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Current treatment landscape

A total of six novel therapies have been approved for the treatment of mRCC in the last 3–5 years, including the humanised(The process of making a monoclonal antibody from an animal more similar to a human antibody to reduce the likelihood of toxic effects) monoclonal anti-VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) antibody Avastin,1 the TKIs sunitinib, sorafenib and pazopanib,2–4 and the mTOR(A serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription) inhibitors temsirolimus and everolimus.5,6

The European ESMO guidelines recommend Avastin plus IFN(A type of immunotherapy. A natural substance produced in the body in tiny amounts as part of the immune response. It is given in much larger quantities as treatment to boost the immune system and help fight cancer) or sunitinib as first-line therapy in good and intermediate MSKCC risk(A validated and widely used prognostic score in patients with metastatic renal cell carcinoma (mRCC). Also known as Motzer score) patients7

  • The recently updated US NCCN guidelines recommend Avastin plus IFN, sunitinib or pazopanib as a first-line treatment option in patients with good- and intermediate-MSKCC risk.8
  • In poor MSKCC risk patients, temsirolimus is recommended.7,8


ESMO guidelines 2009: algorithm for systemic treatment of renal carcinoma7

Histology and setting Risk group Standard Option
Clear-cell first line Good or intermediate Avastin + IFN, sunitinib
 Cytokines (including high dose IL-2)
Poor Temsirolimus Sunitinib
Clear cell second line Post cytokines
Post TKIs
 Sorafenib
Everolimus
 Sunitinib
Non-clear cell histology     Temsirolimus
Sunitinib
Sorafenib
Escudier B, et al. Annals of Oncology 2009; 20(Suppl. 4): by permission of Oxford University Press.

AVOREN: phase III trial of Avastin plus IFN

The pivotal phase III randomised(How subjects are assigned to a treatment arm in a study. The treatment a subject receives is determined by chance alone), double blind, 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) trial of first-line Avastin plus IFN compared with IFN plus placebo in patients with advanced RCC.1,9

Trial endpoints

  • Primary: OS(The time from trial entry to death from any cause)
  • Secondary: 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), safety.

Treatment administration

  • Avastin/placebo 10mg/kg every 2 weeks until progression(A carcinogenic process whereby genetically altered cells undergo a second (non-genetic) cell expansion resulting in uncontrollable growth).
  • IFN 9MIU three times a week (maximum of 52 weeks; dose reduction allowed).

Stratification factors: country and MSKCC score.

Patients were recruited from 101 trial centres in 18 countries (excluding the USA).

AVOREN was a large pivotal, randomised, 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), placebo-controlled trial of Avastin plus IFN in patients with untreated mRCC

AVOREN: effect of Avastin plus IFN on PFS

Avastin plus IFN first-line significantly improves median PFS beyond 10 months

Two phase III studies showed statistically significant(Pertaining to an event that is unlikely to have occurred by chance) improvement of PFS

In AVOREN, median PFS was significantly extended by the addition of Avastin to IFN, from 5.4 to 10.2 months (HR(An estimate of relative risk of an event occurring)=0.63, p<0.0001 [unstratified]) compared with IFN plus placebo1

  • This represents an 89% improvement in median PFS with Avastin plus IFN.

Independent review confirms the robustness of the investigator PFS assessment

  • Median PFS of 10.4 months with Avastin plus IFN compared with a median PFS of 5.5 months with IFN plus placebo (HR=0.57; p<0.001 [stratified(The process of dividing members of the population into homogeneous subgroups before sampling)]).9

Avastin plus IFN significantly improves median PFS in both favourable- and intermediate-MSKCC risk categories (12.9 vs 7.6 months and 10.2 vs 4.5 months, respectively).1


 Investigator
 IRC
Avastin + IFN
(n=327)		 Placebo + IFN
(n=322)		 Avastin + IFN
(n=288)		 Placebo + IFN
(n=281)
Median PFS (months) 10.2 5.4
 10.4 5.5
HR; p value
 0.63; <0.0001 0.57; <0.001

CALGB 90206 is a US-based phase III trial comparing Avastin plus IFN with IFN monotherapy(Treatment of a condition by means of a single drug).10–12

