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Keywords:

  • renal cell carcinoma;
  • sunitinib;
  • rechallenge;
  • VEGF

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

Sunitinib was a standard initial therapy in metastatic renal cell carcinoma (mRCC). Given the fact that many patients progressed through many available therapies and antitumor activity had been demonstrated with sequential vascular endothelial growth factor-targeting approaches, a retrospective review was performed of the experience of rechallenge with sunitinib in sunitinib-refractory mRCC.

METHODS:

mRCC patients who received sunitinib therapy after disease progression on prior sunitinib and other therapy were retrospectively identified. Patient characteristics, toxicity, clinical outcome, Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate, and progression-free survival (PFS) were recorded.

RESULTS:

Twenty-three mRCC patients who were rechallenged with sunitinib were identified. Upon rechallenge, 5 patients (22%) achieved an objective partial response. The median PFS with initial treatment was 13.7 months and 7.2 months with rechallenge. Patients with >6-month interval between sunitinib treatments had a longer PFS with rechallenge than patients who started the rechallenge within 6 months (median PFS, 16.5 vs 6.0 months; P = .03). There was no significant difference in outcome to sunitinib rechallenge based on number or mechanism of intervening treatments. Substantial new toxicity or significantly increased severity of prior toxicity was not seen during rechallenge in this cohort.

CONCLUSIONS:

Sunitinib rechallenge had potential benefits and was tolerated in select metastatic RCC patients. Additional prospective investigation was warranted. Cancer 2010. © 2010 American Cancer Society.

The treatment of metastatic renal cell cancer (mRCC) has significantly changed over the past several years with the addition of targeted agents inhibiting elements of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways.1-7 Sunitinib (Sutent, Pfizer Inc., New York, NY) is a small molecule inhibitor of the tyrosine kinase portion of the VEGF family of receptors. Sunitinib has become a standard of care for initial therapy of good and intermediate prognosis patients with mRCC based on significant advantages over interferon alpha in a phase III trial.2 Despite the benefits of existing agents, initial or eventual resistance develops in all patients. As such, many patients receive multiple sequential therapies during the course of their disease. Given the lack of validated biomarkers to predict benefit from any particular agent, current practice in the application of these agents is an empiric sequence of single agents.8 Patients with favorable underlying biology are the most likely to receive several therapies, and indeed, in the absence of clinical trials of investigational agents, may progress through several currently Food and Drug Administration-approved agents.

The mechanism of resistance to VEGF-targeting therapy in mRCC is based on hypotheses derived from preclinical data and includes transition to alternative tumor-promoting pathways, up-regulation of alternative proangiogenic factors (eg, angiopoietin, interlekin-8, platelet-derived growth factor), and inadequate target inhibition.9 In addition, the antitumor activity of sequential VEGF-targeting therapy has been previously identified in both retrospective and prospective series in mRCC.10-12 The precise mechanism by which a tumor progresses through a given VEGF-targeted therapy, and then responds to the sequential administration of another VEGF-targeting therapy, is unknown. Based on these considerations, it was hypothesized that rechallenge of patients with a VEGF-targeting agent previously used, specifically sunitinib, could be a reasonable strategy for tumor burden control. A retrospective review was thus undertaken to describe the experience of rechallenge with sunitinib in metastatic RCC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

A retrospective review was conducted in 7 centers across 3 different countries: the United States (Cleveland Clinic Taussig Cancer Institute [CCF], Cleveland, Ohio; Dana Farber Cancer Institute [DFCI], Boston Mass; Massachusetts General Hospital [MGH], Boston Mass; and Baylor Sammons Cancer Center, Dallas Tex), Canada (Princess Margaret Hospital, Toronto, Ontario; Tom Baker Cancer Center, Calgary, Alberta), and France (Institut Gustave Roussy, Villejuif, France). Eligibility included patients with confirmed metastatic RCC (any histology) who had previously received sunitinib with disease progression or intolerance, received 1 or more antitumor therapies subsequently, and then received sunitinib for a second time. Data on both sunitinib treatment regimens, intervening treatments, and prognostic factors based on the Memorial Sloan-Kettering Cancer Center (MSKCC) and Cleveland Clinic Foundation (CCF) criteria were collected.13-15 Investigator-assessed objective response rate, percentage of tumor burden shrinkage by Response Evaluation Criteria in Solid Tumors (RECIST)16 and progression-free survival (PFS) were recorded. Review of patient data was undertaken with the institutional review board approval for chart review at each participating center, from clinical trial data and tumor registry.

