Medical Oncology

, Volume 27, Issue 3, pp 899–906

Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET

Authors

    • Centre Leon Berard and Claude Bernard University
  • E. Jäger
    • Krankenhaus Nordwest
  • C. Porta
    • IRCCS San Matteo University Hospital Foundation
  • D. McDermott
    • Beth Israel Deaconess Medical Center
  • M. Moore
    • Princess Margaret Hospital
  • J. Bellmunt
    • University Hospital del Mar
  • S. Anderson
    • Bayer Pharmaceuticals
  • F. Cihon
    • Bayer Pharmaceuticals
  • J. Lewis
    • Bayer Pharmaceuticals
  • B. Escudier
    • Institut Gustave Roussy
  • R. Bukowski
    • Cleveland Clinic Cancer Center
Original Paper

DOI: 10.1007/s12032-009-9303-z

Cite this article as:
Negrier, S., Jäger, E., Porta, C. et al. Med Oncol (2010) 27: 899. doi:10.1007/s12032-009-9303-z

Abstract

Before the development of targeted therapies, administration of cytokines (e.g., interleukin-2, interferon-α) was the primary systemic treatment option for advanced renal cell carcinoma. Sorafenib, an oral targeted, multikinase inhibitor, significantly prolonged progression-free survival and overall survival in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a large (N = 903) phase III, double-blind, randomised, placebo-controlled study of patients with advanced renal cell carcinoma resistant to standard therapy. This analysis of a patient subgroup from TARGET evaluated the safety and efficacy of sorafenib in patients who had received prior cytokine therapy (sorafenib: n = 374; placebo: n = 368) and in patients who were cytokine-naïve (sorafenib: n = 77; placebo: n = 84). Progression-free survival was significantly prolonged with sorafenib therapy compared with placebo among patients with and without prior cytokine therapy (respectively 5.5 vs. 2.7 months; hazard ratio, 0.54; 95% confidence interval, 0.45–0.64 and 5.8 vs. 2.8 months; hazard ratio, 0.48; 95% confidence interval, 0.32–0.73). Clinical benefit rates for sorafenib-treated patients compared with placebo patients were also higher (cytokine-treated: 83 vs. 54.3%; cytokine-naïve: 85.7 vs. 56.0%). Sorafenib was well tolerated in both subgroups (grade 3/4: 20 and 22%, respectively). Sorafenib demonstrated a consistent, significant clinical benefit against advanced renal cell carcinoma, with a twofold improvement in progression-free survival and disease control rate, with similar toxicities in patients with or without prior cytokine treatment.

Keywords

SorafenibCytokineInterferonInterleukinRenal cell cancerMultikinase inhibitorSubanalysis

Introduction

Approximately 85% of kidney cancers are renal cell carcinomas (RCCs), and 75% of those have clear cell histology [1]. Approximately 54,390 new cases and 13,010 deaths from kidney cancer were expected in the United States during 2008 [2]. Globally, it is the 14th most common cancer, with incidence rates that have been rising steadily each year over the past 3 decades in Europe [3, 4]. Symptoms of RCC frequently present late in the disease course, leading to a high proportion of patients being diagnosed with advanced disease [5].

Advanced RCC typically does not respond to available chemotherapy, radiotherapy, or hormonal therapies [6]. Until recently, the primary systemic treatment option was an immunomodulatory regimen, including the administration of cytokines (e.g., interleukin-2 [IL-2] or interferon-α [IFN-α]) [7]. Cytokine therapies are associated with an overall objective response rate of 14%, with complete responses reported in 5% of patients receiving high-dose IL-2 [8]. Administration of cytokines, however, is commonly associated with a relatively high incidence of adverse events (AEs) [7]. A study comparing cytokine regimens found that the highest toxicity was associated with IL-2-based therapy [9]. Multiple grade 3 and 4 AEs were prevalent in these patients, including hypotension resistant to vasopressor agents (68%), fever (50%), performance status impairment (37%), nausea or vomiting (32%), diarrhoea (26%), and anaemia (17%) [9].

