Juvenile Animal Toxicity Data
`Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks
`exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and
`severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.
`
`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 A vastin 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)].
`
`11 DESCRIPTION
`Bevacizumab is a vascular endothelial growth factor inhibitor. Bevacizumab is a recombinant humanized
`monoclonal IgG 1 antibody that contains human framework regions and murine complementarity-determining
`regions. Bevacizumab has an approximate molecular weight of 149 kDa. Bevacizumab is produced in a
`mammalian cell (Chinese Hamster Ovary) expression system.
`
`Avastin (bevacizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale
`brown solution in a single-dose vial for intravenous use. A vastin contains bevacizumab at a concentration of 25
`mg/mL in either a 100 mg/4 mL or 400 mg/16 mL single-dose vial.
`
`Each mL of solution contains 25 mg bevacizumab, a,a-trehalose dihydrate (60 mg), polysorbate 20 (0.4 mg),
`sodium phosphate dibasic, anhydrous (1.2 mg), sodium phosphate monobasic, monohydrate (5.8 mg), and
`Water for Injection, USP. The pH is 6.2.
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Bevacizumab binds VEGF and prevents the interaction ofVEGF to its receptors (Flt-1 and KDR) on the surface
`of endothelial cells. The interaction ofVEGF 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 A vastin 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.
`
`Distribution
`The mean(% coefficient of variation [CV%]) central volume of distribution is 2.9 (22%) L.
`
`Elimination
`The mean (CV%) clearance is 0.23 (33) L/day. The estimated half-life is 20 days (11 to 50 days).
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0024
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Specific Populations
`The clearance of bevacizumab varied by body weight, sex, and tumor burden. After correcting for body weight,
`males had a higher bevacizumab clearance (0.26 L/day vs. 0.21 L/day) and a larger central volume of
`distribution (3.2 L vs. 2.7 L) than females. Patients with higher tumor burden (at or above median value of
`tumor surface area) had a higher bevacizumab clearance (0.25 L/day vs. 0.20 L/day) than patients with tumor
`burdens below the median. In Study AVF2107g, there was no evidence oflesser efficacy (hazard ratio for
`overall survival) in males or patients with higher tumor burden treated with A vastin as compared to females and
`patients with low tumor burden.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No studies have been conducted to assess potential ofbevacizumab for carcinogenicity or mutagenicity.
`
`Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended
`human dose ofbevacizumab 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 ofreversibility. 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 CLINICAL STUDIES
`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-lFL, or Avastin (5 mg/kg every 2 weeks)
`with fluorouracil and leucovorin. Enrollment to the A vastin with fluorouracil and leucovorin arm was
`discontinued after enrollment of 110 patients in accordance with the protocol-specified adaptive design. A vastin
`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 A vastin improved survival across subgroups defined by age ( < 65 years, ~ 65 years) and sex.
`Results are presented in Table 11 and Figure 1.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0025
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 11: Efficacy Results in Study A VF2107g
`
`Efficacy Parameter
`
`Overall Survival
`Median, in months
`Hazard ratio
`(95% CI)
`p-value•
`Progression-Free Survival
`Median, in months
`Hazard ratio
`(95% CI)
`o-value•
`Overall Response Rate
`Rate(%)
`p-valueb
`Duration of Response
`Median, in months
`• by stratified log-rank test.
`b by x2 test
`
`Avastin with bolus-lFL I Placebo with bolus-IFL
`(N=411)
`(N=402)
`
`20.3
`
`10.6
`
`45%
`
`10.4
`
`I
`0.66
`(0.54, 0.81)
`< 0.001
`
`I
`0.54
`(0.45, 0.66)
`< 0.001
`
`I
`< 0.01
`
`I
`
`15.6
`
`6.2
`
`35%
`
`7.1
`
`Figure 1: Kaplan-Meier Curves for Duration of Survival in Metastatic Colo rectal Cancer in Study
`AVF2107g
`
`O>
`
`.£ 1 :, "' C
`.Q l a.
