Figure 5: Kaplan-Meier Curves for Overall Survival in Persistent, Recurrent, or Metastatic Cervical
`Cancer in Study GOG-0240
`
`1.0
`
`0.8
`
`.;
`
`·" 2: ::,
`
`v, 0.0 1 0
`
`5
`'e 0.4
`8.
`e
`a.
`
`0.2
`
`Chemo alone (n- 225)
`- - - Chemo+Bev (n=227)
`0.0t====:::::;::=====;;::::'....---~---~----~---~---~_J
`24
`42
`36
`6
`18
`30
`0
`12
`
`Overal Survival (months)
`
`Number et Risk:
`Chemo alone
`Chemo+Bev
`
`225
`227
`
`171
`188
`
`102
`128
`
`49
`73
`
`21
`35
`
`8
`12
`
`1
`3
`
`Table 13: Efficacy Results in Study GOG-0240
`
`Efficacy Parameter
`
`Overall Survival
`Median, in months•
`Hazard ratio (95% CI)
`p-valueb
`• Kaplan-Meier estimates.
`log-rank test ( stratified).
`b
`
`A vastin with
`Chemotherapy
`(N=227)
`
`Chemotherapy
`(N=225)
`
`16.8
`
`12.9
`
`0.74 (0.58, 0.94)
`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% Cl: 28,40)].
`
`Table 14: Efficacy Results in Study GOG-0240
`
`Efficacy Parameter
`
`Overall Survival
`Median, in months•
`Hazard ratio (95% CI)
`p-value
`
`• Kaplan-Meier estimates.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Topotecan and
`Paclitaxel with or
`without A vastin
`(N=223)
`
`Cisplatin and Paclitaxel
`with or without Avastin
`(N=229)
`
`13.3
`
`15.5
`
`1.15 (0.91, 1.46)
`0.23
`
`Novartis Exhibit 2259.0033
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`The HR for OS with A vastin with cisplatin and paclitaxel as compared to cisplatin and paclitaxel alone was
`0.72 (95% Cl: 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 Ill or IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Following Initial
`Surgical Resection
`
`Study GOG-0218
`The safety and efficacy of A vastin were evaluated in a multicenter, randomized, double-blind, placebo
`controlled, three arm study [Study GOG-0218 (NCT00262847)] evaluating the effect of adding Avastin to
`carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube or
`primary peritoneal cancer (N= 1873) following initial surgical resection. Patients were randomized ( 1: 1 : 1) to one
`of the following arms:
`
`• CPP: carboplatin (AUC 6) and paclitaxel (175 mg/m2
`) for six cycles, with concurrent placebo started at cycle
`2, followed by placebo alone every three weeks for a total of up to 22 cycles of therapy (n=625) or
`
`• CPB15: carboplatin (AUC 6) and paclitaxel (175 mg/m2
`) for six cycles, with concurrent Avastin started at
`cycle 2, followed by placebo alone every three weeks for a total of up to 22 cycles of therapy (n=625) or
`
`• CPB15+: carboplatin (AUC 6) and paclitaxel (175 mg/m2) for six cycles, with concurrent Avastin started at
`
`cycle 2, followed by A vastin as a single agent every three weeks for a total of up to 22 cycles of therapy
`(n=623).
`
`The main outcome measure was investigator-assessed PFS. OS was a secondary outcome measure.
`
`The median age was 60 years (range 22-89 years) and 28% of patients were >65 years of age.
`Overall, approximately 50% of patients had a GOG PS of O at baseline, and 43% a GOG PS score of 1. Patients
`had either epithelial ovarian cancer (83%), primary peritoneal cancer (15%), or fallopian tube cancer (2%).
`Serous adenocarcinoma was the most common histologic type (85% in CPP and CPB 15 arms, 86% in CPB 15+
`arm). Overall, approximately 34% of patients had resected FIGO Stage III with residual disease < 1 cm, 40%
`had resected Stage III with residual disease > 1 cm, and 26% had resected Stage IV disease.