Statistical Analysis

Categorical data were summarized as frequency counts and percents, and continuous variables were summarized as medians and ranges. PFS, which was measured from the start of treatment to documented progression, was summarized using the Kaplan-Meier method. McNemar test was used to compare response rates between the 2 treatment periods and the Wilcoxon signed-rank test was used to compare PFS. The log rank test was used to compare PFS during the rechallenge phase in patients who had a <6-month lag between termination of their initial treatment with sunitinib and the start of the rechallenge versus those with a 6-month or greater lag; and the Cochran-Armitage trend test was used to compare the 2 groups with respect to the MSKCC risk stratification. All tests of statistical significance were 2-sided and all analyses were performed using SAS (version 8.0, SAS Institute Inc., Cary, NC) and StatXact (version 6, Cytel Software Corporation, Cambridge, Mass).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Initial Sunitinib

Twenty-four patients were initially identified. One patient was excluded because of lack of intervening therapy between completion of initial treatment with sunitinib and rechallenge; and because the interval between treatments was approximately 7 weeks. Patient characteristics and outcome associated with the initial sunitinib treatment are summarized in Table 1. Most patients were male, median age at first sunitinib therapy was 59 years, and all but 2 (9%) patients had prior nephrectomy. All patients had clear cell histology. Most patients had a Karnofsky Performance Scale (KPS) status of 90% to 100%. Lung and lymph nodes were the most common sites of metastatic disease. All patients on initial sunitinib were in a clinical trial. Most patients had favorable or intermediate risk based on MSKCC risk group criteria for untreated patients and 73% had a favorable or intermediate risk by CCF tyrosine kinase inhibitor criteria.9-11 The starting dose of sunitinib was 50 mg (schedule 4 weeks on followed by 2 weeks off) for all but 2 patients (37.5 mg). Initial sunitinib treatment produced a partial response rate of 65% and a median PFS of 13.7 months. All patients discontinued initial sunitinib for disease progression per investigator assessment and none for intolerance or adverse effects of sunitinib.

Table 1. Patient Characteristics at Time of First Sunitinib Therapy
Characteristic (n=23)N (%)
  • KPS indicates Karnofsky Performance Scale; VEGF, vascular endothelial growth factor; PR, partial response; SD, stable disease; PD, disease progression; MSKCC, Memorial Sloan-Kettering Cancer Center (MSKCC); CCF TKI, Cleveland Clinic Foundation tyrosine kinase inhibitor.

  • a

    Muscle (n=5), kidney (n=2), renal bed (n=1), pelvis (n=1), retroperitoneum (n=1), pleura (n=1), skin (n=1).

  • b

    Sorafenib (n=4), bevacizumab (n=2), pazopanib (n=1).

Gender:
 male18 (78%)
 Female5 (22%)
Median age (range)59 (35-73)
Prior nephrectomy21 (91%)
KPS at initial sunitinib
 100%8 (35%)
 90%13 (57%)
 70%1 (4%)
 Unknown1 (4%)
Median time from diagnosis to first systemic treatment (months)5.9 (1.8-140)
Metastatic sites
 Lung20 (87%)
 Lymph nodes13 (57%)
 Bone9 (39%)
 Liver7 (30%)
 Adrenal7 (30%)
 Pancreas4 (17%)
 Brain4 (17%)
 Othera10 (43%)
Number of metastatic sites
 1-210 (43%)
 >213 (57%)
Prior systemic treatment 
 None6 (26%)
 Cytokines only10 (43%)
 Cytokines + anti-VEGFb7 (30%)
 Median (range) duration of sunitinib (months):13.8 (1.1-27.9)
Best response:
 PR15 (65%)
 SD7 (29%)
 PD1 (4%)
Median (range) progression-free survival (months):13.7 (1.1-27.9)
MSKCC risk group:
 Favorable3 (13%)
 Intermediate17 (74%)
 Unfavorable1 (4%)
 Unknown2 (9%)
CCF TKI risk group 
 Favorable10 (43%)
 Intermediate7 (30%)
 Unfavorable4 (17%)
 Unknown2 (9%)