`
`IFL + Placebo
`-
`IFL + AvasLin
`-
`0.0 ~ - - - - - - - - - - - - - - - -~
`0
`12
`18
`24
`30
`6
`No.of patienls at risk
`IFL + Placebo 411
`IFL + Avaslin 402
`
`349
`353
`
`247
`77
`105
`295
`Duration of Survival (Months)
`
`15
`27
`
`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 ofresponse was 8.5 months.
`
`StudyE3200
`The safety and efficacy of A vastin were evaluated in a randomized, open-label, active-controlled study [E3200
`(NCT00025337)] in 829 patients who were previously treated with irinotecan and fluorouracil for initial therapy
`for metastatic disease or as adjuvant therapy. Patients were randomized (1: 1: 1) to FOLFOX4 (Day 1: oxaliplatin
`85 mg/m2 and leucovorin 200 mg/m2 concurrently, then fluorouracil 400 mg/m2 bolus followed by 600 mg/m2
`continuously; Day 2: leucovorin 200 mg/m2, then tluorouracil 400 mg/m2 bolus followed by 600 mg/m2
`continuously; every 2 weeks), Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4,
`or Avastin alone (10 mg/kg every 2 weeks). Avastin was continued until disease progression or unacceptable
`toxicity. The main outcome measure was OS.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0026
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`The A vastin alone arm was closed to accrual after enrollment of 244 of the planned 290 patients following a
`planned interim analysis by the data monitoring committee based on evidence of decreased survival compared
`to FOLFOX4 alone.
`
`The median age was 61 years; 60% were male, 87% were White, 49% had an ECOG performance status of 0,
`26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior
`irinotecan with or without fluorouracil for metastatic disease, and 1 % received prior irinotecan and fluorouracil
`as adjuvant therapy.
`
`The addition of A vastin to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone;
`median OS was 13.0 months vs. 10.8 months [hazard ratio (HR) 0.75 (95% CI: 0.63, 0.89), p-value of 0.001
`stratified log-rank test] with clinical benefit seen in subgroups defined by age (<65 years, :?:65 years) and sex.
`PFS and ORR based on investigator assessment were higher in patients receiving Avastin with FOLFOX4.
`
`Study TRC-0301
`The activity of Avastin with fluorouracil (as bolus or infusion) and leucovorin was evaluated in a single arm
`study [TRC-0301 (NCT00066846)] enrolling 339 patients with mCRC with disease progression following both
`irinotecan- and oxaliplatin-based chemotherapy. Seventy-three percent of patients received concurrent bolus
`fluorouracil and leucovorin. One objective partial response was verified in the first 100 evaluable patients for an
`ORR of 1 % (95% CI: 0%, 5.5%).
`
`Study ML18147
`The safety and efficacy of A vastin 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 A vastin 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 A vastin 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.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0027
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 12: Efficacy Results in Study ML18147
`
`Efficacy Parameter
`
`Overall Survival"
`Median, in months
`
`Hazard ratio (95% CI)
`
`Proe:ression-Free Survivalb
`Median, in months
`
`Hazard ratio (95% Cl)
`
`• p=0.0057 by unstratified log-rank test.
`b p-value < 0.0001 by unstratified log-rank test.
`
`Avastin with Chemotherapy
`(N=409)
`
`Chemotherapy
`(N=4)1)
`
`11.2
`
`5.7
`
`0.81 (0.69, 0.94)
`
`0.68 (0.59, 0.78)
`
`9.8
`
`4.0
`
`Figure 2: Kaplan-Meier Curves for Duration of Survival in Metastatic Colorectal Cancer in Study
`ML18147
`
`Proportion Surviving
`
`1.0
`
`0~
`
`0.7
`
`o.e
`
`O..!I
`
`OA
`
`O.J
`
`0 .2
`
`0.1
`
`o.o
`
`0
`
`6
`
`12
`
`18
`
`30
`
`36
`
`not ri!k
`rn
`Cllemo
`Clemo + AwStin 409
`
`Rondomited lreotment
`
`29J
`J28
`
`162
`188
`
`~I
`s.