`
`The majority of patients in all three treatment arms received subsequent antineoplastic treatment, 78.1 % in the
`CPP arm, 78.6% in the CPB15 arm, and 73.2% in the CPB15+ arm. A higher proportion of patients in the CPP
`arm (25.3%) and CPB 15 arm (26.6%) received at least one anti-angiogenic (including bevacizumab) treatment
`after discontinuing from study compared with the CPB15+ arm (15.6%).
`
`Study results are presented in Table 15 and Figure 6.
`
`Table 15: Efficacy Results in Study GOG-0218
`
`Efficacy Parameter
`
`Progression-Free Survival per
`lnvestie:ator
`Median, in months
`Hazard ratio (95% Cl)l
`p - valueb
`Overall Survivalc
`Median, in months
`Hazard ratio (95% CI)a
`
`Avastin with carboplatin
`and paclitaxel followed
`by A vastin alone
`(N=623)
`
`A vastin with carboplatin
`and paclitaxel
`(N=625)
`
`Carboplatin and
`paclitaxel
`(N= 625)
`
`18.2
`0.62 (0.52, 0.75)
`< 0.0001
`
`43.8
`0.89 (0.76, 1.05)
`
`12.8
`0.83 (0.70, 0.98)
`NS
`
`38.8
`1.06 (0.90, 1.24)
`
`12.0
`
`40.6
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0034
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`NS=not significant
`• Relative to the control arm; stratified hazard ratio
`b Two-sided p-value based on re-randomization test
`c Final overall survival analysis
`
`Figure 6: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Stage III or IV
`Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Following Initial Surgical Resection in
`Study GOG-0218
`
`1.0
`
`0.8
`
`0.2
`
`0.0
`
`0
`
`Nurrbcr o1 patients at risk
`625
`CFP
`625
`CFB1S
`623
`CF815t
`
`t--= cen sored \lfl lue
`
`CP? (n:::-625)
`
`CPB1 0 (n:625)
`
`CPB1 5+ (n.;;23)
`
`6
`
`391
`<09
`419
`
`12
`
`152
`173
`193
`
`18
`
`T
`24
`
`52
`21
`65
`22
`27
`74
`Progrc:!t.slOl'I- F, ec Sur'Vi\1'1!11 mcnth s)
`
`30
`,,
`
`10
`9
`
`36
`
`6
`s
`5
`
`42
`
`48
`
`14.8 Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
`
`Study MO22224
`The safety and efficacy of Avastin were evaluated in a multicenter, open-label, randomized study [MO22224
`(NCT00976911)] comparing Avastin with chemotherapy versus chemotherapy alone in patients with
`platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within
`<6 months from the most recent platinum-based therapy (N=361). Patients had received no more than 2 prior
`chemotherapy regimens. Patients received one of the following chemotherapy regimens at the discretion of the
`investigator: paclitaxel (80 mg/m2 on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin 40
`mg/m2 on day 1 every 4 weeks; or topotecan 4 mg/m2 on days 1, 8 and 15 every 4 weeks or 1.25 mg/m2 on days
`1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty
`percent of patients on the chemotherapy alone arm received A vastin alone upon progression. The main outcome
`measure was investigator-assessed PFS. Secondary outcome measures were ORR and OS.
`
`The median age was 61 years (25 to 84 years) and 37% of patients were :2::65 years. Seventy-nine percent had
`measurable disease at baseline, 87% had baseline CA-125 levels 2:2 times ULN and 31 % had ascites at baseline.
`Seventy-three percent had a platinum-free interval (PFI) of 3 months to 6 months and 27% had PFI of <3
`months. ECOG performance status was O for 59%, 1 for 34% and 2 for 7% of the patients.
