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Keywords:

  • renal cell carcinoma;
  • sequential therapy;
  • sorafenib;
  • sunitinib;
  • tyrosine kinase inhibition

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

BACKGROUND:

Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.

METHODS:

Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent.

RESULTS:

Twenty-nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P = .016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P = .061).

CONCLUSIONS:

The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation. Cancer 2009. © 2008 American Cancer Society.

Targeted therapies using sorafenib and sunitinib have recently been approved for use as orally administered agents for the treatment of advanced renal cell carcinoma. Sorafenib is reserved primarily for patients who are refractory to cytokine therapy,1 whereas sunitinib is used for the treatment of cytokine-naive patients.2 Although sorafenib and sunitinib have significantly improved the treatment of this disease, the efficacy of sequencing these agents as a treatment for metastatic disease is unknown.

Both sorafenib and sunitinib are multitarget tyrosine kinase inhibitors (TKI), although each has distinct affinities for target kinases and distinct pharmacokinetics.3, 4 Sorafenib is a potent Raf kinase inhibitor that directly suppresses tumor cell proliferation; it also targets vascular growth through inhibition of vascular endothelial growth factor receptors (VEGFR)-2 (IC50, 90 nmol/L), VEGFR-3 (IC50, 20 nmol/L) and platelet-derived growth factor receptor (PDGFR)-β (IC50, 57 nmol/L).3 Sunitinib is an inhibitor of c-KIT, FLT-3, PDGF-α (IC50, 69 nmol/L), PDGF-β (IC50, 39 nmol/L), and VEGFR-2 (IC50, 4 nmol/L).4 Inhibition of VEGF and PDGF pathways decreases vascularization and endothelial cell proliferation and prevents tumor progression. Compared with sorafenib, sunitinib has lower IC50s for kinases involved in angiogenesis.

In clinical practice, sorafenib and sunitinib are both used as first-line and second-line treatments for renal cell carcinoma. When patients fail therapy with 1 agent, the other agent is often used, resulting in de facto sequential treatment. Scientific data supporting this practice are limited and mainly derive from single-agent studies. Sorafenib has shown efficacy in a phase 3 trial for treatment-refractory renal cell carcinoma patients, with progression free survival (PFS) nearly doubling compared with placebo controls (5.5 vs 2.8 months; P < .01).1 Data supporting the use of sorafenib in a first-line setting, however, are limited. Results of a randomized phase 2 study of sorafenib versus interferon in a first-line setting showed no differences in PFS or response rate between study arms.5 Sunitinib has been evaluated as a second-line treatment in a phase 2 trial, and this drug was found to produce a median overall survival (OS) of 16.4 months and a median PFS of 8.7 months.6 In treatment-naive patients, sunitinib has been compared with interferon-alpha (IFN-α) in a randomized phase 3 trial in which the median PFS was reported to be 11 months for sunitinib versus 5 months for IFN-α (P < .001).2 In patients who failed to respond to prior antiangiogenic therapy, both sorafenib and sunitinib have been reported to have antitumor activity against advanced renal cell carcinoma, with an overall median time to progression of 10.4 months.7 However, little is known about the optimal sequential treatment strategy.

In the present study, we hypothesized that because of lower IC50 for the receptor kinases targeted by sunitinib, drug resistance that emerged after initial use of sorafenib would be overcome by sunitinib, whereas development of resistance to initial sunitinib would not be salvaged by sorafenib. We, therefore, performed a retrospective chart review to compare the efficacy measured by time to progression of sequential therapy with sorafenib followed by sunitinib, versus sunitinib followed by sorafenib.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Study Design and Patient Eligibility

A retrospective analysis was performed on all renal cell carcinoma patients treated with sunitinib and sorafenib between March 2004 and October 2007 at the University of Minnesota Comprehensive Cancer Center in Minneapolis, Minnesota and at the Department of Clinical Oncology, Central Clinical Hospital Ministry of National Defense in Warsaw, Poland. The purpose of this analysis was to evaluate the effectiveness of switching from one TKI agent to another after disease progression (either after initial response or outright progression after first 2 cycles) or toxicity.