Data from CALGB 90206 support the improvement in PFS observed in AVOREN: PFS was 8.4 months with Avastin plus IFN compared with 4.9 months with IFN monotherapy (HR=0.71; p<0.001 [stratified]).12

While AVOREN and CALGB 90206 are similar trials evaluating Avastin plus IFN in patients with mRCC, there are number of important differences between the two trials

  • AVOREN is a pivotal, double-blind, placebo-controlled, randomised trial whereas CALGB 90206 is an open-label(A type of clinical trial in which both the researchers and participants know which treatment is being administered), randomised cooperative group trial. 
  • The median duration of trial therapy was shorter in CALGB 90206 (3.8 months)10 compared with AVOREN (9.7 months).1
  • Prior nephrectomy was a requirement for inclusion in the AVOREN trial, but not in CALGB 90206.
  • The proportion of tumour(An abnormal growth of cells, forming a mass of tissue) with clear cell histology had to be >50% in AVOREN, this was not specified in CALGB 90206.
  • A greater level of proteinuria(The presence of an excess of serum proteins in the urine) was allowed in CALGB 90206 compared to AVOREN (CALGB 90206: <2g/24 hours; AVOREN: ≤0.5g/24 hours).

 

Importance of PFS as a clinical endpoint in mRCC

PFS may be the best primary endpoint to assess the true efficacy(The capacity for beneficial change (or therapeutic effect) of a given intervention) of novel therapies in diseases where multiple lines of therapy are available

  • The FDA and the EMEA accept PFS as a valid measure of clinical benefit, particularly in diseases where patients receive multiple lines of therapy and situations where post-trial therapy is expected to confound analysis of OS benefit.13,14
  • Several therapies including Avastin plus IFN, sunitinib, everolimus and pazopanib have received regulatory approval based on significant PFS benefit observed in phase III trials.

AVOREN: effect of Avastin plus IFN on response rates

High response and tumour control rates with first line Avastin plus IFN therapy

Avastin plus IFN significantly improved ORR compared with IFN plus placebo (31% vs 13%, p<0.0001)1

  • Partial responses were more frequently observed with Avastin plus IFN (30% vs 11%).1
  • Complete responses were observed in 1% of patients treated with Avastin plus IFN and 2% treated with IFN plus placebo.1
  • Tumour control was observed in 77% of patients treated with Avastin plus IFN.1

Duration of response(The length of time after treatment that a patient remains in complete or partial remission) 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)) were longer with Avastin plus IFN compared with IFN plus placebo (13.5 vs 11.1 months; 10.1 vs 7.2 months, respectively).1

AVOREN: tumour response1

  Avastin + IFN (n=306)   Placebo + IFN (n=289)
Overall response (%)

    Complete response
    Partial response
 31

1
30
p<0.0001
 13

2
11
Duration of response (months) 13.5   11.1
Duration of stable disease (months) 10.1   7.2
Reprinted from The Lancet, 370, Escudier, et al., 2103–11, 2007 with permission from Elsevier. http://www.thelancet.com/.

The significant improvement in response rate with Avastin plus IFN in AVOREN was similar to that observed in CALGB 90206 where ORR was 26% with Avastin plus IFN versus 13% with IFN monotherapy (p<0.0001).12

AVOREN: effect of Avastin plus IFN on OS

Patients with metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part) RCC achieved a median OS of approximately 2 years with first-line Avastin plus IFN

OS in the ITT(Usually pertaining to an analysis that is based on the initial treatment intent, not on the treatment eventually administered) population

The final analysis of OS in the AVOREN trial showed a numerical improvement in OS in the Avastin plus IFN arm compared with IFN plus placebo, but the difference was not statistically significant (23.3 vs 21.3 months; HR=0.86 [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)): 0.72–1.04]; p=0.1291 [stratified]).9

AVOREN is the second phase III trial of a novel agent as first-line therapy for mRCC to report a statistically non-significant increase in OS despite significant PFS benefit

  • Several potential reasons may explain why a statistically significant OS benefit was not observed in AVOREN, but the extensive use of active subsequent therapy is likely.

