Avastin: Package Insert / Prescribing Info

1.1 Metastatic Colorectal Cancer

Avastin, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first-or second-line treatment of patients with metastatic colorectal cancer (mCRC).

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.

1.2 First-Line Non-Squamous Non–Small Cell Lung Cancer

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 (NSCLC).

1.3 Recurrent Glioblastoma

Avastin is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

1.4 Metastatic Renal Cell Carcinoma

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

1.5 Persistent, Recurrent, or Metastatic Cervical 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.

1.6 Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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.

1.7 Hepatocellular Carcinoma

Avastin, in combination with atezolizumab, is indicated for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.

2.1 Important Administration Information

Withhold for at least 28 days prior to elective surgery. Do not administer Avastin until at least 28 days following major surgery and until adequate wound healing.

2.2 Metastatic Colorectal Cancer

The recommended dosage when Avastin is administered in combination with intravenous fluorouracil-based chemotherapy is:

• 5 mg/kg intravenously every 2 weeks in combination with bolus-IFL.
• 10 mg/kg intravenously every 2 weeks in combination with FOLFOX4.
• 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line bevacizumab product-containing regimen.

2.3 First-Line Non-Squamous Non-Small Cell Lung Cancer

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.

2.4 Recurrent Glioblastoma

The recommended dosage is 10 mg/kg intravenously every 2 weeks.

2.5 Metastatic Renal Cell Carcinoma

The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.

2.6 Persistent, Recurrent, or Metastatic Cervical Cancer

The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.

2.7 Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

2.8 Hepatocellular Carcinoma

The recommended dosage is 15 mg/kg intravenously after administration of 1,200 mg of atezolizumab intravenously on the same day, every 3 weeks until disease progression or unacceptable toxicity.

Refer to the Prescribing Information for atezolizumab prior to initiation for recommended dosage information.

2.9 Dosage Modifications for Adverse Reactions

Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for Avastin are recommended.

2.10 Preparation and Administration

5.1 Gastrointestinal Perforations and Fistulae

Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see Adverse Reactions (6.1)].

Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from < 1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy.

Avoid Avastin 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. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ.

5.2 Surgery and Wound Healing Complications

In a controlled clinical study in which Avastin was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving Avastin and 4% in patients who did not receive Avastin. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received Avastin and 0.7% in patients who did not receive Avastin [see Adverse Reactions (6.1)].

In patients who experience wound healing complications during Avastin treatment, withhold Avastin until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following major surgery and until adequate wound healing. The safety of resumption of AVASTIN after resolution of wound healing complications has not been established [see Dosage and Administration (2.9)].

Necrotizing fasciitis including fatal cases, has been reported in patients receiving Avastin, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin in patients who develop necrotizing fasciitis.

5.3 Hemorrhage

Avastin can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1 epistaxis, and serious hemorrhage, which in some cases has been fatal. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-5 hemorrhagic events ranged from 0.4% to 7% in patients receiving Avastin [see Adverse Reactions (6.1)].

Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients with non-squamous NSCLC receiving Avastin with chemotherapy compared to none of the patients receiving chemotherapy alone.

An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC. There is lack of clinical data to support the safety of Avastin in patients with variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding because these patients were excluded from clinical trials of Avastin in HCC [see Clinical Studies (14.10)].

Do not administer Avastin to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood. Discontinue in patients who develop a Grades 3-4 hemorrhage.

5.4 Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5% in patients receiving Avastin with chemotherapy compared to ≤2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or >65 years [see Use in Specific Populations (8.5)].

Discontinue in patients who develop a severe ATE. The safety of reinitiating Avastin after an ATE is resolved is not known.

5.5 Venous Thromboembolic Events

An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse Reactions (6.1)]. In Study GOG-0240, Grades 3-4 VTE occurred in 11% of patients receiving Avastin with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of Grades 3-4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving chemotherapy alone.

Discontinue Avastin in patients with a Grade 4 VTE, including pulmonary embolism.

5.6 Hypertension

Severe hypertension occurred at a higher incidence in patients receiving Avastin as compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-4 hypertension ranged from 5% to 18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuing Avastin. Withhold Avastin in patients with severe hypertension that is not controlled with medical management; resume once controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive encephalopathy.

5.7 Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) was reported in < 0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.

Discontinue Avastin in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing Avastin, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin in patients who developed PRES is not known.

5.8 Renal Injury and Proteinuria

The incidence and severity of proteinuria was higher in patients receiving Avastin as compared to patients receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or > 3.5 grams of protein per 24 hours) to Grade 4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies. The overall incidence of proteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (15 days to 37 months) after initiating Avastin. Median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required discontinuation of Avastin in 30% of the patients who developed proteinuria [see Adverse Reactions (6.1)].

