median PFS of 6.2 months (vs 4.5 months with PC alone, HR=0.66 [95% CI, ], P<0.001) in Study E4599, based on investigator assessment (not independently verified) 1,6 Avastin plus PC had a response rate of 35% vs 15% with PC alone (P<0.001), based on investigator assessment (not independently verified) 6 Study E4599 is the first and only prospective Phase III randomized clinical trial of an FDA-approved biologic in first-line metastatic NSCLC to demonstrate statistically significant improvement in OS (>12 months), its primary endpoint, in an intent-to-treat population 1,6 Study E4599 also improved PFS and objective response rate, its secondary endpoints, in an intent-to-treat population, based on investigator assessment (not independently verified) 1,6 The intent-to-treat population included all patients randomized before start of treatment. The results of Study E4599 included both progressors and non-progressors. 1,6 nsnsclc data * Study E4599 was a large, multicenter, randomized trial of Avastin 15 mg/kg IV every 3 weeks plus PC vs PC alone (N=878). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone until disease progression or unacceptable toxicity. 18

11 AVOREN*: Phase III trial of Avastin plus IFN in mrcc Avastin plus IFN improved median PFS by 89% over placebo plus IFN (10.2 months vs 5.4 months, HR=0.60 [95% CI, ], P<0.0001) 1 Grade 3 5 adverse events in AVOREN (occurring at higher incidence [ 2%] in Avastin plus IFN vs placebo plus IFN) 1 Adverse event Avastin + IFN (n=337) Placebo + IFN (n=304) Proportion Progression Free Number at Risk Avastin + IFN Placebo + IFN Median PFS: 10.2 vs 5.4 months (HR=0.60 [95% CI, ], P<0.0001) Avastin + IFN (n=327) Placebo + IFN (n=322) PFS (Months) Fatigue 13% 8% Asthenia 10% 7% Proteinuria 7% 0% Hypertension 6% 1% Hemorrhage 3% 0.3% Includes hypertensive crisis. Includes epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma. PFS was statistically significantly prolonged among patients receiving Avastin plus IFN compared to those receiving placebo plus IFN 3 There was no improvement in OS, with a median OS of 23 months in the Avastin plus IFN arm and 21 months in the placebo plus IFN arm (HR=0.86 [95% CI, ] based on the final analysis conducted after 444 deaths) 1 Avastin + IFN (n=306) Placebo + IFN (n=289) P value Objective response rate, % < * AVOREN was a large, multicenter, randomized, double-blind trial of Avastin 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity plus IFN vs placebo plus IFN (N=649). 3 PFS and objective response rate were investigator assessed in AVOREN. 1,11 20 mrcc data

12 Study GOG-0240*: Phase III trial of Avastin plus chemotherapy in CC 1,7 The first biologic regimen with OS benefit in CC vs chemotherapy alone 1 Avastin plus chemotherapy demonstrated a statistically significant 30% increase in median OS vs chemotherapy alone (16.8 months vs 12.9 months, respectively) 1 Proportion Surviving Number at Risk Avastin + chemo Chemo alone ORR, % GOG=Gynecologic Oncology Group Overall Survival (months) Avastin + chemotherapy 45 (95% CI, 39 52) 3.9-month increase in median OS (HR=0.74 [95% CI, ], P=0.0132) 12 8 Avastin + chemotherapy (n=227) Chemotherapy alone (n=225) Chemotherapy alone 34 (95% CI, 28 40) Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. * Study GOG-0240 was a randomized, active-controlled, multicenter trial comparing Avastin 15 mg/kg IV every 3 weeks plus chemotherapy vs chemotherapy alone (N=452). Avastin plus chemotherapy in CC: Study GOG-0240 grade 1 4 adverse events (with incidence difference of 5% between treatment arms) 1 Avastin + chemotherapy (n=218) Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. Grade 1 4 reactions Chemotherapy alone (n=222) Metabolism and nutrition disorders Decreased appetite 34% 26% Hyperglycemia 26% 19% Hypomagnesemia 24% 15% Weight decreased 21% 7% Hyponatremia 19% 10% Hypoalbuminemia 16% 11% General disorders Fatigue 80% 75% Edema peripheral 15% 