At both institutions, all screened patients were at least 18 years of age with histologically confirmed renal cell carcinoma. All renal cell carcinoma patients were screened for inclusion in this analysis when they had experienced disease progression or unacceptable toxicity after receiving either sorafenib or sunitinib, and then these patients were subsequently switched to the other TKI agent. Standard doses of both sorafenib and sunitinib were used, with a 28-day sorafenib cycle and a 42-day sunitinib cycle. Clinical response was assessed by using Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation and then once every 2 cycles. The chest, abdomen, and pelvis were imaged with a computed tomography (CT) scan or by magnetic resonance imaging (MRI), when appropriate. There was no fixed number of cycles for each agent. The number of cycles of therapy was limited only by drug toxicity or disease progression. For purposes of this chart review, patients who received sorafenib as their initial treatment were identified as Group A, and patients who received sunitinib as their initial treatment were identified as Group B. The University of Minnesota Institutional Review Board approved the study.

Data Collection

Data were collected from patient medical records as follows: demographics, date of renal cell carcinoma diagnosis, pathology subtype, Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic scores,8 history of nephrectomy, sites of metastatic disease, prior therapy, start and end dates for sorafenib and sunitinib, reason for sorafenib or sunitinib termination (progression of disease or adverse reaction), response to therapy, sites of disease progression, last follow-up, and time of death.

Statistical Methods

Patient characteristics and risk factors were summarized separately for the 2 sequence groups, Group A and Group B. A Comparison between treatment groups was performed by using the Fisher exact test for categorical variables and the nonparametric Wilcoxon rank-sum test for age. Time to progression was determined for the initial treatment and also for sequential treatment. Time to progression after initial treatment with either sorafenib or sunitinib was calculated as the time from the start of treatment until date of progression or toxicity. Time to progression after sequential treatment was calculated as the time from the start of the first agent to the time that progression, toxicity, or end of follow-up occurred after the start of the second agent. The median time to progression for both time periods was estimated by the Kaplan-Meier method. Subjects that withdrew from treatment because of adverse drug reactions or ended the study period without progression were censored.

Univariate analysis included the Kaplan-Meier estimate of median time to progressin and the log-rank test for each variable. The Cox proportional hazards model was used to evaluate time to progression by using a combination of risk factors present before initial TKI therapy and resulting in relative risk ratios (RRs) and 95% confidence intervals (Cis) that were adjusted for other factors in the model. The significance of each variable in the model was evaluated by the Wald chi-square test, and all significant risk factors in the Cox regression models were checked for the proportional hazard assumption by using the interaction between the factor and the log of the event time.

Kaplan-Meier estimates of overall survival were compared with therapy groups by using the log rank test. All statistical procedures were performed by SAS version 9.1 (SAS Institute, Cary, NC). P values less than .05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Patient Characteristics

Forty-nine patients were included in this retrospective chart review (Table 1). Group A (sorafenib followed by sunitinib) included 29 patients and Group B (sunitinib followed by sorafenib) included 20 patients. The majority of patients had clear cell histology (25 in Group A and 16 in Group B). In Group A, there were 2 patients with the sarcomatoid type and 2 patients with the granular variant of renal cell carcinoma. In Group B, there were 3 patients with sarcomatoid and 1 with papillary renal cell carcinoma. All patients had a prior nephrectomy, with the exception of 1 patient in Group A. The distribution of Memorial Sloan-Kettering Cancer Center prognostic scores was comparable between groups. Median age was 62 years and 58.5 years for Groups A and B, respectively.

Table 1. Patient Characteristics and Risk Factors by Sequence Groups
Demographic DataGroup AGroup BP*
  • MSKCC indicates Memorial Sloan-Kettering Cancer Center.

  • *

    Prior cytokine therapy consisted of interferon, interleukin-2, or a combination of both.

No. of subjects2920 
Age, y  .294
Median, min/max62 (32/75)58.5 (39/69) 
Sex, %  1.000
 Men22 (75.9)16 (80.0) 
 Women7 (24.1)4 (20.0) 
Institution, no. (%)  .512
 Univ of Minn23 (79.3)14 (70.0) 
 Central Clinical Hosp6 (20.7)6 (30.0) 
MSKCC risk score, no. (%)  .750
 Favorable10 (34.5)9 (45.0) 
 Intermediate16 (55.2)10 (50.0) 
 Poor3 (10.3)1 (5.0) 
Clear cell histology, no. (%)25 (86.2)16 (80.0).700
Prior nephrectomy, %28 (96.6)20 (100)1.000
Prior cytokine therapy, %*16 (55.2)16 (80.0).126
Time from diagnosis to treatment, no. (%).009
 <1 y19 (65.5)5 (25.0) 
 >1 y10 (34.5)15 (75.0) 
Median follow-up, wk86.943.9.063