`
`The addition of Avastin to chemotherapy demonstrated a statistically significant improvement in
`investigator-assessed PFS, which was supported by a retrospective independent review analysis. Results for the
`ITT population are presented in Table 16 and Figure 7. Results for the separate chemotherapy cohorts are
`presented in Table 17.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0035
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 16: Efficacy Results in Study M022224
`
`Efficacy Parameter
`
`A vastin with
`Chemotherapy
`(N=179)
`
`Chemotherapy
`(N=182)
`
`13.3 (I 1.9, 16.4)
`16.6 (13.7, 19.0)
`0.89 (0.69, 1.14)
`
`Pro2ression-Free Survival per Investi2ator
`3.4 (2.1, 3.8)
`Median (95% Cl), in months
`6.8 (5.6, 7.8)
`HR(95% Cl)"
`0.38 (0.30, 0.49)
`p-value "
`<0.0001
`Overall Survival
`Median (95% CI), in months
`HR(95% CI)•
`Overall Response Rate
`Number of Patients with
`Measurable Disease at Baseline
`Rate, % (95% CI)
`Duration of Response
`Median, in months
`• per stratified Cox proport10nal hazards model
`b per stratified Jog-rank test
`
`142
`
`144
`
`28% (21%, 36%)
`
`13% (7%, 18%)
`
`9.4
`
`5.4
`
`Figure 7: Kaplan-Meier Curves for Investigator-Assessed Progression-Free Survival in Platinum(cid:173)
`Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study
`M022224
`
`1.0
`
`0.8
`
`0.2
`
`0.0
`
`0
`
`CT (n=162)
`CT+BV (n=179)
`
`6
`
`9
`
`12
`
`15
`
`18
`
`Duration of Progression-free Survival (months}
`
`Number at R iSk
`CT
`CT+BV
`
`182
`179
`
`92
`144
`
`35
`91
`
`18
`51
`
`9
`19
`
`1
`6
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`21
`
`0
`
`0
`0
`
`Novartis Exhibit 2259.0036
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 17: Efficacy Results in Study M022224 by Chemotherapy
`
`Efficacy
`Parameter
`
`Paclitaxel
`
`Topotecan
`
`Pegylated Liposomal
`Doxorubicin
`
`A vastin with Chemotherapy
`Chemotherapy
`(N=60)
`
`(N=SS)
`
`A vastin with Chemotherapy
`Chemotherapy
`(N=57)
`
`(N=63)
`
`A vastin with Chemotherapy
`Chemotherapy
`(N=62)
`
`(N=64)
`
`9.6
`(7.8, 11.5)
`
`3.9
`(3.5, 5.5)
`
`0.47
`(0.31, 0.72)
`
`22.4
`(16.7, 26.7)
`
`13.2
`(8.2, 19.7)
`
`0.64
`(0.41, 1.01)
`
`Progression-Free Survival per Investigator
`Median, in
`months
`(95% CI)
`Hazard
`ratio a
`(95%CD
`Overall Survival
`Median, in
`months
`(95% CI)
`Hazard
`ratio a
`(95% CI)
`Overall Response Rate
`Number of
`patients
`with
`measurable
`disease at
`baseline
`Rate,%
`53
`(39 68)
`(95% CI)
`Duration of Response
`Median, in
`months
`• per stratified Cox proportional hazards model
`NE=Not Estimable
`
`45
`
`43
`
`30
`(17 44)
`
`11.6
`
`6.8
`
`6.2
`(5.3, 7.6)
`
`2.1
`(1.9, 2.3)
`
`5.1
`(3.9, 6.3)
`
`3.5
`(1.9, 3.9)
`
`0.24
`(0.15, 0.38)
`
`0.47
`(0.32, 0.71)
`
`13.8
`(11.0, 18.3)
`
`13.3
`(10.4, 18.3)
`
`13.7
`(11.0, 18.3)
`
`14.1
`(9.9, 17.8)
`
`1.12
`(0.73, 1.73)
`
`0.94
`(0.63, 1.42)
`
`46
`
`50
`
`51
`
`51
`
`17
`(6. 28)
`
`5.2
`
`2
`(0. 6)
`
`NE
`
`16
`(6 26)
`
`8
`(0 15)
`
`8.0
`
`4.6
`
`14.9 Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
`
`Study AVF4095g
`The safety and efficacy of A vastin were evaluated in a randomized, double-blind, placebo-controlled study
`[A VF4095g (NCT00434642)] 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). Patients
`were randomized (1:1) to receive Avastin (15 mg/kg day 1) or placebo every 3 weeks with carboplatin (AUC 4,
`day 1) and gemcitabine ( 1000 mg/m2 on days 1 and 8) a for 6 to 10 cycles followed by A vastin or placebo alone
`until disease progression or unacceptable toxicity. The main outcome measures were investigator-assessed PFS.