22% Infections and infestations Urinary tract infection 22% 14% Infection 10% 5% Vascular disorders Hypertension 29% 6% Thrombosis 10% 3% Nervous system disorder Headache 22% 13% Dysarthria 8% 1% Gastrointestinal disorders Stomatitis 15% 10% Proctalgia 6% 1% Anal fistula 6% 0.0% Blood and lymphatic system disorders Neutropenia 12% 6% Lymphopenia 12% 5% Psychiatric disorders Anxiety 17% 10% Reproductive system and breast disorders Pelvic pain 14% 8% Respiratory, thoracic, and mediastinal disorders Epistaxis 17% 1% Renal and urinary disorders Blood creatinine increased 16% 10% Proteinuria 10% 3% CC data 22

13 AURELIA study*: Phase III trial of Avastin plus chemotherapy in proc 1,8 Avastin plus chemotherapy in proc: AURELIA study grade 3 4 adverse events (with 2% higher incidence in the Avastin plus chemotherapy arm) 1 The first biologic regimen with statistically significant PFS benefit in proc vs chemotherapy alone 1 Adverse events Avastin + chemotherapy (n=179) (%) Chemotherapy alone (n=181) (%) Proportion Progression Free Number at Risk Avastin + chemo Chemo alone 3.4-month increase in median PFS (HR=0.38 [95% CI, ], P<0.0001) Avastin + chemotherapy (n=179) Chemotherapy alone (n=182) PFS (Months) Hypertension Palmar-plantar erythrodysaesthesia syndrome Chemotherapy included paclitaxel, PLD, or topotecan There were no grade 5 events occurring at a higher incidence ( 3%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone 8 Grade 2 4 adverse events occurring at a higher incidence ( 5%) in patients receiving Avastin plus chemotherapy compared with patients receiving chemotherapy alone included neutropenia (31% vs 25%), mucosal inflammation (13% vs 6%), infection (11% vs 4%), peripheral sensory neuropathy (18% vs 7%), proteinuria (12% vs 1%), epistaxis (5% vs 0%), palmar-plantar erythrodysaesthesia syndrome (11% vs 5%), and hypertension (19% vs 6%) 1 proc data Chemotherapy included paclitaxel, PLD, or topotecan. Avastin plus chemotherapy demonstrated A 62% reduction in the risk of progression vs chemotherapy alone Doubled median PFS vs chemotherapy alone (6.8 vs 3.4 months) Avastin + chemotherapy Chemotherapy alone HR Number of patients OS ORR Median duration of response 16.6 months (median) (95% CI, ) 28% (n=142) (95% CI, 21 36) 13.3 months (median) (95% CI, ) 13% (n=144) (95% CI, 7 18) 9.4 months 5.4 months 0.89 (95% CI, ) Chemotherapy included paclitaxel, PLD, or topotecan. * The AURELIA study was a multicenter, open-label, randomized trial comparing Avastin 10 mg/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks plus chemotherapy vs chemotherapy alone in patients with proc that recurred within <6 months from the most recent platinum-based therapy (N=361). 24

14 OCEANS study*: Phase III trial of Avastin plus chemotherapy in platinum-sensitive ovarian cancer 1 Avastin plus chemotherapy in psoc: OCEANS study grade 3 4 adverse events (with incidence difference of 2% between treatment arms) 1 Proportion Progression Free Number at Risk Avastin + chemo Placebo + chemo 4-month increase in median PFS (HR=0.46 [95% CI, ], P<0.0001) Avastin + chemotherapy (n=242) Placebo + chemotherapy (n=242) PFS (Months) PFS data are based on investigator assessment. * The OCEANS study was a randomized, double-blind, placebo-controlled study studying Avastin with chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment (N=484). Median PFS: 12.4 months with Avastin plus chemotherapy vs 8.4 months with placebo plus chemotherapy (HR=0.46 [95% CI, ], P<0.0001) ORR: 78% with Avastin plus chemotherapy vs 57% with placebo plus chemotherapy (P<0.0001) 1 OS: OS was not significantly improved with the addition of Avastin to chemotherapy (HR=0.95 [95% CI, ]) 1 Grade 3 4 adverse events observed in the OCEANS study (with 2% higher incidence in the Avastin + chemotherapy arm) 1 Adverse events Avastin + chemotherapy (n=247) (%) Placebo + chemotherapy (n=233) (%) Thrombocytopenia Nausea Fatigue 6 4 Headache Proteinuria