A similar numerical, not statistically significant, improvement in survival with Avastin plus IFN was observed in CALGB 90206: OS was 18.3 months with Avastin plus IFN compared with 17.4 months with IFN monotherapy (HR=0.86; p=0.069 [stratified]).10

Differences in trial design and patient inclusion/exclusion criteria(The standards used to determine whether a person may or may not be allowed to participate in a clinical trial) may account for the differences in OS observed with AVOREN versus CALGB 90206.

AVOREN: effect of Avastin plus reduced-dose IFN on efficacy

IFN dose reduction appears not to impact Avastin plus IFN efficacy

Retrospective analysis of AVOREN suggests that efficacy was maintained in patients in whom the dose of IFN was reduced in combination with Avastin to manage tolerability

  • PFS rate in the Avastin plus reduced-dose IFN population was 52% at 12 months (median 12.4 months),15,16 which is comparable to the overall Avastin plus IFN population.

Effect of known RCC prognostic factors

Adjustment for known RCC prognostic factors results in a more pronounced treatment effect on OS in AVOREN

A prespecified multiple Cox regression(A characteristic of diseases to show lighter symptoms without completely disappearing. At a later point, symptoms may return ) model indicated that several baseline prognostic factors were associated with survival independent of treatment

  • Adjustment for these baseline factors resulted in a treatment HR of 0.78 (95% CI [0.63–0.96], p=0.0219), indicating a 22% reduction in the risk of death for patients in the Avastin plus IFN arm compared with IFN plus placebo.9

AVOREN: multivariate Cox regression analysis9

Variables HR 95% CI p-value
Randomised treatment (Avastin + IFN vs IFN + placebo) 0.78
 0.63–0.96

0.0219
Gender (male vs female)
 0.78
 0.62–0.97

0.0275
Baseline WBC Count (≤ULN vs >ULN) 0.71 0.52–0.96

0.0250
Baseline platelets (≤ULN vs >ULN) 0.73 0.54–0.99 0.0397
Body weight loss (≤10% vs >10%) 0.73
 0.54–0.99

0.0435
Number of metastatic sites (1 vs all other) 0.68
 0.52–0.91

0.0087

Baseline SLD (<median vs ≥median)

 0.64
 0.51–0.80

<0.0001

Motzer score (intermediate vs all other)

 0.42
 0.29–0.59

<0.0001

Motzer score (favourable vs all other)

 0.24
 0.16–0.36

<0.0001
© 2010 American Society of Clinical Oncology. All rights reserved.

Summary

Avastin plus IFN first-line significantly improves PFS to beyond 10 months.

References

  1. Escudier B, Pluzanska A, Koralewski P, et al. Lancet 2007;370:2103–11.
  2. Escudier B, Eisen T, Stadler WM, et al. J Clin Oncol 2009;27:3312–8.
  3. Motzer RJ, Hutson TE, Tomczak P, et al. J Clin Oncol 2009;27:3584–90.
  4. Sternberg CN, Davis, ID, Mardiak J, et al. J Clin Oncol 2010;28:1061–8.
  5. Hudes G, Carducci M, Tomczak P, et al. N Engl J Med 2007;356:2271–81
  6. Motzer RJ, Escudier B, Oudard S, et al. Lancet 2008;372:449–56.
  7. Escudier B, Kataja V. Ann Oncol 2009;20(Suppl. 4):81–2.
  8. National Comprehensive Cancer Network. Clinical practice guidelines in oncology - v.1.2009: Kidney Cancer. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  9. Escudier B, Bellmunt J, Negrier S, et al. J Clin Oncol 2010;28:2144–50.
  10. Rini B, Halabi S, Rosenberg JE, et al. J Clin Oncol 2010;28:2137–43.
  11. Rini BI, Halabi S, Rosenberg JE, et al. J Clin Oncol 2008;26:5422–8.
  12. Rini BI, Halabi S, Rosenberg J, et al. J Clin Oncol 2009;27(June 20 Suppl.):798s (Abstract LBA5019 and associated oral presentation).
  13. Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. Published May 2007.
  14. European Agency for the Evaluation of Medicinal Products. Guideline on the Evaluation of Anticancer Medicinal Products in Man. Published December 2005.
  15. Melichar B, Koralewski P, Ravaud A, et al. Ann Oncol 2008;19:1470–6.
  16. Melichar B, Koralewski P, Pluzanska A, et al. Eur J Cancer Suppl 2007;5:304 (Abstract 4518).

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