`
`24
`29
`
`7
`13
`
`Chtmo
`Chemo + A-.ostin
`
`48
`
`Study Month
`
`0
`0
`
`14.2 Lack of Efficacy in Adjuvant Treatment of Colon Cancer
`Lack of efficacy of A vastin 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 [BO 17920 (NCT00 112918)] 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= l 155) or on
`a 3-weekly schedule with XELOX (N= l 145) or FOLFOX4 alone (N= l 151). The main outcome measure was
`disease free survival (DFS) in patients with stage ill colon cancer.
`
`The median age was 58 years; 54% were male, 84% were White and 29% were 2:: 65 years. Eighty-three percent
`had stage ill disease.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0028
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`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 A vastin with FOLFOX4 or with XELOX. The hazard ratios for DFS
`were 1.17 (95% CI: 0.98, 1.39) for A vastin 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
`A vastin with XELOX versus FOLFOX4 alone, respectively. Similar lack of efficacy for DFS was observed in
`the A vastin-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 A vastin 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
`
`StudyE4599
`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-naive 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 ofred 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 A vastin 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 A vastin with paclitaxel and carboplatin
`compared to chemotherapy alone. Results are presented in Figure 3.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0029
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Figure 3: Kaplan-Meier Curves for Duration of Survival in First-Line Non-Squamous Non-Small Cell
`Lung Cancer in Study E4599
`
`1.0
`
`08
`
`0.2
`
`0.0
`
`-
`-
`
`PC(n=444)
`PC+Avastin (n=434)
`
`No.of patients at risk
`-
`PC
`-
`PC+Avastin
`
`444
`434
`
`10
`
`219
`256
`
`30
`20
`Duration of Survival (months)
`
`76
`101
`
`9
`25
`
`40
`
`T
`50
`
`In an exploratory analysis across patient subgroups, the impact of A vastin on OS was less robust in the
`following subgroups: women [HR0.99 (95% CI: 0.79, 1.25)], patients ~65 years [HR0.91 (95% CI: 0.72,
`1.14)] and patients with ~5% weight loss at study entry [HR0.96 (95% CI: 0.73, 1.26)].
`
`Study BO 17704
`The safety and efficacy of Avastin in patients with locally advanced, metastatic or recurrent non-squamous
`NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind,
`placebo-controlled study [BO17704 (NCT00806923)]. A total of 1043 patients were randomized (1 :1:1) to
`receive cisplatin and gemcitabine with placebo, Avastin 7.5 mg/kg or Avastin 15 mg/kg. The main outcome
`measure was PFS. Secondary outcome measure was OS.
`
`The median age was 58 years; 36% were female and 29% were ~ 65 years. Eight percent had recurrent disease
`and 77% had Stage IV disease.
`
`PFS was significantly higher in both Avastin-containing arms compared to the placebo arm [HR 0.75 (95% CI:
`0.62, 0.91), p-value of0.0026 for Avastin 7.5 mg/kg and HR 0.82 (95% CI: 0.68; 0.98), p-value of0.0301 for
`A vastin 15 mg/kg] . The addition of A vastin to cisplatin and gemcitabine failed to demonstrate an improvement
`in the duration of OS [HR 0.93 (95% CI: 0.78; 1.11), p-value of0.420 for Avastin 7.5 mg/kg and HR 1.03 (95%
`CI: 0.86, 1.23), p-value of 0.761 for Avastin 15 mg/kg].
`
`14.4 Recurrent Glioblastoma
`
`Study EORTC 26101
`The safety and efficacy of Avastin were evaluated in a multicenter, randomized (2:1), open-label study in
`patients with recurrent GBM (EORTC 26101, NCT01290939). Patients with first progression following
`radiotherapy and temozolomide were randomized (2:1) to receive Avastin (10 mg/kg every 2 weeks) with
`lomustine (90 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6 weeks) alone until disease progression or
`unacceptable toxicity. Randomization was stratified by World Health Organization performance status (0 vs.