In Group A, 16 patients had prior interferon, interleukin-2, or a combination of both; 1 patient was also treated with an m-TOR inhibitor. In Group B, 16 patients had been treated earlier with interferon, interleukin-2, or a combination of both. In Group A, there were 10 patients with a history of kidney cancer longer than 12 months in duration from time of diagnosis to start of sorafenib therapy; 9 of these had previously been treated with interferon, interleukin-2, or a combination of both. In Group B, there were 15 patients with a history of kidney cancer longer than 12 months in duration from time of diagnosis to start of sunitinib therapy; all of these had previously been treated with interferon, interleukin-2, or a combination of both.

Median time between ending first-line therapy and starting the second agent was 2 days (range, 1 day to 388 days) in Group A and 8 days (range, 1 day to 77 days) in Group B.

Treatment Toxicities and Response Rates

Patients experienced the expected toxicities associated with sorafenib and sunitinib treatment. Sorafenib treatment was terminated mainly because of grade 3 skin rash in 6 (14%) patients, and 3 of these were taken off sorafenib during first-line therapy. Sunitinib treatment was terminated mainly because of grade 3 gastrointestinal toxicities (nausea, vomiting, and diarrhea) in 4 (10%) patients, and 2 of these were taken off sunitinib during first-line therapy.

Table 2 lists response rates for first and second agents in both treatment groups. In patients treated first with sunitinib, there was 1 documented partial response as defined by RECIST criteria and 13 patients with stable disease. In patients treated first with sorafenib, there were 2 documented partial responses and 18 patients with stable disease. For sequential treatment, 6 (21%) patients in Group A had an objective partial response; 11 patients had stable disease, of which 6 continued to have stable disease at the time of last follow-up. Only 1 (5%) patient in Group B had an objective partial response after tumor resection in which sunitinib and sorafenib were given preoperatively, and 5 patients continued to have stable disease at the time of last follow-up.

Table 2. Response Rates and Adverse Events
Response VariableGroup AGroup B
Sorafenib, First AgentSunitinib, Second AgentSunitinib, First AgentSorafenib, Second Agent
No. (%)No. (%)No. (%)No. (%)
  • CR indicates complete response; PR, partial response; SD, stable disease; PD, progressive disease; AE, adverse event.

  • *

    Therapy was stopped for patients with an adverse event. Responses in these patients were not assessable.

CR0 (0)0 (0)0 (0)0 (0)
PR2 (7)6 (21)1 (5)1 (5)
SD18 (62)11 (38)13 (65)6 (30)
PD6 (21)10 (34)4 (20)11 (55)
AE*3 (10)2 (7)2 (10)3 (15)

Time to Progression After Initial Treatment

Time to progression for patients who were treated with sunitinib (Group B) as a first agent was 25 weeks. Time to progression for patients treated with sorafenib (Group A) as a first agent was 22 weeks. This difference was not statistically significant (P = .299). According to univariate analysis (Table 3), time to progression was not significantly associated with any risk factors, with the exception of prior cytokine therapy. In multivariate Cox regression analysis, time to progression after initial treatment with sunitinib or sorafenib was not associated with any risk factor after adjusting for other factors in the model (Table 4).

Table 3. Univariate Analysis of Time to Progression by Risk Factors After the First Treatment
VariableCategoryNo.Median TTP, wkP
  • TTP indicates time to progression; MSKCC, Memorial Sloan-Kettering Cancer Center; F, favorable risk; I, intermediate risk; P, poor risk.

  • *

    P value derived from the log-rank test.

AgentSorafenib2920.7.299
Sunitinib2024.7
MSKCC risk score*F1926.4.057
I2626.1
P414.5
Prior cytokine therapyNo1716.7.012
Yes3227.6
SexMen3825.2.819
Women1120.7
Age, y≤602824.7.537
>602122.5
Time from diagnosis to treatment<1 y2416.7.112
>1 y2529.0
InstitutionCentral1229.7.061
Univ of Minn3719.3
Table 4. Multivariate Cox Regression for Time to Progression Following First Agent*
VariableRisk Ratio (95% CI)P
  • CI indicates confidence interval; MSKCC, Memorial Sloan-Kettering Cancer Center.

  • *

    Including univariate risk factors with P < .15.

  • For the regression analysis, the categories for favorable and intermediate risk were combined.