`Secondary outcome measures were ORR and OS.
`
`The median age was 61 years (28 to 87 years) and 37% of patients were 265 years. All patients had measurable
`disease at baseline, 74% had baseline CA-125 levels >ULN (35 U/mL). The platinum-free interval (PFI) was 6
`months to 12 months in 42 % of patients and >1 2 months in 58% of patients. The ECOG performance status
`was O or 1 for 99 .8% of patients.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0037
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`A statistically significant prolongation in PFS was demonstrated among patients receiving A vastin with
`chemotherapy compared to those receiving placebo with chemotherapy (Table 18 and Figure 8). Independent
`radiology review of PFS was consistent with investigator assessment [HR 0.45 (95% CI: 0.35, 0.58)]. OS was
`not significantly improved with the addition of Avastin to chemotherapy [HR 0.95 (95% CI: 0.77, 1.17)].
`
`Table 18: Efficacy Results in Study A VF4095g
`
`Efficacy Parameter
`
`Progression-Free Survival
`Median in months
`Hazard ratio
`(95% CI)
`p-value
`Overall Response Rate
`% patients with overall
`response
`P-Value
`
`A vastin with Gemcitabine
`and Carboplatin
`(N=242)
`
`Placebo with Gemcitabine and
`Carboplatin
`(N=242)
`
`12.4
`
`78%
`
`8.4
`
`57%
`
`0.46
`(0.37, 0.58)
`< 0.0001
`
`< 0.0001
`
`Figure 8: Kaplan-Meier Curves for Progression-Free Survival in Platinum-Sensitive Recurrent Epithelial
`Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Study A VF4095g
`,oF ~~~~-=::::-------------------------7
`- -... __ .
`
`09
`
`08
`
`07
`
`03
`
`02
`
`-- .. . I •
`
`,_ ---. --- --- --------------
`CG+& I
`I RandomtZed treatment
`ooi:=:=====::::;::::====-------------.-----------,.------___!,I
`
`0,
`
`0
`
`CG• Bv ~·"
`
`CG•PI
`242
`
`- - CG+PI
`
`-
`
`$
`
`:,00
`
`176
`
`12
`T me si'l::e Randomizatbn (months.)
`
`18
`
`24
`
`30
`
`0,:,
`
`44
`
`,.
`
`11
`
`3
`
`Study GOG-0213
`The safety and efficacy of A vastin were evaluated in a randomized, controlled, open-label study [Study GOG-
`0213 (NCT00565851)] 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). Patients were randomized (1: 1) to receive
`carboplatin (AUC 5) and paclitaxel (175 mg/m2 IV over 3 hours) every 3 weeks for 6 to 8 cycles (N=336) or
`Avastin (15 mg/kg) every 3 weeks with carboplatin (AUC 5) and paclitaxel (175 mg/m2 IV over 3 hours) for 6
`to 8 cycles followed by Avastin (15 mg/kg every 3 weeks) as a single agent until disease progression or
`unacceptable toxicity. The main outcome measure was OS. Other outcome measures were investigator-assessed
`PFS, and ORR.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0038
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`The median age was 60 years (23 to 85 years) and 33% of patients were ~ 65 years. Eighty-three percent had
`measurable disease at baseline and 74% had abnormal CA-125 levels at baseline. Ten percent of patients had
`received prior bevacizumab. Twenty-six percent had a PFI of 6 months to 12 months and 74% had a PFI of > 12
`months. GOG performance status was O or 1 for 99% of patients.
`
`Results are presented in Table 19 and Figure 9.
