EURURO Vol. 73 No. 1

RCC

[6] .

Previous data have shown that non

–

clear cell

tumour subtypes represent a very diverse group of

malignancies that usually have less robust responses to

VEGF inhibitors compared with clear cell tumours

[6] .

Therefore, inclusion of patients with non

–

clear cell

tumours in the ASSURE trial may have skewed data towards

a null result

[9]

. The second aspect of patient inclusion

criteria is risk of recurrence, and again the trials differ

markedly: ASSURE and, to a lesser extent, PROTECT both

included a broader risk profile in their enrolment criteria

than S-TRAC

[8 – 10]

. ASSURE included patients with T1b

tumours and higher, and PROTECT included patients

with T2b tumours and higher; conversely, S-TRAC was

exclusively limited to patients with T3 and higher-stage

tumours

[8 – 10]

In terms of the assessment of recurrence, S-TRAC

analysed progression by independent central review,

whereas both PROTECT and ASSURE relied on investigator

assessment alone, an inherently biased approach

[8 – 10] .

Importantly, all three trials demonstrated how crucial

appropriate dosing is in this setting: the starting dose

of sunitinib in S-TRAC was 50 mg/d and reductions to

37.5 mg/d were permitted, whereas a trial amendment in

ASSURE changed the starting dose of sunitinib to 37.5 mg/d

and allowed reductions to 25 mg/d

[8,9]

. Similarly, an

amendment in PROTECT changed the starting dose of

pazopanib from 800 mg/d to 600 mg/d

[10]

. Encouragingly,

analysis of PROTECT in the population that received the full

effective dose of 800 mg/d (

= 403) showed a significant

difference in DFS in the pazopanib-treated patients relative

to the placebo-treated patients (hazard ratio 0.69, 95%

confidence interval 0.51

–

0.94;

= 0.02)

[10]

. Together, these

data strongly indicate that maintaining the dose at effective

levels might be required to realise clinical benefit in this

setting.

The safety profile of sunitinib and pazopanib in these

adjuvant therapy trials was consistent with that previously

observed in the metastatic setting, and all toxicities were

manageable

[8 – 10] .

Interestingly, compared with patients

treated with VEGF inhibitors, patients treated with placebo

had a similar cumulative incidence of adverse effects that

were likely associated with treatment-related anxiety.

Table 2

–

Key differences between the ASSURE, S-TRAC, and PROTECT trials

ASSURE

S-TRAC

PROTECT

Assessment of recurrence (investigator vs central review)

Investigator

Central

Investigator

Patient inclusion criteria

Clear cell histology

79.1%

99.0%

100%

Performance status: ECOG 0

81.8%

73.8%

Not reported

Performance status: KPS 100%

67% (600 mg)

66% (800 mg)

Primary (AJCC) tumour stage I

–

33.4%

16% (600 mg)

15% (800 mg)

Dose of active agent administered

Starting dose levels

(50 mg/37.5 mg)

(50 mg)

(600 mg/800 mg)

Standard dose as starting dose

69.6%

100%

26%

Minimum dose permitted

25 mg

37.5 mg

400 mg

1 yr completion rate

49%

56%

48%

AJCC = American Joint Committee on Cancer; ECOG = Eastern Cooperative Oncology Group; KPS = Karnofsky performance status.

Refers to dose of sunitinib only.

Table 1

–

Basic trial characteristics and outcomes of ASSURE, S-TRAC, and PROTECT

ASSURE

S-TRAC

PROTECT

Patients enrolled (

)

1943

615

1135 (600 mg)

403 (800 mg)

Primary endpoint

DFS

Population analysed

ITT

Treatment groups (

)

Sunitinib (647)

Sorafenib (649)

Placebo (647)

Sunitinib (309)

Placebo (306)

ITT (600 mg)

Pazopanib (571)

Placebo (564)

ITT (800 mg)

Pazopanib (198)

Placebo (205)

Primary endpoint outcome

No signi

cant difference

Signi

cant difference

No signi

cant difference

Median disease-free survival

5.8 yr (IQR 1.6

–

8.2) in the sunitinib group and

6.6 yr (IQR 1.5

–

NE) in the placebo group

(HR 1 02, 97 5% CI 0 85

–

1 23,

= 0 8038)

6.8 yr (95% CI 5.8

–

NR) in the sunitinib group

and 5.6 yr (95% CI 3.8

–

6.6) in the placebo group

(HR 0.76, 95% CI 0.59

–

0.98,

= 0.03)

Not yet reached

CI = con

dence interval; DFS = disease-free survival; HR = hazard ratio; IQR = interquartile range; ITT = intention to treat; NE = not estimable; NR = not reached.

Patients were originally planned to be analysed by ITT; however, a protocol amendment changed the starting dose of pazopanib from 800 to 600 mg and the

primary endpoint from disease-free survival in the ITT population to disease-free survival in all patients treated with 600 mg pazopanib (modified ITT).

Median disease-free survivals in ASSURE are shown only for the sunitinib and placebo groups.

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