Tumour angiogenesis plays a central role in RCC disease progression. As frequently seen in RCCs with clear cell histology, [10] Von Hippel-Lindau (VHL) mutations and loss of heterozygosity permit unregulated transcription of multiple genes responsible for tumour growth, [11] including the transactivation of angiogenic growth factors [12]. Sorafenib is a multikinase inhibitor that blocks several angiogenic kinase receptors, including vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)-α and -β, as well as signalling for cell proliferation through Raf-1, wild-type B-Raf, B-Raf V600E, Flt-3, and c-KIT [1315]. Sorafenib targets a variety of receptors, and thereby has the ability to slow tumour progression by several mechanisms, including interfering with tumour-cell proliferation and preventing tumour angiogenesis [16]. The broad tumour stabilisation achieved with sorafenib in advanced RCC reflects the importance of sorafenib-targeted kinases in this tumour type.

Positive results for sorafenib (Nexavar®; Bayer HealthCare Pharmaceuticals, Onyx Pharmaceuticals, Inc) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), [17] the largest trial ever conducted in RCC, led to the first US Food and Drug Administration (FDA) approval of a systemic therapy for patients with advanced RCC in over a decade, as well as worldwide approval. In TARGET (N = 903), continuous daily administration of sorafenib was well tolerated, and doubled progression-free survival (PFS) from 2.8 to 5.5 months (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.43, 0.60; P < 0.001). This formal independent analysis, using data available at the time of crossover, was the basis for regulatory approval. The final overall survival of patients receiving sorafenib was comparable with that of placebo-randomised patients (17.8 vs. 15.2 months; HR, 0.88; P = 0.146), however, when post-crossover placebo survival data were censored, the difference became significant (17.8 vs. 14.3 months; HR 0.78; P = 0.029) [18].

Many patients receive cytokine therapy during the course of their disease, but if they have refractory disease or if the tumour recurs, they may be prescribed sorafenib. In this subset analysis of TARGET, we set out to evaluate the efficacy and safety of sorafenib in patients who had received cytokine therapy vs. patients who were cytokine-naïve prior to trial enrolment.

Materials and methods

Patient eligibility

This study is a subset analysis of the phase III TARGET designed to evaluate the safety and efficacy of sorafenib in patients with and without prior cytokine therapy. Prior cytokine therapy was defined as treatment with cytokines IL-2 and IFN-α.

As per the TARGET (sponsor study number 11213) design, [17] eligible patients were 18 years of age or older, had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2, a Motzer score [19] of intermediate or low, and a histologic or cytologic diagnosis of advanced RCC with at least 1 unidimensional measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI). Inclusion criteria required 1 prior systemic therapy (>30 days and <8 months from randomisation), which could have been treatment with cytokines, hormonal therapies, and/or antineoplastic agents, with disease progression during or following prior treatment (Response Evaluation Criteria in Solid Tumors [RECIST]), and adequate hepatic function at screening, defined as total bilirubin <1.5× the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate transaminase (AST) <2.5× ULN, amylase and lipase <1.5× ULN, serum creatinine <2.0× ULN, prothrombin time (PT) or partial PT <1.5× ULN, and partial thromboplastin time (PTT) <1.5× ULN.

Patients were excluded if they had a history of other malignancies, organ allografts, seizure disorders requiring medication, clinically serious infections, cardiac arrhythmias, symptomatic coronary artery disease, ischaemia, or congestive heart failure. All patients provided informed consent prior to study screening according to local institutional guidelines. The study followed the Declaration of Helsinki and good clinical practice guidelines.

Trial design

This subgroup analysis of TARGET compared sorafenib vs. placebo end points prior to crossover in patients who received or did not receive prior cytokine therapy, defined as palliative and/or adjuvant interleukin and/or IFN-α therapy. Efficacy variables included PFS, best tumour response, and clinical benefit rate. Safety variables included treatment-related and haematologic AEs.