Dyspnea Epistaxis Hypertension There were no grade 5 events occurring at a higher incidence ( 3%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone 12,13 In OCEANS, grade 1 5 adverse events occurring at a higher incidence ( 5%) in the Avastin plus chemotherapy arm vs placebo plus chemotherapy arm included thrombocytopenia (58% vs 51%), diarrhea (38% vs 29%), gingival bleeding (7% vs 0%), hemorrhoids (8% vs 3%), nausea (72% vs 66%), stomatitis (15% vs 7%), fatigue (82% vs 75%), mucosal inflammation (15% vs 10%), sinusitis (15% vs 9%), contusion (17% vs 9%), arthralgia (28% vs 19%), back pain (21% vs 13%), dizziness (23% vs 17%), headache (49% vs 30%), insomnia (21% vs 15%), proteinuria (20% vs 3%), cough (26% vs 18%), dysphonia (13% vs 3%), dyspnea (30% vs 24%), epistaxis (55% vs 14%), oropharyngeal pain (16% vs 10%), rhinorrhea (10% vs 4%), sinus congestion (8% vs 2%), and hypertension (42% vs 9%) 1 psoc OCEANS data 26

15 GOG-0213 study*: Phase III trial of Avastin plus chemotherapy in platinum-sensitive ovarian cancer 1 Avastin plus chemotherapy in psoc: Study GOG-0213 grade 3 4 adverse events (with incidence difference of 2% between treatment arms) 1 Proportion Surviving Number at Risk Avastin + chemo Chemo alone 5.3-month increase in median OS (HR=0.84 [95% CI, ] [IVRS]) (HR=0.82 [95% CI, ] [ecrf]) Avastin + chemotherapy (n=337) Chemotherapy alone (n=336) OS (Months) IVRS=interactive voice response system; ecrf= electronic case report form. * Study GOG-0213 (NCT ) was a randomized, controlled, open-label study of Avastin with chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy (N=673). Median OS: 42.6 months with Avastin plus chemotherapy vs 37.3 months with chemotherapy alone (HR=0.84 [95% CI, ] [IVRS]; HR=0.82 [95% CI, ] [ecrf]) 1 Median PFS: 13.8 months with Avastin plus chemotherapy vs 10.4 months with chemotherapy alone (HR=0.61 [95% CI, ] [IVRS]) 1 Objective response rate 1 Number (%) of patients treated Avastin + chemotherapy Chemotherapy alone 213/274 (78%) 159/286 (56%) More patients had a complete response (86/274 [31%] vs 31/286 [11%]) or partial response (127/274 [46%] vs 128/286 [45%]) with Avastin plus chemotherapy vs chemotherapy alone 1,9 Grade 3 4 adverse events observed in the GOG-0213 study (with 2% higher incidence in the Avastin + chemotherapy arm) 1 Adverse events Avastin + chemotherapy (n=325) (%) Chemotherapy alone (n=332) (%) Hypertension Fatigue 8 3 Febrile neutropenia 6 3 Proteinuria 8 0 Abdominal pain Hyponatremia Headache Pain in extremity 3 0 There were no grade 5 events occurring at a higher incidence ( 3%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone 9,14 In GOG-0213, grade 1 5 adverse events occurring at a higher incidence ( 5%) in the Avastin plus chemotherapy arm vs chemotherapy alone arm included diarrhea (39% vs 32%), abdominal pain (33% vs 28%), vomiting (33% vs 25%), stomatitis (33% vs 16%), decreased appetite (35% vs 25%), hyperglycemia (31% vs 24%), hypomagnesemia (27% vs 17%), hyponatremia (17% vs 6%), hypoalbuminemia (11% vs 6%), hypocalcemia (12% vs 5%), hyperkalemia (9% vs 3%), arthralgia (45% vs 30%), myalgia (29% vs 18%), pain in extremity (25% vs 14%), back pain (17% vs 10%), muscular weakness (13% vs 8%), neck pain (9% vs 0%), dyspnea (30% vs 25%), cough (30% vs 17%), epistaxis (33% vs 2%), rhinitis allergic (17% vs 4%), nasal mucosal disorder (14% vs 3%), headache (38% vs 20%), dizziness (13% vs 8%), dysarthria (14% vs 2%), aspartate aminotransferase increased (15% vs 9%), weight decreased (15% vs 4%), blood creatinine increased (13% vs 5%), exfoliative rash (23% vs 16%), nail disorder (10% vs 2%), dry skin (7% vs 2%), hypertension (42% vs 3%), proteinuria (17% vs 1%), chest pain (8% vs 2%), and sinusitis (7% vs 2%) 1 psoc GOG 213 data 28

