Elsevier

The Lancet Oncology

Volume 10, Issue 8, August 2009, Pages 757-763
The Lancet Oncology

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Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial

https://doi.org/10.1016/S1470-2045(09)70162-7Get rights and content

Summary

Background

Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted.

Methods

Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897.

Findings

As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1–25). Reasons for discontinuation included lack of efficacy (n=1168 [27%]) and adverse events (n=362 [8%]). The most common treatment-related adverse events were diarrhoea (n=1936 [44%]) and fatigue (n=1606 [37%]). The most common grade 3–4 adverse events were fatigue (n=344 [8%]) and thrombocytopenia (n=338 [8%]) with incidences of grade 3–4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]) and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10·9 months (95% CI 10·3–11·2) and overall survival was 18·4 months (17·4–19·2).

Interpretation

In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials.

Funding

Pfizer Inc.

Introduction

Kidney cancer accounts for almost 3% of adult malignancies globally with more than 210 000 new cases and 100 000 deaths annually.1 5-year survival for patients diagnosed with early-stage renal cell carcinoma (RCC) is as high as 66%.2 However, for the 30% of patients with RCC who present with advanced or metastatic disease, 5-year survival is only 10%.3, 4, 5 Additionally, local recurrence or distant metastasis develops in up to 40% of patients treated for localised tumours.4, 6

Sunitinib malate (Pfizer Inc; New York, NY, USA) is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor of vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and other RTKs with direct antitumour and antiangiogenic activity.7, 8, 9, 10, 11 It has been approved worldwide for the first-line and second-line treatment of advanced RCC.

Sunitinib showed impressive activity in two sequential single-arm phase II trials of patients with cytokine-refractory metastatic RCC.12, 13 In a multicentre, randomised phase III trial of 750 treatment-naive patients with metastatic RCC, sunitinib showed significantly better efficacy than interferon α.14 By investigator assessment, the objective response rate (ORR) was 37% versus 9%, respectively (p<0·001), and median progression-free survival (PFS) was 11 versus 4 months, respectively (p<0·001). This trial established sunitinib as a reference standard of care for first-line treatment of metastatic RCC. A recent update of this trial reported a median overall survival of more than 2 years (26·4 months) for patients given sunitinib, compared with 21·8 months for those given interferon α (hazard ratio=0·821, 95% CI 0·673–1·001; p=0·0510).15

A commonly asked question is whether patients with RCC in clinical trials are representative of the general population for this disease. Many patients with RCC do not meet inclusion criteria, particularly those with a poorer prognosis. For instance, 10–20% of patients with metastatic RCC present with brain metastases;16, 17 these patients can have an extremely short life expectancy, 4–6 months,18 and are poorly represented in trials. Similarly, patients with metastatic RCC and a poor performance status have a shorter survival19, 20, 21 and are often excluded from clinical trials. Additionally, RCC trials tend to focus on patients with clear-cell histology, the predominant histological subtype,3, 13 and exclude patients with other histologies. Thus, little is known about the activity of targeted therapies, such as sunitinib, in these subsets of patients.

We report results of sunitinib use derived from an ongoing, global, expanded-access study of patients with metastatic RCC, the aim of which was to provide sunitinib on a compassionate-use basis to patients in countries where regulatory approval had not yet been granted, and who did not otherwise have access to sunitinib because of trial ineligibility.

Section snippets

Patients

This expanded-access study is ongoing at 246 sites in 52 countries (in North, Central, and Latin America, Europe, Asia-Pacific, Australia, and Africa). The first patient was enrolled in June, 2005. Accrual has discontinued on a country-by-country basis according to treatment availability. The last patient enrolled in December, 2007.

Inclusion criteria were: age 18 years or more; histologically confirmed metastatic RCC (of all histological subtypes); adequate organ function; resolution of all

Results

As of December, 2007, 4564 patients had been enrolled and patients are no longer being recruited. At the time of analysis, data for safety, treatment duration, tumour response, and survival were available for 4371 patients, comprising the modified ITT population. Most patients had prior nephrectomy, and only a few had prior antiangiogenic therapy (table 1). Most patients had an ECOG performance status of 0–1 and clear-cell histology. The main site of metastasis was lung (table 1). More than

Discussion

We have shown the safety of sunitinib in a broad RCC population, particularly in subgroups who might be predicted to tolerate therapy less well than patients in well-defined, selected populations in the initial phase II and III trials.12, 13, 14, 15 Furthermore, we have shown that the safety profile of sunitinib is very similar for these poor-prognosis groups to that reported in well-defined patient populations.12, 13, 14, 15 This assertion is supported by the observation that the overall

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