As per the TARGET design, patient screening was performed ≤28 days prior to study entry. Patients were stratified to either placebo or sorafenib arms according to country of study and Memorial Sloan-Kettering Cancer Center (MSKCC) score (either intermediate or low). Sorafenib (400 mg) or placebo was administered twice daily on a continuous schedule for 6-week cycles for the first 24 weeks of treatment, beyond which the cycle length was extended to 8 weeks. Patients remained on study until disease progression or discontinuation for unacceptable AEs.

A single formal planned analysis of PFS in February 2005 demonstrated a statistically significant benefit of sorafenib, with a median PFS that was double that of patients on placebo (5.5 vs. 2.8 months). Based on PFS benefit, crossover from placebo to sorafenib was permitted beginning in May 2005. An updated, descriptive analysis of PFS as of May 2005, when the study was fully accrued with 903 patients, is described in Escudier et al. [17].

Assessments

Safety measurements assessed in this sub-analysis included AE assessment following National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0). Patient visits for safety assessment were every 3 weeks until week 24, and every 4 weeks thereafter while patients were on study.

Tumour measurements were taken 28 days prior to study entry, on day 1 of cycle 2, and every cycle thereafter, and at the 30-day follow-up visit. Tumours of the chest, abdomen, and pelvis were evaluated by computed tomography (CT) or magnetic resonance imaging (MRI). Tumour responses were centrally reviewed and assessed following RECIST.

Statistics

PFS and best tumour response were evaluated based on the intent-to-treat population for patients with prior or no prior history of cytokine therapy. Descriptive statistics for patient characteristics and toxicities were compiled. Safety analysis included all patients receiving study drug. Subgroup analyses were conducted based on sex, baseline Motzer score, ECOG status, and baseline sites of metastases.

Results

Seven hundred forty-two patients in TARGET (82%) had received prior cytokine therapy, and 161 patients (18%) were cytokine-naïve at study enrolment. Patient characteristics for both subsets were generally similar, and are summarised in Table 1. Median time from diagnosis of metastatic disease to treatment initiation was 10.8 months in the prior cytokine therapy group and 9.3 months in the cytokine-naïve group. Prior systemic regimens in cytokine-naïve patients included pyrimidine analogues, vinca alkaloid agents, and progestrogens. Overall, the proportions of metastases were similar in those who had prior cytokine therapy and those who had not had prior cytokine therapy; metastases were detected in the liver (26% for each subgroup), lung (78 vs. 71%), and bone (22 vs. 33%).
Table 1

Baseline patient characteristics by prior cytokine therapy and randomisation to study drug

 

No prior cytokine, n (%)

Prior cytokine, n (%)

Sorafenib

(n = 77)

Placebo

(n = 84)

Total

(n = 161)

Sorafenib

(n = 374)

Placebo

(n = 368)

Total

(n = 742)

Male

49 (63.6)

58 (69.0)

107 (66.5)

266 (71.1)

282 (76.6)

548 (73.9)

Female

28 (36.4)

28 (31.0)

54 (33.5)

108 (28.9)

86 (23.4)

194 (26.1)

Median weight (kg)

74.2

77.8

75.7

76.9

78.0

77.9

Median age (year)

60.0

60.5

60.0

58.0

58.5

58.0

Motzer

 Low

41 (53.2)

38 (45.2)

79 (49.1)

192 (51.3)

190 (51.6)

382 (51.5)

 Intermediate

36 (46.8)

46 (54.8)

82 (50.9)

182 (48.7)

177 (48.1)

359 (48.4)

Baseline ECOG PS

 0

40 (51.9)

31 (36.9)

71 (44.1)

179 (47.9)

179 (48.6)

358 (48.2)

 1

36 (46.8)

53 (63.1)

89 (55.3)

187 (50.0)

183 (49.7)

370 (49.9)

 2

1 (1.3)

0 (0.0)

1 (0.6)

6 (1.6)

4 (1.1)

10 (1.3)

Abbreviation: ECOG PS eastern cooperative oncology group performance status

Three hundred seventy-four patients with prior cytokine therapy were randomised to the sorafenib arm and 368 patients to the placebo arm of TARGET (Table 1). Of cytokine-naïve patients, 77 received sorafenib and 84 received placebo. Prior nephrectomy was common in patients in TARGET, with 93% of patients having undergone the procedure. In the sorafenib arm, 94% (n = 352) of patients had received both prior cytokine therapy and a nephrectomy, while 91% (n = 70) of patients in the no prior cytokine group had received a nephrectomy.