MSKCC score, poor2.4 (0.8, 7.4).133
Prior cytokine therapy0.5 (0.2, 1.2).109
Institution, Univ of Minn1.7 (0.7, 3.8).230
Time from diagnosis to treatment >1 y1.2 (0.5, 2.8).622

Time to Progression and Overall Survival After Sequential Treatment

Sequential treatment with sorafenib followed by sunitinib (Group A) resulted in a trend toward improved time to progression (P = .115) (Fig. 1), suggesting that this drug administration sequence is associated with better overall disease control. Group A had a median time to progression of 78 weeks, which is more than twice as long as the 37 weeks seen for Group B (Table 5). Multivariate analysis confirmed this result by revealing that Group B had a significantly shorter time to progression than Group A after adjusting for other risk factors, with a risk ratio (RR) of 3.0 (P = .016) (Table 6). Patients with poor versus good or intermediate prognostic factors had higher risk of disease progression (RR, 6.3; P = .008) (Table 6). In addition, patients who had a partial response or stable disease during initial treatment had a slightly lower risk of disease progression during sequential therapy (RR, 0.3; P = .011) (Table 6). None of the significant factors violated the proportional hazard assumption, including the treatment group. Therefore, the risk associated with the treatment sequence was consistent over time.

thumbnail image

Figure 1. Time to progression (TTP) after sequential treatment is depicted.

Download figure to PowerPoint

Table 5. Univariate Analysis of Time to Progression by Risk Factors After Sequential Therapy
VariableCategoryNo.Median TTP, wkP
  • TTP indicates time to progression; MSKCC, Memorial Sloan-Kettering Cancer Center; F, favorable risk; I, intermediate risk; P, poor risk; PR, partial response; SD, stable disease; PD, progressive disease; AE, adverse event; TKI, tyrosine kinase inhibitor.

  • *

    The P value was derived from the log-rank test.

GroupA2978.1.115
B2036.9
MSKCC risk score*F19106.7.013
I2652.1
P427.9
Prior cytokine therapyNo1752.1.116
Yes3274.6
SexMen3859.1.434
Women11106.7
Age, y≤602874.6.703
>602152.1
Time from diagnosis to treatment<1 y2452.1.399
>1 y2574.6
InstitutionCentral12114.9.113
Univ of Minn3752.1
Best response for first treatmentPR + SD3474.6.019
PD + AE1540.6
Time between TKI treatments≤1 wk2765.4.564
>1 wk2267.0
Table 6. Multivariate Cox Regression for Time to Progression After Sequential Therapy*
VariableRisk Ratio (95% CI)P
  • CI indicates confidence interval; MSKCC, Memorial Sloan-Kettering Cancer Center; SD, stable disease; PR, partial response.

  • *

    Including univariate risk factors with P < .15.

  • For the regression analysis, the categories for favorable and intermediate risk were combined.

Group B3.0 (1.2, 7.2).016
MSKCC score, poor6.3 (1.6, 24.4).008
Prior cytokine therapy0.6 (0.2, 1.3).185
Institution, Univ of Minn1.8 (0.7, 4.7).222
Best response for first treatment, SD + PR0.3 (0.1, 0.8).011

The median time to progression after the second treatment was 46.9 weeks for those switching to the other agent because of toxicity of first-line therapy and 67.0 weeks for those switching because of disease progression (P = .495).

After starting sunitinib, Group A had a median duration of stable disease of 20 weeks (range, 2 weeks to 82 weeks), whereas after starting sorafenib, Group B had a median duration of stable disease of 9.5 weeks (range, 1 weeks to 56 weeks). Median follow-up for Groups A and B was 86.9 weeks and 43.9 weeks, respectively. Adverse reactions occurred at a rate of 17% and 25% in Groups A and B, respectively. Disease progression at the end of follow-up occurred in 63% of patients in both groups combined. The overall disease control rate for both groups combined was 26.5% (95% confidence interval [CI], 14.1%, 38.9%), with the disease control rate for Groups A and B being 27.6% and 25.0%, respectively.