16 EORTC study* : Phase III trial of Avastin plus lomustine vs lomustine alone in recurrent glioblastoma BRAIN study (AVF3708g) : Phase II trial of Avastin as single agent or in combination with irinotecan in recurrent glioblastoma Endpoint Avastin + chemotherapy (n=283) Chemotherapy alone (n=149) Single-agent Avastin 95% Cl Primary OS (median) There was no difference in median OS between study arms Secondary PFS (median) 4.2 months 1.5 months EORTC=European Organisation for Research and Treatment of Cancer. * The EORTC study was a randomized, multicenter, open-label Phase III trial comparing the efficacy of Avastin plus lomustine vs lomustine alone. 1 Patients were randomized to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n=283) plus lomustine (90 mg/m 2 [maximum dose 160 mg] every 6 weeks) or lomustine monotherapy dose (110 mg/m 2 every 6 weeks) (n=149) until disease progression or unacceptable toxicity. 1 HR=0.91, P= HR=0.52 (95% CI, ). Number of patients 85 Objective response rate # 25.9% 17.0% 36.1% Median duration of response # 4.2 months The BRAIN study was a Phase II, multicenter, randomized, non-comparative clinical trial evaluating the efficacy and safety of Avastin alone or in combination with irinotecan for the treatment of glioblastoma (N=167) 1 N=167 for overall population. # Objective response rate and median duration of response were measured by a blinded independent review facility. No difference in OS (HR=0.91, P value of ) was observed between arms; therefore, all secondary outcome measures are descriptive only 1 Among the 50% of patients receiving corticosteroids at the time of randomization, 11% more patients treated with Avastin plus lomustine discontinued corticosteroids (23% vs 12%) 1 The demographics of the safety population were similar to the demographics of the efficacy population. In the Avastin with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications 1 The BRAIN study was a noncomparative study, with an Avastin + irinotecan arm 1 National Cancer Institute (NCI) study**: Phase II trial of Avastin as single agent in recurrent glioblastoma Single-agent Avastin 95% Cl Number of patients 56 Objective response rate** 19.6% 10.9% 31.3% Median duration of response** 3.9 months ** The NCI study (Study NCI 06-C-0064E) was a single arm, single center study that evaluated the efficacy and safety of Avastin 10 mg/kg every 2 weeks in patients with previously treated GBM GBM EORTC 26101, NCI and BRAIN data

17 Hypertension monitoring and management with Avastin Monitoring blood pressure (BP) 1 The incidence of severe hypertension is increased in patients receiving Avastin compared to patients receiving chemotherapy alone BP monitoring should be conducted every 2 to 3 weeks during treatment with Avastin In clinical trials, appropriate antihypertensives were used to help manage hypertension 2,5,6 Withhold Avastin in patients with severe hypertension that is not controlled with medical management If appropriate, resume Avastin after hypertension is well controlled in patients with hypertensive crisis or hypertensive encephalopathy Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their BP monitored at regular intervals Proteinuria monitoring and management with Avastin Diagnosing and monitoring proteinuria 1 The incidence and severity of proteinuria are increased in patients receiving Avastin Urine dipstick or urinalyses are performed to detect proteinuria in most cases Patients should be monitored for the development or worsening of proteinuria with serial urinalyses Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% CI: 0.17, 0.57)] Proteinuria monitoring and management with Avastin 1 The following information should not be a substitute for your professional medical judgment and should be individualized for the patient. Hypertension and proteinuria Hypertension monitoring and management with Avastin 1 The following information should not be a substitute for your professional medical judgment and should be individualized for the patient. Monitoring Method Monitor urine protein (urine dipstick) Monitoring Method