The recommended dose of sorafenib is 800 mg daily [20]. Patients who were previously treated with cytokines received a median daily dose of 796 mg of sorafenib for a median of 5.5 months, or a median daily dose of 788 mg of placebo for a median of 2.8 months. Cytokine-naïve patients were treated with a median dose of 813 mg of sorafenib daily for a median of 4.4 months, or a 791-mg median dose of placebo for a median of 3.0 months.

Thirty-four percent of cytokine-treated patients in the sorafenib arm of TARGET (n = 126) had a dose reduction or interruption, and 9% (n = 32) had dose delays. Twenty percent of patients with prior cytokine therapy who were on placebo (n = 84) had a dose reduction or interruption, and 1% (n = 2) had dose delays. Forty-six percent (n = 35) of cytokine-naïve patients in the sorafenib arm had a dose reduction or interruption, and 16% (n = 12) had dose delays, compared with 23% (n = 19) having a dose reduction or interruption and 6% (n = 5) having dose delays in the placebo arm. In cytokine-treated patients, sorafenib-associated dose reductions and interruptions were due to AEs in 83% (105) of patients, most frequently hand-foot skin reaction (HFSR) (17%, n = 22), diarrhoea (6%, n = 7), and hypertension (4%, n = 5). Among cytokine-naïve patients on sorafenib, the dose reductions or interruptions were due to AEs in 54% (n = 19) of patients, most frequently diarrhoea or fatigue (each 5%, n = 4).

Efficacy

PFS was significantly prolonged with sorafenib therapy compared with placebo for both subsets. Among patients with prior cytokine therapy, PFS was 5.5 vs. 2.7 months for the sorafenib and placebo arms, respectively (HR, 0.54; 95% CI, 0.45, 0.64), and for cytokine-naïve patients, PFS was 5.8 vs. 2.8 months, respectively (HR, 0.48; 95% CI, 0.32, 0.73) (Fig. 1). The improvement in PFS with sorafenib was similar across patient subgroups (i.e., sex, baseline ECOG PS, baseline prognostic MSKCC score, or baseline sites of metastasis), irrespective of prior cytokine therapy (Fig. 2).
https://static-content.springer.com/image/art%3A10.1007%2Fs12032-009-9303-z/MediaObjects/12032_2009_9303_Fig1_HTML.gif
Fig. 1

Progression-free survival in sorafenib- and placebo-treated patients by prior cytokine treatment. Abbreviations: CI confidence interval, HR hazard ratio

https://static-content.springer.com/image/art%3A10.1007%2Fs12032-009-9303-z/MediaObjects/12032_2009_9303_Fig2_HTML.gif
Fig. 2

Hazard ratio (95% CI) by prior cytokine treatment for patient subgroups. Abbreviation: ECOG PS eastern cooperative oncology group performance status

Best tumour response for patients treated with sorafenib vs. placebo for each of the cytokine subgroups is given in Table 2. In the prior cytokine group treated with sorafenib, 36 patients (9.6%) had a partial response (PR), 275 (73.5%) had stable disease (SD), and 48 (12.8%) had progressive disease (PD). In the cytokine-naïve group treated with sorafenib, seven patients (9.1%) had a PR, 58 (75.3%) had SD, 8 (10.4%) had PD, and one patient (1.3%) had a complete response (CR). Similar rates of SD (52.2 vs. 56.0%) and PD (38.3 vs. 31.0%) were observed in patients receiving placebo with and without prior cytokine treatment, respectively. Eight patients in the cytokine-treated group receiving placebo had a PR. Overall, sorafenib achieved substantially higher clinical benefit (CR + PR + SD) rates (≈84%) vs. placebo (≈55%) independent of prior cytokine treatment (Table 2).
Table 2

