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The pivotal AVF2107g trial: first-line Avastin in combination with irinotecan-based chemotherapy

Phase III, multicentre, double-blind(A study in which both the investigator and the participant are blind to (unaware of) the nature of the treatment the participant is receiving), active-controlled(When a treatment exists that is clearly better than doing nothing for the subject (i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy), randomised(How subjects are assigned to a treatment arm in a study. The treatment a subject receives is determined by chance alone) trial in patients with previously untreated mCRC.1

Patients were randomised to receive1

  • IFL (bolus(The administration of a drug, medication or other substance in the form of a single, large dose) 5-FU 500mg/m2; LV 20mg/m2; irinotecan 125mg/m2 given once weekly for 4 weeks with a cycle repeated every 6 weeks) plus placebo: n=411.
  • Avastin (5mg/kg every 2 weeks) plus IFL: n=402.
  • Avastin (5mg/kg every 2 weeks) plus 5-FU/LV (bolus 5-FU 500mg/m2; LV 500mg/m2 given every 6/8 weeks): n=110.

After approximately 100 patients had been enrolled into each treatment arm, a planned, interim safety analysis by the DSMB (independent data-monitoring committee) concluded that the combination of Avastin with IFL had an acceptable safety profile. Therefore, assignment to this arm will continue.

Primary endpoint

  • OS(The time from trial entry to death from any cause).

Secondary endpoints

  • PFS(The time from trial entry to disease progression or death from any cause).
  • ORR(The proportion of patients with defined tumour shrinkage; generally the sum of partial responses plus complete responses).
  • Duration of response(The length of time after treatment that a patient remains in complete or partial remission).
  • QoL(A phrase used to refer to an individual’s total well-being).
  • Safety.

Treatment duration

  • Median duration of Avastin therapy was 40.4 weeks in the group receiving Avastin plus IFL and 27.6 weeks in the group receiving IFL plus placebo.1

AVF2107g: effect of Avastin on OS

The combination of Avastin with IFL resulted in a statistically and clinically significant(A measure of the importance of a therapy, treatment or a related side effect that may impact clinical practice) improvement in OS.1

Patients treated with Avastin combined with IFL had increased OS (20.3 months) compared with patients treated with IFL plus placebo (15.6 months)

  • HR(An estimate of relative risk of an event occurring)=0.66; 95% CI(A range of values used to indicate the reliability of an estimate (or a set of values within which there is a specified probability)): 0.54–0.81; p<0.001.
  • This corresponds to a reduction of 34% in the risk of death.

The 1-year survival(Number of patients who are surviving 1 year after starting treatment) rates were 74.3% in patients receiving Avastin combined with IFL and 63.4% in patients receiving IFL plus placebo (p<0.001).

AVF2107g: effect of Avastin on OS in predefined subgroups

Combination of Avastin with IFL resulted in improved OS in patients regardless of2

  • ECOG performance status.
  • Sex.
  • Location of primary tumour(The original cancer, located at the site where it first arose).
  • Duration of metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part) disease.
  • Number of baseline metastatic sites.
  • Prior adjuvant chemotherapy.
  • Prior radiotherapy.
  • Serum albumin, alkaline phosphatase, lactate dehydrogenase.
  • Age.
  • Race.

Demonstrated by a HR <1 (denoting increased OS for patients treated with Avastin plus IFL versus those treated with IFL plus placebo).2

AVF2107g: effect of Avastin on PFS

Patients receiving Avastin plus IFL had significantly longer median PFS (10.6 months) than those treated with IFL plus placebo (6.2 months)1

  • HR=0.54; 95% CI: 0.45–0.66, p<0.001. This corresponds to a 46% decrease in the risk of progression(A carcinogenic process whereby genetically altered cells undergo a second (non-genetic) cell expansion resulting in uncontrollable growth).

AVF2107g: effect of Avastin on ORR and duration of response

Combining Avastin with IFL significantly improved the ORR compared with IFL plus placebo (44.8% vs 34.8%, respectively, p=0.004).1

Duration of response was prolonged by 3.3 months in patients receiving Avastin plus IFL compared with those receiving IFL plus placebo (10.4 vs 7.1 months, respectively)1

  • HR=0.62; p=0.001.

AVF2107g: comparison of response rate and duration1

  IFL + placebo (n=411) IFL + Avastin (n=402)
ORR
    95% CI
    Complete response (%)
    Partial response (%)
    p value
 34.8
30.2–39.6
2.2
32.6
 44.8
39.9–49.8
3.7
41.0
0.004
Median duration of response (months)
    95% CI
    p value
 7.1
6.0–9.1
 10.4
9.3–11.7
0.001

NO16966: first-line Avastin in combination with oxaliplatin-based chemotherapy in mCRC

Originally designed as a two-arm, open-label(A type of clinical trial in which both the researchers and participants know which treatment is being administered) study, to which 634 patients were randomised to receive either FOLFOX4 or XELOX.