In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving Avastin with chemotherapy experienced Grades 2-4 (defined as urine dipstick 2+ or greater or > 1 gram of protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2-4 proteinuria resolved in 74% of patients. Avastin was reinitiated in 42% of patients. Of the 113 patients who reinitiated Avastin, 48% experienced a second episode of Grades 2-4 proteinuria.

Nephrotic syndrome occurred in < 1% of patients receiving Avastin across clinical studies, in some instances with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received Avastin with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received Avastin. Serum creatinine levels did not return to baseline in approximately one-third of patients who received Avastin.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome.

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)].

5.9 Infusion-Related Reactions

Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in < 3% of patients and severe reactions occurred in 0.4% of patients.

Decrease the rate of infusion for mild, clinically insignificant infusion-related reactions. Interrupt the infusion in patients with clinically significant infusion-related reactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).

5.10 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, Avastin may cause fetal harm when administered to pregnant women. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal 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 Avastin and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.11 Ovarian Failure

The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing Avastin, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving Avastin. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or an FSH level < 30 mIU/mL during the post-treatment period. Long-term effects of Avastin on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating Avastin [see Adverse Reactions (6.1), Use in Specific Populations (8.3)].

5.12 Congestive Heart Failure (CHF)

Avastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥ 3 left ventricular dysfunction was 1% in patients receiving Avastin compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% for patients receiving Avastin with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone.

In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left ventricular ejection fraction (LVEF) were increased in patients receiving Avastin with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportion of patients with a decline in LVEF from baseline of ≥ 20% or a decline from baseline of 10% to < 50%, was 10% in patients receiving Avastin with chemotherapy compared to 5% in patients receiving chemotherapy alone. Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% of the patients and was resolved in 62% of the patients who developed CHF in the Avastin arm compared to 82% in the placebo arm. Discontinue Avastin in patients who develop CHF.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data in Warnings and Precautions and described below reflect exposure to Avastin in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218), or HCC (IMbrave150) at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving Avastin as a single agent or in combination with other anti-cancer therapies at a rate > 10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Across clinical studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)].

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bevacizumab in the studies described below with the incidence of antibodies in other studies or to other bevacizumab products may be misleading.

In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: Polyserositis

Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation

Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

Effects of Avastin on Other Drugs

No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38, interferon alfa, carboplatin or paclitaxel was observed when Avastin was administered in combination with these drugs; however, 3 of the 8 patients receiving Avastin with paclitaxel and carboplatin had lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel and carboplatin alone had a greater paclitaxel exposure at Day 63 than at Day 0.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of Avastin in pediatric patients have not been established.

In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who received Avastin. Avastin is not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight pediatric patients with relapsed GBM who received bevacizumab and irinotecan. Addition of Avastin to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical studies, one in high grade glioma (n= 121) and one in metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n= 154).

Based on the population pharmacokinetics analysis of data from 152 pediatric and young adult patients with cancer (7 months to 21 years of age), bevacizumab clearance normalized by body weight in pediatrics was comparable to that in adults.

8.5 Geriatric Use

In an exploratory pooled analysis of 1745 patients from five randomized, controlled studies, 35% of patients were ≥ 65 years old. The overall incidence of ATE was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in the incidence of ATE was greater in patients ≥ 65 years (8% vs. 3%) as compared to patients < 65 years (2% vs. 1%) [see Warnings and Precautions (5.4)].

12.1 Mechanism of Action

Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

12.3 Pharmacokinetics

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Avastin every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady state concentration is 84 days. The accumulation ratio following a dose of 10 mg/kg once every 2 weeks is 2.8.

Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/mL on Day 84 (10th, 90th percentile: 45, 128) following a dose of 5 mg/kg once every two weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity.

Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea, as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.

13.2 Animal Toxicology and/or Pharmacology

Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

14.1 Metastatic Colorectal Cancer

Study AVF2107g

The safety and efficacy of Avastin was evaluated in a double-blind, active-controlled study [AVF2107g (NCT00109070)] in 923 patients with previously untreated mCRC who were randomized (1:1:1) to placebo with bolus-IFL (irinotecan 125 mg/m2, fluorouracil 500 mg/m2, and leucovorin 20 mg/m2 given once weekly for 4 weeks every 6 weeks), Avastin (5 mg/kg every 2 weeks) with bolus-IFL, or Avastin (5 mg/kg every 2 weeks) with fluorouracil and leucovorin. Enrollment to the Avastin with fluorouracil and leucovorin arm was discontinued after enrollment of 110 patients in accordance with the protocol-specified adaptive design. Avastin was continued until disease progression or unacceptable toxicity or for a maximum of 96 weeks. The main outcome measure was overall survival (OS).