Best tumour response using RECIST, by prior cytokine therapy

Best response

No prior cytokine, n (%)

Prior cytokine, n (%)

Sorafenib

(n = 77)

Placebo

(n = 84)

Sorafenib

(n = 374)

Placebo

(n = 368)

Complete response

1 (1.3)

0 (0)

0 (0)

0 (0)

Partial response

7 (9.1)

0 (0)

36 (9.6)

8 (2.2)

Stable disease

58 (75.3)

47 (56.0)

275 (73.5)

192 (52.2)

Progressive disease

8 (10.4)

26 (31.0)

48 (12.8)

141 (38.3)

Clinical benefit (%)

85.7

56.0

83.2

54.3

Abbreviation: RECIST response evaluation criteria in solid tumours

Safety and tolerability

The overall incidence of treatment-related AEs was slightly higher in patients who received prior cytokine therapy than in cytokine-naïve patients (85.3 vs. 72.7%) (Table 3).
Table 3

Drug-related adverse events (AEs) by prior cytokine therapy

Drug-related adverse events

No prior cytokine therapy

Prior cytokine therapy

Sorafenib (n = 77)

Placebo (n = 83)

Sorafenib (n = 374)

Placebo (n = 368)

Any grade

n (%)

Grade 3/4

n (%)

Any grade

n (%)

Grade 3/4

n (%)

Any grade

n (%)

Grade 3/4

n (%)

Any grade

n (%)

Grade 3/4

n (%)

Any AE

56 (73)

15 (20)

40 (48)

3 (4)

319 (85)

84 (22)

189 (51)

22 (6)

Nonhaematologic AEsa

 Alopecia

23 (30)

0

3 (4)

0

95 (26)

0

10 (3)

1 (<1)

 Anorexia

8 (10)

0

7 (8)

1 (1)

36 (10)

2 (1)

20 (5)

2 (1)

 Constipation

3 (4)

0

1 (1)

0

26 (7)

0

13 (4)

0

 Diarrhoea

21 (27)

1 (1)

9 (11)

0

149 (40)

9 (2)

33 (9)

3 (1)

 Dry skin

5 (7)

0

1 (1)

0

42 (11)

0

11 (3)

0

 Fatigue

19 (25)

1 (<1)

11 (13)

0

90 (24)

10 (3)

59 (16)

5 (2)

 Flushing

3 (4)

0

2 (2)

0

29 (8)

1 (<1)

9 (2)

0

 HFSR

17 (22)

2 (3)

3 (4)

0

113 (30)

23 (6)

25 (7)

0

 Hypertension

5 (7)

0

0

0

52 (14)

9 (2)

5 (1)

1 (<1)

 Nausea

10 (13)

0

12 (15)

0

63 (17)

1 (<1)

44 (12)

1 (<1)

 Oral mucositis

4 (5)

3 (4)

0

0

24 (6)

1 (<1)

2 (1)

0

 Pruritis

12 (16)

0

2 (2)

0

62 (17)

1 (<1)

17 (5)

0

 Rash/desquamation

24 (31)

0

10 (12)

1 (1)

148 (40)

0

47 (13)

0

 Sensory neuropathy

10 (13)

0

2 (2)

0

44 (12)

1 (<1)

10 (3)

0

 Vomiting

4 (5)

0

1 (1)

0

41 (11)

2 (1)

25 (7)

1 (<1)

 Weight loss

6 (8)

2 (3)

1 (1)

0

11 (3)

0

4 (1)

0

Haematologic AEs

 Haemoglobin

1 (1)

0

0

0

7 (2)

3 (1)

5 (1)

1 (<1)

 Neutrophils

0

0

0

0

3 (1)

2 (1)

1 (<1)

1 (<1)

 Platelets

0

0

0

0

1 (<1)