`>O), steroid use (yes vs. no), largest tumor diameter (:S 40 vs. > 40 mm), and institution. The main outcome
`measure was OS. Secondary outcome measures were investigator-assessed PFS and ORR per the modified
`Response Assessment in Neuro-oncology (RANO) criteria, health related quality oflife (HRQoL), cognitive
`function, and corticosteroid use.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0030
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`A total of 432 patients were randomized to receive lomustine alone (N=l49) or Avastin with lomustine
`(N=283). The median age was 57 years; 24.8% of patients were 2'.: 65 years. The majority of patients with were
`male (61 %); 66% had a WHO performance status score> O; and in 56% the largest tumor diameter was:::; 40
`mm. Approximately 33% of patients randomized to receive lomustine received Avastin following documented
`progression.
`
`No difference in OS (HR 0.91, p-value of 0.4578) was observed between arms; therefore, all secondary
`outcome measures are descriptive only. PFS was longer in the A vastin with lomustine arm [HR 0.52 (95% CI:
`0.41, 0.64)] with a median PFS of 4.2 months in the Avastin with lomustine arm and 1.5 months in the
`lomustine arm. Among the 50% of patients receiving corticosteroids at the time of randomization, a higher
`percentage of patients in the Avastin with lomustine arm discontinued corticosteroids (23% vs. 12%).
`
`Study AVF3708g and Study NCI 06-C-0064E
`The efficacy and safety of A vastin 10 mg/kg every 2 weeks in patients with previously treated GBM were
`evaluated in one single arm single center study (NCI 06-C-0064E) and a randomized noncomparative
`multicenter study [AVF3708g (NCT00345163)]. Response rates in both studies were evaluated based on
`modified WHO criteria that considered corticosteroid use. In AVF3708g, the response rate was 25.9% (95% CI:
`17%, 36.1 %) with a median duration ofresponse of 4.2 months (95% CI: 3, 5.7). In Study NCI 06-C-0064E, the
`response rate was 19.6% (95% CI: 10.9%, 31.3%) with a median duration ofresponse of 3.9 months (95% CI:
`2.4, 17.4).
`
`14.5 Metastatic Renal Cell Carcinoma
`
`Study BO 17705
`The safety and efficacy of A vastin were evaluated in patients with treatment-naive mRCC in a multicenter,
`randomized, double-blind, international study [BOl 7705 (NCT00738530)] comparing interferon alfa and
`A vastin 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%
`m1ssmg.
`
`PFS was statistically significantly prolonged among patients receiving A vastin 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 of23 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.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0031
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Metastatic Renal Cell Carcinoma in
`Study BO17705
`
`1.0
`
`0.8
`
`0 .2
`
`0 .0 -t.:==========-------------,-J
`
`18
`
`24
`
`-
`-
`
`Placebo + IFN-alfa (n=322 )
`Avastin + IFN-alfa (n=327)
`
`12
`
`No.of patients at risk
`Placebo + IFN-alfa 322
`-
`-
`Avastin + IFN-alfa 327
`
`Progression Free Survival (Months)
`
`116
`176
`
`49
`87
`
`10
`9
`
`14.6 Persistent, Recurrent, or Metastatic Cervical Cancer
`
`Study GOG-0240
`The safety and efficacy of A vastin were evaluated in patients with persistent, recurrent, or metastatic cervical
`cancer in a randomized, four-arm, multicenter study comparing A vastin 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 A vastin, or paclitaxel and topotecan with or without A vastin.
`
`The dosing regimens for A vastin, 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 17 5 mg/m2 over 3 hours with cisplatin 50 mg/m2 with A vastin;
`• 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 ofless than 6 months. Patients had a GOG performance status of O (58%) or 1
`( 42% ). Demographic and disease characteristics were balanced across arms.
`
`Results are presented in Figure 5 and Table 13.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0032
`Regeneron v. Novartis, IPR2021-00816
`
`