`
`Table 19: Efficacy Results in Study GOG-0213
`
`Efficacy Parameter
`
`Overall Survival
`Median, in months
`Hazard ratio (95% Cl) (IVRS)•
`Hazard ratio (95% Cl) (eCRF)b
`Progression-Free Survival
`Median, in months
`Hazard ratio (95% CI) (TVRS)•
`Overall Response Rate
`Number of patients with
`measurable disease at baseline
`
`Avastin with Carboplatin and
`Paclitaxel
`(N=337)
`
`Carboplatin and Paclitaxel
`(N=336)
`
`42.6
`
`13.8
`
`274
`
`0.84 (0.69, 1.01)
`0.82 (0.68. 0.996)
`
`0.61 (0.51 0.72)
`
`37.3
`
`10.4
`
`286
`
`Rate, %
`
`213 (78%)
`
`159 (56%)
`
`• HR was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval pnor to enrolling onto this study per
`IVRS (interactive voice response system) and secondary surgical debulking status.
`b HR was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per
`eCRF (electronic case report form) and secondary surgical debulking status.
`
`Figure 9: Kaplan Meier Curves for Overall Survival in Platinum-Sensitive Recurrent Epithelial Ovarian,
`Fallopian Tube, or Primary Peritoneal Cancer in Study GOG-0213
`---
`
`~ede re .atinent
`
`-
`
`Cftl.•P.IC!
`
`-
`
`-
`
`Ctb.P1c.+g
`
`' 0
`
`00
`
`00
`
`07
`
`f ••
`r· n,
`
`03
`
`02
`
`01
`
`00
`
`C rb•P10
`
`.. ,.f ... ..,
`.,.
`,,,
`
`C11>•Ptc,+e..,
`
`,,
`
`••
`
`27•
`
`322
`
`305
`
`>20 - .,.
`
`2•
`
`235
`
`...
`
`3()
`
`....
`...
`
`~
`
`...
`.. ,
`
`STIJOYilr,tON'1l-i
`
`.,
`. ..
`
`,,.
`
`••
`,.
`
`70
`
`..
`..
`'"
`
`..
`
`22
`
`»
`
`..
`
`72
`
`71
`
`..
`
`0
`
`0
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0039
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`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. 2:400 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 A vastin, 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 O 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 O (62%) or 1 (38%). HCC risk factors were Hepatitis Bin 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 Band 3% had stage A.
`
`The major efficacy outcome measures were overall survival (OS) and independent review facility (IRF)(cid:173)
`assessed progression free survival (PFS) per RECIST vl.1. Additional efficacy outcome measures were IRF(cid:173)
`assessed overall response rate (ORR) per RECIST and mRECIST.
`
`Efficacy results are presented in Table 20 and Figure 10.
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0040
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Table 20: Efficacy Results from 1Mbrave150
`
`Avastin in combination with Atezolizumab
`(N= 336)
`
`Overall Survival
`Number of deaths(%)
`Median OS in months
`(95% CI)
`Hazard ratio 1 (95% CI)
`p-value2
`Progression-Free Survival3
`Number of events(%)
`Median PFS in months (95% CI)
`
`Hazard ratio 1 (95% CI)
`p-value
`Overall Response Rate3•5 (ORR), RECIST 1.1
`Number of responders(%)
`
`(95% CI)
`p-value4
`
`Complete responses, n (%)
`
`Partial responses, n (%)
`Duration ofResponse3•5 (DOR) RECIST 1.1
`
`Median DOR in months
`(95% CI)
`
`Range (months)
`
`Overall Response Rate3•5 (ORR), HCC mRECIST
`Number of responders(%)
`(95% Cl)
`p-value4
`
`Complete responses, n (%)
`Partial responses, n (%)
`Duration of Response3•5 (DOR) HCC mRECIST
`
`Median DOR in months
`(95% CI)
`Range (months)
`
`96 (29)
`NE
`(NE, NE)
`
`197 (59)
`6.8 (5.8, 8.3)
`
`93 (28)
`
`(23, 33)
`
`22 (7)
`
`71 (21)
`
`(n=93)
`NE
`(NE, NE)
`
`(1.3+, 13.4+)
`
`112 (33)
`(28, 39)
`
`37 (11)
`75 (22)
`
`(n= l 12)
`NE
`(NE, NE)
`(1.3+, 13.4+)
`
`0.58 (0.42, 0.79)
`0.00062
`
`0.59 (0.47, 0.76)
`<0.0001
`
`<0.0001
`
`<0.0001
`
`Sorafenib
`(N=165)
`
`65 (39)
`13.2
`(10.4, NE)
`
`109 (66)
`4.3 (4.0, 5.6)
`
`19 (12)
`
`(7,17)
`
`0
`
`19 (12)
`
`(n= l9)
`6.3
`(4.7, NE)
`
`(1.4+, 9.1+)
`
`21 (13)
`(8, 19)
`
`3 (1.8)
`18 (11)
`
`(n=21)
`6.3
`(4.9, NE)
`(1.4+, 9.1+)
`
`1 Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs.