Observations Actions Hypertension Administer appropriate antihypertensive therapy Measure BP every 2 to 3 weeks Hypertensive crisis or hypertensive encephalopathy Observations Actions <2+ urine dipstick Continue to monitor 2+ urine dipstick* Undergo further assessment with 24-hour urine collection Withhold Avastin if 2 g of protein/24 hours and monitor regularly Nephrotic syndrome Continue to monitor nephrotic syndrome as appropriate Continue to monitor BP regularly Withhold Avastin with severe hypertension not controlled with medical management If appropriate, resume Avastin after hypertension is well controlled Continue to monitor BP regularly Pregnancy warning Resume Avastin when protein level is <2 g/24 hours *Clinician s decision to continue or hold Avastin dose during the 24-hour collection period. Based on the mechanism of action and animal studies, Avastin may cause fetal harm Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin Advise nursing women that breastfeeding is not recommended during treatment with Avastin and for 6 months following their last dose of treatment Avastin may impair fertility 32

18 NCI-CTCAE V4.03 and USPI recommendations for Avastin adverse events management 1,15 NCI-CTCAE definition of grade Grade 1 Grade 2 Grade 3 Grade 4 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated AE Hypertension 15 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL* Prehypertension Systolic BP mm Hg or diastolic BP mm Hg Grade Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Stage 1 Stage 2 hypertension Systolic BP mm Hg or diastolic BP mm Hg Medical intervention indicated Recurrent or persistent ( 24 hrs) Symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously WNL Monotherapy indicated hypertension Systolic BP 160 mm Hg or diastolic BP 100 mm Hg) Medical intervention indicated >1 drug or more intensive therapy than previously used indicated Life-threatening consequences; urgent intervention indicated NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ADL=activities of daily living. * Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not being bedridden. Hypertension Life-threatening consequences Eg, malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis Urgent intervention indicated ATE/VTE AE Thromboembolic event 15 Treatment with Avastin: ATE 1 Treatment with Avastin: VTE Venous thrombosis (eg, superficial thrombosis) Continue Avastin treatment Continue Avastin treatment Grade Venous thrombosis (eg, uncomplicated deep vein thrombosis) Medical intervention indicated Continue Avastin treatment Continue Avastin treatment Thrombosis (eg, uncomplicated pulmonary embolism [venous]; nonembolic cardiac mural [arterial] thrombus) Medical intervention indicated Life threatening (eg, pulmonary embolism, cerebrovascular event, arterial insufficiency) Hemodynamic or neurologic instability; urgent intervention indicated treatment Continue Avastin treatment ATE=arterial thromboembolic event; VTE=venous thromboembolic event. Discontinue Avastin treatment This information should not be a substitute for your professional medical judgment and should be individualized for the patient. NCI-CTCAE and USPI recommendations Treatment with Avastin 1 34 Continue Avastin treatment WNL=within normal limits. Continue Avastin treatment Withhold Avastin treatment if not controlled with medical management Discontinue Avastin treatment