The median age was 60 years; 60% were male, 79% were White, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. The dominant site of disease was extra-abdominal in 56% of patients and was the liver in 38% of patients.

The addition of Avastin improved survival across subgroups defined by age (< 65 years, ≥ 65 years) and sex. Results are presented in Table 11 and Figure 1.

Table 11: Efficacy Results in Study AVF2107g

Efficacy Parameter	Avastin with bolus-IFL (N=402)	Placebo with bolus-IFL (N=411)
* by stratified log-rank test. † by χ2 test
Overall Survival
Median, in months	20.3	15.6
Hazard ratio (95% CI)	0.66 (0.54, 0.81)
p-value*	< 0.001
Progression-Free Survival
Median, in months	10.6	6.2
Hazard ratio (95% CI)	0.54 (0.45, 0.66)
p-value*	< 0.001
Overall Response Rate
Rate (%)	45%	35%
p-value†	< 0.01
Duration of Response
Median, in months	10.4	7.1

Figure 1: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study AVF2107g

Among the 110 patients randomized to Avastin with fluorouracil and leucovorin, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, overall response rate (ORR) was 39%, and median duration of response was 8.5 months.

Study ML18147

The safety and efficacy of Avastin were evaluated in a prospective, randomized, open-label, multinational, controlled study [ML18147 (NCT00700102)] in 820 patients with histologically confirmed mCRC who had progressed on a first-line Avastin containing regimen. Patients were excluded if they progressed within 3 months of initiating first-line chemotherapy and if they received Avastin for less than 3 consecutive months in the first-line setting. Patients were randomized (1:1) within 3 months after discontinuing Avastin as first-line treatment to receive fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy with or without Avastin (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). The choice of second-line treatment was contingent upon first-line chemotherapy. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS. A secondary outcome measure was ORR.

The median age was 63 years (21 to 84 years); 64% were male, 52% had an ECOG performance status of 1, 44% had an ECOG performance status of 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of Avastin as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each arm.

The addition of Avastin to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of OS and PFS. There was no significant difference in ORR. Results are presented in Table 12 and Figure 2.

Table 12: Efficacy Results in Study ML18147

Efficacy Parameter	Avastin with Chemotherapy (N=409)	Chemotherapy (N=411)
* p=0.0057 by unstratified log-rank test. † p-value < 0.0001 by unstratified log-rank test.
Overall Survival*
Median, in months	11.2	9.8
Hazard ratio (95% CI)	0.81 (0.69, 0.94)
Progression-Free Survival†
Median, in months	5.7	4.0
Hazard ratio (95% CI)	0.68 (0.59, 0.78)

Figure 2: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study ML18147

14.2 Lack of Efficacy in Adjuvant Treatment of Colon Cancer

Lack of efficacy of Avastin as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical studies.

The first study [BO17920 (NCT00112918)] was conducted in 3451 patients with high-risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent. Patients were randomized to receive Avastin at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule with FOLFOX4 (N=1155) or on a 3-weekly schedule with XELOX (N=1145) or FOLFOX4 alone (N=1151). The main outcome measure was disease free survival (DFS) in patients with stage III colon cancer.

The median age was 58 years; 54% were male, 84% were White and 29% were ≥ 65 years. Eighty-three percent had stage III disease.

The addition of Avastin to chemotherapy did not improve DFS. As compared to FOLFOX4 alone, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher for patients receiving Avastin with FOLFOX4 or with XELOX. The hazard ratios for DFS were 1.17 (95% CI: 0.98,1.39) for Avastin with FOLFOX4 versus FOLFOX4 alone and 1.07 (95% CI: 0.90, 1.28) for Avastin with XELOX versus FOLFOX4 alone. The hazard ratios for OS were 1.31 (95% CI: 1.03, 1.67) and 1.27 (95% CI: 1, 1.62) for the comparison of Avastin with FOLFOX4 versus FOLFOX4 alone and Avastin with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in the Avastin-containing arms compared to FOLFOX4 alone in the high-risk stage II cohort.

In a second study [NSABP-C-08 (NCT00096278)], patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Avastin administered at a dose equivalent to 2.5 mg/kg/week with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% White. Seventy-five percent had stage III disease. The main outcome was DFS among stage III patients. The HR for DFS was 0.92 (95% CI: 0.77, 1.10). OS was not significantly improved with the addition of Avastin to mFOLFOX6 [HR 0.96 (95% CI: 0.75,1.22)].