Median overall survival time was 74.9 weeks for those who switched to the other agent because of adverse reaction and 81.3 weeks for those who switched because of disease progression (P = .773). Median overall survival was 102 weeks and 45 weeks for Groups A and B, respectively (P = .061) (Fig. 2).

thumbnail image

Figure 2. Overall survival is shown.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Herein, we show that responses can be seen in second-line TKI therapy after first-line TKI failure. In this retrospective analysis of advanced renal cell carcinoma, patients who received sequential therapy, treatment with sunitinib after sorafenib failure provided more durable disease control than the reverse order. Indeed, this difference in overall disease control was maintained even after other factors, including Memorial Sloan-Kettering Cancer Center prognostic grade, were taken into consideration. In addition to the small sample size of the present retrospective study, we recognize that the observed differences between the groups could be due to a higher potency of sunitinib salvage therapy. Moreover, although the 2 drugs have never directly been compared prospectively in a first-line setting, the level of evidence supporting the use of sunitinib as frontline therapy is superior to that of sorafenib. Nevertheless, the extent of the differences between these 2 sequences in our study raises important questions related to the optimal treatment schema for patients with renal cell carcinoma and the maximization of treatment benefit when using targeted agents.

At present, there are limited data to support specific guidelines for using targeted agents after disease progression on prior antiangiogenic regimens. Patients who had failed prior antiangiogenic therapy with thalidomide, lenalidomide, bevacizumab, volociximab, AG13736, sorafenib, or sunitinib responded to subsequent treatment with either sorafenib or sunitinib.7 Tamaskar et al7 concluded that response to prior therapy does not appear to predict subsequent clinical benefit to either sunitinib or sorafenib. In that study, only 4 patients received the sequence of sorafenib followed by sunitinib, and only 5 patients received the sequence of sunitinib followed by sorafenib. In addition, a recent report demonstrated that sunitinib can be effective in bevacizumab-refractory renal cell carcinoma patients.9

Differential tumor response to antiangiogenic agents can possibly be explained by different molecular targets or differential affinity for target interaction. In the present study, our data are consistent with the hypothesis that drug resistance emerging after initial use of sorafenib would be overcome by sunitinib, whereas development of resistance to initial sunitinib would not be salvaged by sorafenib. This effect may be related to a lower IC50 for the angiogenic receptor kinases that sunitinib targets. Minor differences in molecular targets between sorafenib and sunitinib could explain responses to sorafenib after sunitinib failure. Sablin et al10 have reported progression-free survival rates comparable to our study. In their retrospective analysis, 68 patients who received sorafenib followed by sunitinib had a median progression-free survival of 26.1 weeks, whereas 22 patients who received the reverse sequence had a median progression-free survival of 22 weeks. There were also patients who responded to second-line agents in both groups. The authors concluded that sequential use of sorafenib and sunitinib was supported by their data. We realize, however, that both retrospective analyses only help with hypothesis construction and that firm conclusions about the superiority of 1 sequence over the other cannot be drawn.

Resistance to single-agent antiangiogenic therapy may develop by way of compensatory mechanisms that are driven by upregulation of plasma VEGF, fibroblast growth factors, ephrin-A1, or angiopoietin-2, or through the development of hypoxia-inducible factor alpha (HIF1α)-independence through activation of angiogenesis by interleukin-8, cycloxygenase-2, prostaglandin E2, NF-kB, RAS, PI3K/Akt or p38.11 Options for overcoming acquired resistance to antiangiogenic therapy may include the novel strategy of decreasing the transcription of HIF by blocking the mammalian target of rapamycin (mTOR).12 This strategy is now being tested in clinical trials, which are comparing the efficacy of temsirolimus to salvage therapy with sorafenib (NCT00474786; temsirolimus vs sorafenib in patients with advanced renal cell carcinoma who failed first-line sunitinib). In a randomized, placebo-controlled, phase 3 study of everolimus versus placebo, an mTOR inhibitor was shown to have a progression-free survival and an overall survival advantage when used in patients who had progressed on prior sorafenib, sunitinib, or both.13 Until this novel therapy is proven safe and effective in this setting, however, clinicians face the decision of which available antiangiogenic agents to use in first-line, second-line, or third-line settings. To improve progression-free survival and overall survival, it is crucial to identify the appropriate sequence of treatment. In an era of multiple therapeutic options for patients with metastatic kidney cancer, prospective clinical trials must address the crucial question of optimal sequencing of antiangiogenic agents.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

We thank the following investigators from the Oncology Department, Military Institute of Medicine in Warsaw, Poland, who were involved in patient care and data collection in this study: Pawel Nurzyński, Sylwia Oborska, Anna Waśko, and Ewa Kusztal. We thank Michael Franklin for editorial support

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

No commercial or extramural funding was used to perform this research. Arkadiusz Z. Dudek has received honoraria from Pfizer Speaker's Bureau.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References
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