19 Proposed mechanism of action as observed in preclinical models Angiogenesis is required for tumor growth 19,20 Tumors need a blood supply to grow and to metastasize Somatic Small Tumor secretion of Rapid tumor Angiogenic inhibitors mutation avascular pro-angiogenic growth and may cause regression tumor factors stimulates metastasis of tumor vasculature ( 2 mm) angiogenesis VEGF ANGIOGENESIS As demonstrated in preclinical models: Avastin may exert certain effects to inhibit tumor growth and development A pro-angiogenic factor that is present throughout tumor progression While expressed in normal tissues, VEGF is also present at physiologically relevant levels in tumors 19,20 A VEGF ligand binds to receptors on endothelial cells to help drive angiogenesis 16,18,21 Essential process in tumor development 19 Implicated in tumor growth 19 AVASTIN Directly binds VEGF to inhibit angiogenesis 1 May regress existing tumor vasculature and inhibit new and recurrent tumor vessel growth 20,22-28 Proposed effects Potential effect on vessels Potential impact on tumor Anti-vascular Anti-angiogenesis Regression of existing tumor vasculature Reduction of tumor size Inhibition of new and recurrent tumor vessel growth 23,28,30 Inhibition of tumor growth Proposed early and later effects of Avastin 22,27,29,31,33-36 Proposed mechanism of action VEGF=vascular endothelial growth factor. Avastin is designed to directly bind to VEGF extracellularly to prevent interaction with VEGF receptors on the surface of endothelial cells, and may thereby inhibit VEGF s angiogenic activity 1 The mechanism of action of Avastin has been elucidated in preclinical models. Its clinical significance is unknown. ATTAINING VEGF INHIBITION CONTINUING VEGF INHIBITION Most common adverse events Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% were: Epistaxis Proteinuria Lacrimation disorder Headache Taste alteration Back pain Hypertension Dry skin Exfoliative dermatitis Rhinitis Rectal hemorrhage Across all studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions 36 Early effects Anti-vascular effects Anti-angiogenesis Later effects

20 YOUR RESOURCE FOR EFFECTIVE ACCESS SERVICES WE KNOW THAT HELPING PATIENTS IS A PRIVILEGE We are dedicated to ensuring our medications are accessible for the patients who need them. We can help your patients and practice by providing: Benefits investigations (BIs) Prior authorization (PA) resources Sample billing and coding information Resources for appeals Patient assistance options Information about authorized specialty pharmacies (SPs) and specialty distributors COMMERCIALLY INSURED PATIENTS PUBLICLY INSURED PATIENTS UNINSURED PATIENTS REFERRALS TO AVASTIN PATIENT SUPPORT GENENTECH BIOONCOLOGY CO-PAY CARD* AVASTIN ACCESS SOLUTIONS REFERRALS TO PATIENT ASSISTANCE REFERRALS TO CO-PAY ASSISTANCE FOUNDATIONS THE GENENTECH ACCESS TO CARE FOUNDATION (GATCF) * To be eligible for the Genentech BioOncology Co-pay Card, patients must have commercial insurance and must meet other criteria. Patients with Medicare, Medicaid or other public insurance are not eligible. Genentech does not influence or control the operations or eligibility criteria of any independent co-pay assistance foundation and cannot guarantee co-pay assistance after a referral from Avastin Access Solutions. The foundations to which we refer patients are not exhaustive or indicative of Genentech s endorsement or financial support. There may be other foundations to support the patient s disease state. To be eligible for free Genentech medicine from GATCF, insured patients must have exhausted all other forms of patient assistance (including the Genentech BioOncology Co-pay Card and support from independent co-pay assistance foundations) and meet financial criteria. Uninsured patients must meet different financial criteria. 38 TO LEARN MORE about our programs and services Visit Genentech-Access.com/Avastin Call (888) References: 1. Avastin Prescribing Information. Genentech, Inc Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25: Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370: Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol. 2013;14: Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350: Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355: Tewari KS, Sill MW, Long HJ III, et al. N Engl J Med. 2014;370: Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol. 2014;32: Data on file. Genentech, Inc. 10. Sandler A, Leon L, Fages S, et al. Poster presented at: World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, The Netherlands. 