Efficacy in MCRC

Significant survival benefits seen in first-line MCRC with Avastin plus IV 5-FU–containing regimens

Avastin in combination with IFL

Study 2107

The pivotal trial of Avastin in first-line MCRC was Study 2107. In this randomized, controlled Phase III trial (N=923), patients were randomized to receive IFL plus placebo (Arm 1), IFL plus Avastin 5 mg/kg IV every 2 weeks (q2w) (Arm 2), or IV 5-FU/LV plus Avastin 5 mg/kg IV q2w (Arm 3). The primary endpoint in Study 2107 was OS; secondary efficacy endpoints—ORR, PFS, and response duration—were also assessed.1,2 In situations where early discontinuation of chemotherapy was required due to increased toxicity, Avastin could be continued until disease progression per study protocol.2

Phase III Study 2107 study design1,2

Avastin based therapy - Phase III Study design

Arm 3 was initiated so that an analysis could be completed in the event that safety issues required discontinuation of Arm 2. As prespecified, enrollment in this treatment arm was discontinued when the relative safety of Avastin plus IFL was established in an interim analysis.1,2

Significant increase in OS

In Study 2107, Avastin plus IFL achieved its primary endpoint by demonstrating a statistically significant 30% increase in median OS vs IFL alone (20.3 vs 15.6 months, HR=0.66, P<0.001). The 4.7-month increase in survival attributable to Avastin plus IFL is larger than that observed in any Phase III MCRC trial to date. This survival benefit was achieved with Avastin given until disease progression, per study protocol. The median duration of therapy in the treatment group was 40.4 weeks.1,2

Boxed WARNINGS

  • Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 2.4%) in Avastin-treated patients compared to controls. Discontinue Avastin for GI perforation
  • Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage: Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Click here for additional important safety information.

30% increase in median OS* with Avastin plus IFL in first-line MCRC1-3

30% increase in overall survival (OS) with Avastin plus IFL in first-line MCRC

  • *Median OS: 20.3 vs 15.6 months (HR=0.66, P<0.001).1,2

The 4.7-month increase in survival attributable to Avastin plus IFL in Study 2107 is longer than that observed in any Phase III MCRC trial to date.1

Significant increases in other efficacy endpoints

In addition to the significant increase in OS, Avastin plus IFL also demonstrated significant benefits in secondary trial endpoints. Compared with IFL alone, Avastin plus IFL resulted in a 4.4-month (71%) increase in median PFS (10.6 vs 6.2 months, P<0.001).1,2

Early separation of the PFS curves in Study 2107 reflects the significant reduction in the risk of disease progression with Avastin plus IFL. In pivotal first-line Study 2107, nearly 90% of patients who remained progression free at 1 year were still receiving Avastin.2,3 Compared with IFL alone, Avastin plus IFL also resulted in a significant increase in ORR (45% vs 35%, P<0.01).1,2

71% increase in median PFS† in first-line MCRC1,2

Avastin based therapy - Progression-free survival in Study 2107

  • †Median PFS: 10.6 vs 6.2 months (HR=0.54, P<0.001).1,2

Avastin plus IFL also resulted in significant increases in tumor response. The ORR was 45% with Avastin plus IFL vs 35% with IFL alone (P<0.01), while duration of response increased by 46% in the Avastin arm (10.4 vs 7.1 months).1,2

Tumor response in Study 21071,2

Avastin based therapy - Tumor response in Study 2107

  • ‡P<0.01.
Important safety information—Study 2107
  • The most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

Bevacizumab-based therapy: an NCCN-recommended regimen to consider for challenging patient types and resectable candidates

  • Bevacizumab plus IV 5-FU/LV is an NCCN-recommended option for patients who cannot tolerate intensive chemotherapy4

Phase II first-line Study 2192

  • Study 2192 was a randomized, controlled Phase II study of IV 5-FU/LV ± Avastin in patients deemed not suitable for first-line irinotecan (age ≥65 years, ECOG 1 or 2, albumin ≤3.5 g/dL, or prior radiotherapy to abdomen or pelvis)5
67% increase in PFS§ in patients not suitable for first-line combination chemotherapy5

67% increase in PFS in patients not suitable for first-line combination chemotherapy

  • NCCN=National Comprehensive Cancer Network.
  • ECOG=Eastern Cooperative Oncology Group.
  • §Median PFS: 9.2 vs 5.5 months (HR=0.50, P=0.0002).4

For resectable and unresectable candidates who will be treated with bevacizumab-based therapy, the 2010 NCCN guidelines recommend the following5||

2010 NCCN guidelines for resectable and unresectable candidates who will be treated with bevacizumab-based therapy

  • ||Excerpted from NCCN guidelines.
  • Treatment given before surgery in order to reduce the size of the tumor.

NCCN treatment timeline for resectable first-line MCRC patients1,5,6

NCCN treatment timeline for resectable first-line MCRC patients

  • #Hold bevacizumab for 28 days or until incision is fully healed.

  • Considering its approximately 20-day half-life (range 11–50 days), bevacizumab should be suspended for at least 28 days prior to elective surgery1
    • NCCN guidelines recommend at least a 6-week interval prior to surgery5
  • Bevacizumab should not be initiated (or reinitiated) for at least 28 days following surgery and until the surgical wound is fully healed1,6
    • NCCN guidelines recommend reinitiation at least 6–8 weeks postoperatively, if reinitiation is decided5

First-line Avastin improves outcomes across patient subgroups

Increased survival demonstrated across subgroups in first-line MCRC1-3**

Increased survival demonstrated across subgroups in first-line MCRC

  • **All of the above were prespecified analyses, with the exception of the liver-only disease subgroup analysis. Additional prespecified subgroups with survival increases included age <40, age 40–64, sex, race, location of primary tumor, duration of metastatic disease, baseline albumin, baseline alkaline phosphatase, baseline lactate dehydrogenase, duration of disease, sum of the longest diameters of target lesions, and prior radiotherapy.
  • †† The organs with the most frequent occurrence of metastatic disease were liver (78%), lung (48%), and lymph nodes (25%).
  • ‡‡Based on an exploratory analysis of prospectively collected data.

In second-line Study E3200, increased survival was demonstrated in prespecified subgroups including age, sex, race, ECOG performance status, prior radiotherapy, number of involved sites, and baseline tumor burden.1,3

Indication

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information

  • Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

  • Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

  • Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

  • Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

  • The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

Please see full Prescribing Information, including Boxed WARNINGS for additional safety information.

Next: Second-line MCRC

References
  1. Avastin Prescribing Information, Genentech, Inc. July 2009.
  2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  3. Data on file. Genentech, Inc.
  4. Kabbinavar FF, Schulz J, McCleod M, et al. J Clin Oncol. 2005;23:3697-3705.
  5. The NCCN Colon Cancer Clinical Practice Guidelines in Oncology (Version 2.2010). ©2010 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed January 8, 2010. To view the most recent and complete version of the guidelines, go online to www.nccn.org.
  6. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. J Surg Oncol. 2005;91:173-180.