Avastin: Package Insert and Label Information (Page 4 of 6)

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
Figure 3
(click image for full-size original)

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)].

Study BO17704

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 of 0.0026 for Avastin 7.5 mg/kg and HR 0.82 (95% CI: 0.68; 0.98), p-value of 0.0301 for Avastin 15 mg/kg]. The addition of Avastin 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 of 0.420 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. >0), steroid use (yes vs. no), largest tumor diameter (≤ 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 of life (HRQoL), cognitive function, and corticosteroid use.

A total of 432 patients were randomized to receive lomustine alone (N=149) or Avastin with lomustine (N=283). The median age was 57 years; 24.8% of patients were ≥ 65 years. The majority of patients with were male (61%); 66% had a WHO performance status score > 0; 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 Avastin 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 Avastin 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 of response 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 of response of 3.9 months (95% CI: 2.4, 17.4).

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
Figure 4
(click image for full-size original)

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 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 11.

Figure 5: Kaplan-Meier Curves for Overall Survival in Persistent, Recurrent, or Metastatic Cervical Cancer in Study GOG-0240
Figure 5
(click image for full-size original)
Table 11: Efficacy Results in Study GOG-0240
Efficacy ParameterAvastin with Chemotherapy(N=227)Chemotherapy(N=225)
*
Kaplan-Meier estimates.
log-rank test (stratified).
Overall Survival
Median, in months *16.812.9
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 12: Efficacy Results in Study GOG-0240
Efficacy ParameterTopotecan and Paclitaxel with or without Avastin(N=223)Cisplatin and Paclitaxelwith or without Avastin(N=229)
*
Kaplan-Meier estimates.
Overall Survival
Median, in months *13.315.5
Hazard ratio (95% CI)1.15 (0.91, 1.46)
p-value0.23

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

Study GOG-0218

The safety and efficacy of Avastin 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 Avastin 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 0 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 CPB15 arms, 86% in CPB15+ 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 CPB15 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 13 and Figure 6.

Table 13: Efficacy Results in Study GOG-0218
Efficacy ParameterAvastin with carboplatin and paclitaxel followed by Avastin alone(N=623)Avastin with carboplatin and paclitaxel(N=625)Carboplatin and paclitaxel(N= 625)
NS=not significant
*
Relative to the control arm; stratified hazard ratio
Two-sided p-value based on re-randomization test
Final overall survival analysis
Progression-Free Survival per Investigator
Median, in months18.212.812.0
Hazard ratio (95% CI)*0.62 (0.52, 0.75)0.83 (0.70, 0.98)
p –value < 0.0001NS
Overall Survival
Median, in months43.838.840.6
Hazard ratio (95% CI)*0.89 (0.76, 1.05)1.06 (0.90, 1.24)
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

Figure 6
(click image for full-size original)

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