Efficacy in MCRC

k-ras status in MCRC

k-ras as a biomarker for response to therapy

k-ras is the human gene that codes for the Ras signaling protein. In a normal cell, when the endothelial growth factor receptor (EGFR) is activated, Ras is involved in cell growth and migration.1,2 However, approximately 40% of MCRC tumors have k-ras mutations.3,4 Mutations in the k-ras gene may render Ras constitutively activated, independent of the EGFR, thereby resulting in continuous proliferation and survival of the cancer cell.1-5 k-ras mutations have been shown to have negative predictive value for anti-EGFR treatment of MCRC.6,7 Patients with k-ras mutations do not appear to derive clinical benefit from anti-EGFR monoclonal antibody treatment.6,8-11

Association of k-ras with the treatment effect of Avastin-based therapy in first-line MCRC: a retrospective analysis

  • A retrospective analysis of pivotal first-line Study 2107 evaluated whether k-ras mutation status was a predictor of clinical benefit with Avastin-based therapy in a subset of patients who consented to research on tumor tissue samples (n=230)3
    • 78 patients (34%) had mutant k-ras status
    • 152 patients (66%) had wild-type k-ras status
Clinical benefit by k-ras status in Study 21073,7

Clinical benefit by k-ras status in Study 2107

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%)

Based on the results seen in these retrospective analyses, the study investigators concluded

  • Patients derived significant clinical benefits from Avastin-based therapy vs chemotherapy alone, regardless of their k-ras mutation status3
  • The relative clinical benefits associated with Avastin-based therapy, as shown by the PFS and OS results, were comparable in k-ras mutant and k-ras wild-type groups7
  • k-ras status does not predict clinical benefit from Avastin-based treatment in combination with chemotherapy7
  • The role of vascular endothelial growth factor (VEGF) as the primary angiogenic factor is supported by the finding that both k-ras wild-type and k-ras mutant patients derived the same benefit from Avastin-based therapy3
  • These findings should be confirmed prospectively in a large clinical trial7

PFS by k-ras status in Study 2107

Group: Wild-type (n=152)7||

Group: Wild-type (n=152)

  • ||Median PFS: 13.5 vs 7.4 months (HR=0.44, P<0.001).
Group: Mutant (n=78)7¶

Group: Mutant (n=78)

  • Median PFS: 9.3 vs 5.5 months (HR=0.41, P=0.0008).

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: Biomarker Status

References
  1. Fedi P, Kimmelman A, Aaronson SA. In: Holland J, Frei E, eds. Cancer Medicine. 5th ed. Hamilton, Ontario: BC Decker, Inc; 2000:33-55.
  2. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
  3. Ince WI, Jubb AM, Holden SN, et al. J Natl Cancer Inst. 2005;97:981-988.
  4. Andreyev HJ, Norman AR, Cunningham D, et al. J Natl Cancer Inst. 1998;90:675-684.
  5. Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA. Cancer Cell. 2003;3:219-231.
  6. Data on file. Genentech, Inc.
  7. Hurwitz HI, Yi J, Ince W, et al. Oncologist. 2009;14:1-7.
  8. Amado RG, Wolf M, Peeters M, et al. J Clin Oncol. 2008;26:1626-1634.
  9. Bokemeyer C, Bondarenko I, Makhson A, et al. J Clin Oncol. 2009;27:655-658.
  10. Lièvre A, Bachet JB, Le Corre D, et al. Cancer Res. 2006;66:3992-3995.
  11. Di Fiore F, Blanchard F, Charbonnier F, et al. Br J Cancer. 2007;96:1166-1169.