14.3 First-Line Non–Squamous Non–Small Cell Lung Cancer

Study E4599

The safety and efficacy of Avastin as first-line treatment of patients with locally advanced, metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study [E4599 (NCT00021060)]. A total of 878 chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel (200 mg/m2) and carboplatin (AUC 6) with or without Avastin 15 mg/kg. After completing or discontinuing chemotherapy, patients randomized to receive Avastin continued to receive Avastin alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The main outcome measure was duration of survival.

The median age was 63 years; 54% were male, 43% were ≥ 65 years, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease. Of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.

OS was statistically significantly longer for patients receiving Avastin with paclitaxel and carboplatin compared with those receiving chemotherapy alone. Median OS was 12.3 months vs. 10.3 months [HR 0.80 (95% CI: 0.68, 0.94), final p-value of 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Avastin with paclitaxel and carboplatin compared to chemotherapy alone. Results are presented in Figure 3.

Figure 3: Kaplan-Meier Curves for Duration of Survival in First-Line Non-Squamous Non-Small Cell Lung Cancer in Study E4599

In an exploratory analysis across patient subgroups, the impact of Avastin on OS was less robust in the following subgroups: women [HR 0.99 (95% CI: 0.79, 1.25)], patients ≥ 65 years [HR 0.91 (95% CI: 0.72, 1.14)] and patients with ≥ 5% weight loss at study entry [HR 0.96 (95% CI: 0.73, 1.26)].

14.4 Recurrent Glioblastoma

14.5 Metastatic Renal Cell Carcinoma

Study BO17705

The safety and efficacy of Avastin were evaluated in patients with treatment-naïve mRCC in a multicenter, randomized, double-blind, international study [BO17705 (NCT00738530)] comparing interferon alfa and Avastin versus interferon alfa and placebo. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg every 2 weeks; N = 327) or placebo (every 2 weeks; N = 322) with interferon alfa (9 MIU subcutaneously three times weekly for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 60 years (18 to 82 years); 70% were male and 96% were White. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3–5), and 7% missing.

PFS was statistically significantly prolonged among patients receiving Avastin compared to placebo; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI: 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p-value < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the patients receiving Avastin with interferon alfa and 21 months in patients receiving interferon alone [HR 0.86, (95% CI: 0.72, 1.04)]. Results are presented in Figure 4.

Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Metastatic Renal Cell Carcinoma in Study BO17705

14.6 Persistent, Recurrent, or Metastatic Cervical Cancer

Study GOG-0240

The safety and efficacy of Avastin were evaluated in patients with persistent, recurrent, or metastatic cervical cancer in a randomized, four-arm, multicenter study comparing Avastin with chemotherapy versus chemotherapy alone [GOG-0240 (NCT00803062)]. A total of 452 patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without Avastin, or paclitaxel and topotecan with or without Avastin.

The dosing regimens for Avastin, paclitaxel, cisplatin and topotecan were as follows:

• Day 1: Paclitaxel 135 mg/m2 over 24 hours, Day 2: cisplatin 50 mg/m2 with Avastin;
• Day 1: Paclitaxel 175 mg/m2 over 3 hours, Day 2: cisplatin 50 mg/m2 with Avastin;
• Day 1: Paclitaxel 175 mg/m2 over 3 hours with cisplatin 50 mg/m2 with Avastin;
• Day 1: Paclitaxel 175 mg/m2 over 3 hours with Avastin, Days 1-3: topotecan IV 0.75 mg/m2 over 30 minutes

Patients were treated until disease progression or unacceptable adverse reactions. The main outcome measure was OS. Secondary outcome measures included ORR.

The median age was 48 years (20 to 85 years). Of the 452 patients randomized at baseline, 78% of patients were White, 80% had received prior radiation, 74% had received prior chemotherapy concurrent with radiation, and 32% had a platinum-free interval (PFI) of less than 6 months. Patients had a GOG performance status of 0 (58%) or 1 (42%). Demographic and disease characteristics were balanced across arms.

Results are presented in Figure 5 and Table 13.

Figure 5: Kaplan-Meier Curves for Overall Survival in Persistent, Recurrent, or Metastatic Cervical Cancer in Study GOG-0240

Table 13: Efficacy Results in Study GOG-0240

Efficacy Parameter	Avastin with Chemotherapy (N=227)	Chemotherapy (N=225)
* Kaplan-Meier estimates. † log-rank test (stratified).
Overall Survival
Median, in months*	16.8	12.9
Hazard ratio (95% CI)	0.74 (0.58, 0.94)
p-value†	0.0132

The ORR was higher in patients who received Avastin with chemotherapy [45% (95% CI: 39, 52)] compared to patients who received chemotherapy alone [34% (95% CI: 28,40)].