`absence), and baseline AFP (<400 vs. :::400 ng/mL)
`2 Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using
`the OBF method
`3 Per independent radiology review
`4 Based on two-sided Cochran-Mantel-Haesnszel test
`5 Confirmed responses
`+ Denotes a censored value
`CI=confidence interval; HCC mRECIST= Modified RECIST Assessment for Hepatocellular Carcinoma; NE=not estimable; N/A=not
`annlicable; RECIST 1.1 = Resoonse Evaluation Criteria in Solid Tumors vi .1
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0041
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Figure 10: Kaplan-Meier Plot of Overall Survival in IMbrave150
`
`1.0 -i-++-~,,,,_-(cid:173)
`ii 0.9
`>
`-~ 0.8
`:,
`~ 0.7
`~
`~ 0.6
`0
`0 0.5
`? 0.4
`:.:;
`~ 0.3
`0 O:. 0.2
`0.1 + AVASTIN + atozolizOOl8b
`O + Sorafeni>
`0
`2
`
`3
`
`4
`
`I
`
`I I-+ --+
`
`5
`
`6
`
`9
`8
`7
`Time (months)
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`No. of Patients at Risk
`AVASTIN + alezolizumab
`Sorafenib
`
`336
`165
`
`329
`157
`
`320
`143
`
`312
`132
`
`302
`127
`
`288
`118
`
`275
`105
`
`255
`94
`
`222
`86
`
`165
`60
`
`118
`45
`
`87
`33
`
`64
`24
`
`40
`16
`
`20
`7
`
`11
`3
`
`3
`1
`
`NE
`NE
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`A vastin (bevacizumab) injection is a clear to slightly opalescent, colorless to pale brown, sterile solution for
`intravenous infusion supplied as single-dose vials in the following strengths:
`
`• 100 mg/4 mL: carton of one vial (NOC 50242-060-01); carton of 10 vials (NOC 50242-060-10).
`• 400 mg/16 mL: carton of one vial (NOC 50242-061-01); carton of 10 vials (NOC 50242-061-10).
`
`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.
`
`17 PATIENT COUNSELING INFORMATION
`
`Gastrointestinal Perforations and Fistulae: A vastin may increase the risk of developing gastrointestinal
`perforations and fistulae. Advise patients to immediately contact their health care 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 health
`care 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 health care provider for signs and symptoms of arterial or
`venous thromboembolism [see Warnings and Precautions (5.4, 5.5)].
`
`Hypertension: A vastin 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 A vastin treatment. Advise patients to immediately contact their health care provider
`for new onset or worsening neurological function [see Warnings and Precautions (5. 7)].
`
`https://www.gene.com/download/pdf/avastin_prescribing.pdf
`
`Novartis Exhibit 2259.0042
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Renal Injury and Proteinuria: Avastin increases the risk of proteinuria and renal injury, including nephrotic
`syndrome. Advise patients that treatment with A vastin requires regular monitoring of renal function and to
`contact their health care 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: A vastin 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 A vastin and for 6 months after the last dose
`[see Use in Specific Populations (8.2)).
`
`A vastin® (bevacizumab)
`Manufactured by:
`Genentech, Inc.
`A Member of the Roche Group
`I DNA Way
`South San Francisco, CA 94080-4990
`
`A vastin® is a registered trademark of Genentech, Inc.
`©2021 Genentech, Inc.
`
`https://www.gene.com/download/pdf/avastin_prescribing pdf
`
`Novartis Exhibit 2259.0043
`Regeneron v. Novartis, IPR2021-00816
`
`