1 (<1)

0

0

Abbreviation: HFSR hand–foot skin reaction

a≥5% of patients

The most frequent drug-related AEs in the sorafenib arm were similar in patients who were cytokine-naïve and in those who had received prior cytokine therapy, and included diarrhoea (27.3 vs. 39.8%), rash/desquamation (31.2 vs. 39.6%), HFSR (22.1 vs. 30.2%), and fatigue (24.7 vs. 24.1%). The largest differences between the two groups were diarrhoea, which occurred >10% more frequently in patients with prior cytokine therapy, followed by hypertension, hand–foot skin reaction, and rash/desquamation, which occurred >5% more frequently than in patients who had received prior cytokine therapy. The majority of these AEs were grade 1 or 2 in severity and were medically manageable. Grade 3/4 toxicities were similar in both groups: 22.7% for patients with prior cytokine therapy and 19.5% for patients without prior cytokine therapy.

Cardiac-related events leading to dose reductions or interruptions were infrequent among sorafenib-treated patients regardless of prior cytokine treatment. Dose reductions in five patients (1.3%) who had prior cytokine therapy were due to hypertension. One patient (0.3%) had a reduced dosage because of cardiac ischaemia/infarction. In cytokine-naïve patients, the only cardiac-related dose reduction was in one patient (1.3%) who had left ventricular systolic dysfunction. Dose interruptions due to cardiac-related events were less frequent. One cytokine-treated patient (0.3%) had a dose interruption because of a supraventricular arrhythmia, and another patient (0.3%) had dose interruptions due to cardiac ischaemia/infarction. In the cytokine-naïve subgroup, one patient (1.3%) had a dose reduction due to left ventricular systolic dysfunction.

Grade 3/4 haematologic events in patients receiving sorafenib were rare and occurred only in patients who had received prior cytokine therapy (Table 3). Events included 3 incidents (1%) of grade 3 anaemias, 1 incident (<1%) each of grades 3 and 4 neutrocytopaenia, 1 incident (<1%) of grade 3 leukocytopaenia, and 1 incident (<1%) of grade 3 thrombocytopaenia.

The overall drug-related AE rates for cytokine-treated patients were slightly higher than that of those patients who had no prior cytokine therapy (85 vs. 73%). However, the two groups of patients are not directly comparable because of the low sample size of the no-prior cytokine arm and the post-hoc nature of the analysis; the difference in the observed incidence of AEs may be attributable to differences in patient population.

Discussion

In this subgroup analysis of phase III TARGET, patients with advanced RCC benefited from sorafenib, with a similar safety profile, regardless of prior cytokine therapy. Sorafenib consistently and significantly extended median PFS to 5.5 months in cytokine-treated patients with advanced RCC compared with placebo (median PFS, 2.7 months) (HR, 0.54; 95% CI, 0.45, 0.64), even though these patients had relapsed disease or disease refractory to cytokine therapies. Similarly, cytokine-naïve patients in the sorafenib arm had a significantly improved median PFS (5.8 vs. 2.8 months in the placebo arm). Sorafenib conferred a benefit in PFS, regardless of sex, ECOG status, MSKCC score, or baseline sites of metastases, and independent of prior cytokine therapy. Hazard ratios consistently favoured sorafenib treatment in these subgroups, although their associated CIs were large because of the limited number of patients in each group. Tumour response was similar with sorafenib independent of cytokine history, with clinical benefit achieved in approximately 85% of patients compared with ~55% of patients in the placebo arm.

TARGET provides the largest and most complete primary RCC sorafenib data to date [17]. Over 82% of the patients in the trial had received cytokine therapy with either IFN-α or IL-2 prior to enrolment. Although treatment paradigms have evolved since this trial was conducted, cytokine therapy still plays a central role in the treatment of advanced RCC. IFN-α treatment, widely used in Europe, confers a median survival benefit of 3.8 months compared with controls; [21] however, grade 3 and 4 toxicities are common, with fatigue and flu-like symptoms making treatment intolerable for many patients [22]. High-dose IL-2 has shown a consistent response rate of over 20% [22], but grade 3 and 4 AEs are common; the initial trial had a 4% fatality rate due to IL-2 treatment-related toxicity [23]. For both cytokine treatments, the safety profile is more tolerable in patients with a low MSKCC risk score or an ECOG PS of 0; only about 20% of patients at diagnosis may be suitable for cytokine therapy [19, 24].