11. Escudier B, Bellmunt J, Negrier S, et al. Slides presented at: Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, FL. 12. Aghajanian C, Blank S, Goff B, et al. J Clin Oncol. 2012;30: Aghajanian C, Goff B, Nycum LR, et al. Gynecol Oncol :10; Coleman RL, Brady MF, Herzog TJ, et al Lancet Oncol.18; National Cancer Institute. Common terminology criteria for adverse events, version June 14, CTCAE/CTCAE_4.03_ _QuickReference_5x7.pdf. Accessed January 17, Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200: Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3: Rini BI, Small EJ. J Clin Oncol. 2005;23: Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23: Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3: Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: O Connor JPB, Carano RAD, Clamp AR, et al. Clin Cancer Res. 2009;15: Tobelem G. Targ Oncol. 2007;2: Yuan F, Chen Y, Dellian M, et al. Proc Natl Acad Sci U S A. 1996;93: Willett CG, Boucher Y, di Tomaso E, et al. Nat Med. 2004;10: Lee CG, Heijn M, di Tomaso E, et al. Cancer Res. 2000;60: Gerber HP, Ferrara N. Cancer Res. 2005;65: Borgström P, Hillan KJ, Sriramarao P, et al. Cancer Res. 1996;56: Yanagisawa M, Yorozu K, Kurasawa M, et al. Anticancer Drugs. 2010;21: Borgström P, Bourdon MA, Hillan KJ, et al. Prostate. 1998;35: Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16: [and supplemental appendix]. 32. Warren RS, Yuan H, Matli MR, et al. J Clin Invest. 1995;95: Mabuchi S, Terai Y, Morishige K, et al. Clin Cancer Res. 2008;14: Galizia G, Lieto E, Ferraraccio F, et al. Clin Cancer Res. 2004;10: Vosseler S, Mirancea N, Bohlen P, et al. Cancer Res. 2005;65: Nagy JA, Dvorak AM, Dvorak HF. Annu Rev Pathol. 2007;2: Access Solutions

21 Boxed WARNINGS Gastrointestinal (GI) perforation Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy The incidence of GI perforation ranged from 0.3% to 3% across clinical studies 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 Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed Discontinue in patients with wound healing complications 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. In clinical studies, the incidence of grade 3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7% Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis ( 1/2 tsp of red blood) in patients who develop grade 3-4 hemorrhage Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included: Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer) Arterial thromboembolic events (grade 3, 5%, highest in patients with GBM) Renal injury and proteinuria Grade 3 4 proteinuria ranged from 0.7% to 7% in clinical studies Nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included: Venous thromboembolism (grade 3, 11% seen in GOG-0240) Hypertension (grade 3 4, 5% 18%) Posterior reversible encephalopathy syndrome (PRES) (<0.5%) Congestive heart failure (CHF) (1%) Infusion reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.2% of patients Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin Pregnancy warning Based on the mechanism of action and animal studies, Avastin may cause fetal harm Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin Advise nursing women that breastfeeding is not recommended during treatment with Avastin and for 6 months following their last dose of treatment Avastin may impair fertility Most common adverse events Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% were: Epistaxis Rhinitis Dry skin Back pain Headache Proteinuria Rectal hemorrhage Exfoliative dermatitis Hypertension Taste alteration Lacrimation disorder Across all studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions You may report side effects to the FDA at (800) FDA-1088 or You may also report side effects to Genentech at (888) for additional important Genentech USA, Inc. All rights reserved. AVP/111014/0015(5) (01/18)