Table 14: Efficacy Results in Study GOG-0240

Efficacy Parameter	Topotecan and Paclitaxel with or without Avastin (N=223)	Cisplatin and Paclitaxel with or without Avastin (N=229)
* Kaplan-Meier estimates.
Overall Survival
Median, in months*	13.3	15.5
Hazard ratio (95% CI)	1.15 (0.91, 1.46)
p-value	0.23

The HR for OS with Avastin with cisplatin and paclitaxel as compared to cisplatin and paclitaxel alone was 0.72 (95% CI: 0.51,1.02). The HR for OS with Avastin with topotecan and paclitaxel as compared to topotecan and paclitaxel alone was 0.76 (95% CI: 0.55, 1.06).

14.7 Stage III or IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Following Initial Surgical Resection

14.8 Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

14.9 Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

14.10 Hepatocellular Carcinoma

The efficacy of Avastin in combination with atezolizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (<400 vs. ≥400 ng/mL), and by ECOG performance status (0 vs. 1).

A total of 501 patients were randomized (2:1) to receive either atezolizumab as an intravenous infusion of 1200 mg, followed by 15 mg/kg Avastin, on the same day every 3 weeks or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. Patients could discontinue either atezolizumab or Avastin (e.g., due to adverse events) and continue on single-agent therapy until disease progression or unacceptable toxicity associated with the single-agent.

The study enrolled patients who were ECOG performance score 0 or 1 and who had not received prior systemic treatment. Patients were required to be evaluated for the presence of varices within 6 months prior to treatment, and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients with Child-Pugh B or C cirrhosis, moderate or severe ascites; history of hepatic encephalopathy; a history of autoimmune disease; administration of a live, attenuated vaccine within 4 weeks prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases were excluded. Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter.

The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The median age was 65 years (range: 26 to 88) and 83% of patients were male. The majority of patients were Asian (57%) or White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥400 ng/mL. Baseline ECOG performance status was 0 (62%) or 1 (38%). HCC risk factors were Hepatitis B in 48% of patients, Hepatitis C in 22% and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage C (82%) disease at baseline, while 16% had stage B and 3% had stage A.

The major efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression free survival (PFS) per RECIST v1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST.

Efficacy results are presented in Table 20 and Figure 10.

Figure 10: Kaplan-Meier Plot of Overall Survival in IMbrave150

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.

Gastrointestinal Perforations and Fistulae: Avastin may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting [see Warnings and Precautions (5.1)].

Surgery and Wound Healing Complications: Avastin can increase the risk of wound healing complications. Instruct patients not to undergo surgery without first discussing this potential risk with their healthcare provider [see Warnings and Precautions (5.2)].

Hemorrhage: Avastin can increase the risk of hemorrhage. Advise patients to immediately contact their healthcare provider for signs and symptoms of serious or unusual bleeding including coughing or spitting blood [see Warnings and Precautions (5.3)].

Arterial and Venous Thromboembolic Events: Avastin increases the risk of arterial and venous thromboembolic events. Advise patients to immediately contact their healthcare provider for signs and symptoms of arterial or venous thromboembolism [see Warnings and Precautions (5.4, 5.5)].

Hypertension: Avastin can increase blood pressure. Advise patients that they will undergo routine blood pressure monitoring and to contact their healthcare provider if they experience changes in blood pressure [see Warnings and Precautions (5.6)].

Posterior Reversible Leukoencephalopathy Syndrome: Posterior reversible encephalopathy syndrome (PRES) has been associated with Avastin treatment. Advise patients to immediately contact their healthcare provider for new onset or worsening neurological function [see Warnings and Precautions (5.7)].

Renal Injury and Proteinuria: Avastin increases the risk of proteinuria and renal injury, including nephrotic syndrome. Advise patients that treatment with Avastin requires regular monitoring of renal function and to contact their healthcare provider for proteinuria or signs and symptoms of nephrotic syndrome [see Warnings and Precautions (5.8)].

Infusion-Related Reactions: Avastin can cause infusion-related reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.9)].

Congestive Heart Failure: Avastin can increase the risk of developing congestive heart failure. Advise patients to contact their healthcare provider immediately for signs and symptoms of CHF [see Warnings and Precautions (5.12)].

Embryo-Fetal Toxicity: Advise female patients that Avastin may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Ovarian Failure: Avastin may lead to ovarian failure. Advise patients of potential options for preservation of ova prior to starting treatment [see Warnings and Precautions (5.11)].

Lactation: Advise women not to breastfeed during treatment with Avastin and for 6 months after the last dose [see Use in Specific Populations (8.2)].