This subset analysis of TARGET demonstrated clinical benefit for patients with advanced RCC, even after prior cytokine treatment. Prior to the era of molecularly targeted treatments, substantial data on second-line therapies for RCC were lacking. Results of previous studies have indicated that the sequential treatment of IL-2-treated advanced RCC patients with additional cytokine combination therapy does not improve response rates or survival over IL-2 alone [25]. Further, patients progressing after either IL-2 or IFN-α as a first-line therapy did not respond well after crossing over to the other cytokine, with PRs reported in only 3.5% of patients (4 of 113) and no difference in survival [26].

In this study, sorafenib benefited patients regardless of MSKCC risk score, extending PFS to 5.8 months in both low- and intermediate-risk patients. It was previously shown that MSKCC low-risk patients treated with cytokine therapy derived a greater benefit from cytokine therapy (0 risk factors, 27-month median survival) compared with intermediate-risk patients (1 or 2 risk factors, 12-month median survival) [19, 27]. Thus, this subgroup analysis by prior cytokine treatment suggests that sorafenib may benefit a more diverse range of patients with advanced RCC than does cytokine therapy.

Interestingly, all of the PRs observed in the placebo group were found in patients who had received prior cytokine therapy. It is possible that these PRs may be a delayed response to cytokine treatment. Enrolment in TARGET, however, required prior therapy to have ceased within 30 days to reduce the potential for these delayed responses. On the other hand, these PRs may be due to the pathways responsible for the spontaneous remissions that are occasionally observed with RCC; PRs in the placebo arms of other controlled trials have been attributed to these pathways [28]. Regardless of the mechanism, sorafenib had a higher clinical benefit compared with placebo in both cytokine-treated and cytokine-naïve patients.

Combination therapy of sorafenib with IFN-α has been examined in two phase II trials, which reported median PFS of 10 and 7 months, respectively [29, 30]. This extension of PFS compared with either monotherapy suggests that there may be a mechanism that potentiates the activity of sorafenib or vice versa. The safety profile of this regimen, however, retains the toxicity of cytokine therapy and the dermatologic AEs associated with sorafenib, rendering it unsuitable for many patients.

In contrast, the toxicity profile for sorafenib monotherapy in patients who had received prior cytokine treatment was similar to that reported for TARGET overall, in which grades 1 and 2 constitutional (fatigue), gastrointestinal (diarrhoea and nausea), and dermatologic (rash/desquamation, HFSR, alopecia, and pruritis) AEs were most commonly reported. Although there were higher incidences of some AEs in patients who had received prior cytokine therapy, these AEs did not progress to grades 3 or 4 and were medically manageable. Moreover, these differences between cytokine-treated and cytokine-naive patients are unlikely to be statistically significant.

Unlike the toxicity of cytokine treatment for which dose reductions and in-patient monitoring during administration are common, [31] treatment with sorafenib was well tolerated regardless of prior cytokine exposure. Cytokine-treated patients in the sorafenib arm required slightly fewer dose reductions than patients who had not received prior cytokine therapy. The clinical benefit of sorafenib to both subgroups, however, was similar.

Overall, sorafenib demonstrated a consistent, significant clinical benefit, with a twofold improvement in PFS among patients with prior cytokine therapy and cytokine-naïve patients. These results echo the observations of Escudier et al. [17] and indicate that a broad range of patients with advanced RCC may benefit from sorafenib therapy. Sorafenib was well tolerated by both subgroups, indicating that this treatment is safe and effective for all patients with advanced RCC, regardless of prior cytokine treatment.

Copyright information

© Humana Press Inc. 2009