Following data from the pivotal phase III trial of Avastin, AVF2107g, the NO16966 protocol was amended

  • Patients were randomised to receive FOLFOX4 or XELOX combined with Avastin or placebo.
  • FOLFOX4 arm (every 2 weeks): on day 1, patients received either Avastin 5mg/kg or placebo, oxaliplatin 85mg/m2 i.v., leucovorin 200mg/m2 i.v., 5-FU 400mg/m2 i.v. bolus, followed by 5-FU 600mg/m2 i.v.; on day 2, patients received the same treatment as on day 1 but without Avastin/placebo and oxaliplatin.
  • XELOX arm (every 3 weeks): on day 1, patients received either Avastin 7.5mg/kg or placebo, oxaliplatin 130mg/m2 i.v.; on days 2–14 patients received Xeloda 1,000mg/m2 orally twice daily; patients did not receive any treatment on days 15–21.

Phase III, multicentre, placebo-controlled(A way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect), 2x2 factorial, randomised trial in patients with mCRC3,4

  • FOLFOX4 arm (every 2 weeks): on day 1, patients received either Avastin 5mg/kg or placebo, oxaliplatin 85mg/m2 i.v., leucovorin 200mg/m2 i.v., 5-FU 400mg/m2 i.v. bolus, followed by 5-FU 600mg/m2 i.v.; on day 2, patients received the same treatment as on day 1 but without Avastin/placebo and oxaliplatin.
  • XELOX arm (every 3 weeks): on day 1, patients received Avastin 7.5mg/kg or placebo, oxaliplatin 130mg/m2 i.v.; on days 2–14 patients received Xeloda 1,000mg/m2 orally twice daily; patients did not receive any treatment on days 15–21.

Two primary objectives

  • XELOX (with or without Avastin) is at least as effective as FOLFOX4 (with or without Avastin) in terms of PFS.3
  • PFS with Avastin plus either chemotherapy (XELOX or FOLFOX4) is superior to PFS with chemotherapy alone.4

The second primary objective only is reported here.

Primary endpoint

  • PFS.

Secondary endpoints

  • ORR.
  • OS.
  • Time to response(The time from the start of treatment to when the effect of the treatment can be measured).
  • Duration of response.
  • TTF(The time from the start of treatment to when the treatment is no longer effective).
  • Safety.

NO16966: effect of Avastin on PFS

Combining Avastin with XELOX or FOLFOX4 significantly improved PFS compared with chemotherapy alone (median PFS 9.4 vs 8.0 months, respectively; HR=0.83; 97.5% CI: 0.72–0.95; p=0.0023).4

Importance of treatment to progression

  • Only 29% and 47% of Avastin and placebo patients, respectively, were treated until progression, as per the protocol recommendation.
  • For patients who remained ‘on treatment’ (active treatment continued until PD or death) median PFS was further increased in the Avastin plus XELOX or FOLFOX4 arm compared with chemotherapy alone (10.4 vs 7.9 months; p<0.0001).3,4
  • After approximately 6 months, the PFS curve for Avastin treatment in the ‘general’ population deviates from that of the ‘on-treatment’ curve; suggesting that a large group of patients discontinued treatment and were not treated until progression as recommended in the protocol.
  • The reasons why some patients were not treated until progression are not clear. However, these data clearly demonstrate the clinical benefits of treating patients with Avastin to PD.

NO16966: effect of Avastin on OS

Median OS was 21.3 months in the Avastin group and 19.9 months in the placebo group.4 This difference did not reach statistical significance (HR=0.89; 97.5% CI: 0.76–1.03; p=0.077).

NO16966: effect of Avastin on ORR and duration of response

ORR was similar when combining Avastin with oxaliplatin compared with oxaliplatin plus placebo (odds ratio = 0.90)4

  • Response rate assessed by study investigators were in the upper expected range for the chemotherapy regimens used (47% and 49% for Avastin plus chemotherapy vs chemotherapy alone, respectively).
  • Response rate by the IRF were lower than the investigator-assessed rates (38% for both groups).
  • Discrepancies in response rate between the reviewers reflect a common phenomenon with regard to differential judgments of partial response(A 30% decrease in the sum of the longest diameter of target lesions following treatment) and stable disease(Description of a tumour that is neither growing nor shrinking. Stable disease also means that no new tumours have developed, and that the cancer has not spread to any new regions of the body (the cancer is not getting better or worse)).

Duration of response was prolonged by 1 month in patients receiving Avastin plus oxaliplatin compared with those receiving oxaliplatin plus placebo (8.45 vs 7.4 months, respectively; HR=0.82; p=0.0307).4

References

  1. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med 2004;350:2335–42.
  2. Fyfe GA, Hurwitz H, Fehrenbacher L, et al. J Clin Oncol 2004;22(July 15 Suppl.):274s (Abstract 3617 and associated poster presentation).
  3. Cassidy J, Clarke S, Díaz-Rubio E, et al. J Clin Oncol 2008;26:2006–12.
  4. Saltz L, Clarke S, Díaz-Rubio E, et al. J Clin Oncol 2008;26:2013–9.

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