Sunitinib Rechallenge

The starting dose of sunitinib for rechallenge was 50 mg for 12 patients (52%), 37.5 mg for 9 patients (39%), and 25 mg for 2 patients (9%; Table 2). Rechallenge began a median of 6.7 months after progression on the first sunitinib treatment. During the intervening period between progression on the first sunitinib and rechallenge, 52% of patients were treated with sorafenib or sorafenib and bevacizumab; 39% were treated with an mTOR inhibitor; and 26% were treated with both classes of drugs. Two patients had radiotherapy and/or surgery and 1 patient received an experimental VEGF receptor inhibitor, ABT869, on a phase 1 trial. Specifics of intervening systemic treatment were unavailable for 2 patients. Upon sunitinib rechallenge, 5 patients (22%) achieved a partial response (including 1 patient with a best response of stable disease with initial sunitinib) and 17 (74%) had stable disease as their best response. Figure 1 depicts adrenal metastasis before and after both initial sunitinib exposure and sunitinib rechallenge in a representative patient. Sixteen patients (70%) have progressed on rechallenge to date.

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Figure 1. A) Computed tomography (CT) scans of index bilateral adrenal lesions before first sunitinib, at best response to first sunitinib, and on confirmation of progressive disease on first sunitinib. B) Computed tomography (CT) scans of same index adrenal lesions on confirmation of progressive disease on temsirolimus and after 2 cycles of sunitinib rechallenge.

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Table 2. Patient Characteristics and Outcome to Sunitinib Rechallenge
Characteristic (n=23)N (%)
  • VEGF, vascular endothelial growth factor; mTOR, mammalian target of rapamycin; PR, partial response; SD, stable disease; PD, disease progression.

  • a

    Patients may have received more than 1 therapy.

  • b

    Sorafenib (n=9); sorafenib + bevacizumab (n=3).

  • c

    Temsirolimus (n=6); everolimus (n=3).

  • d

    Gemcitabine+capecitabine (n=1); MLN-518 (n=1); perifosine (n=1); ABT869 (n=1).

  • e

    Seven patients are still receiving sunitinib.

Median (range) time between first sunitinib and rechallenge (months)6.7 (1.3-22.0)
Treatment received between first sunitinib and rechallengea
 VEGF inhibitor(s)a6 (26%)
 mTOR inhibitorb3 (13%)
 Both VEGF inhibitor(s) and mTOR inhibitorbc6 (26%)
 Other systemic therapyd4 (17%)
 Radiotherapy4 (17%)
 Surgery2 (9%)
 Unknown systemic therapy2 (9%)
Starting dose for initial/rechallenge (mg)
 50 / 5010 (43%)
 50 / 37.59 (39%)
 50 / 252 (9%)
 37.5 / 502 (9%)
Median (range) duration of treatment (months)e6.8 (1.2 – 28.5+)
Best objective response
 PR5 (21%)
 SD17 (71%)
 PD2 (8%)
Median (range) progression-free survival (months)47.2 (1.2 - 28.5+)

The median PFS is estimated to be 7.2 months. There was no difference in clinical outcome comparing patients who received intervening systemic therapy versus patients who received only intervening radiation and/or surgery (data not shown). Comparing sunitinib treatment periods, the median PFS with initial treatment with sunitinib in this cohort was 13.7 months compared with 7.2 months for rechallenge (PFS was longer with rechallenge than with initial treatment in 6 patients [32%]). These data suggest that, although rechallenge with sunitinib has some efficacy, overall it appears less than that seen with initial treatment; objective response is less frequent (P = .006) and PFS is shorter (P = .04). Figure 2 plots PFS for both treatment periods. Exploratory analysis revealed that patients with a >6-month lag between sunitinib treatments had better PFS with rechallenge than patients who started the rechallenge within 6 months of discontinuing their initial treatment (median PFS 16.5 vs.] 6.0 months, respectively; P = .03). Furthermore, 5 of the 6 patients with a longer PFS at rechallenge compared with initial sunitinib had a greater than 6-month interval (Fig. 3). There was no significant difference in outcome to sunitinib rechallenge based on number or type of intervening treatment(s). In the group with <6-month lag only 3 of 8 patients had another anti-VEGF therapy before rechallenge with sunitinib versus 12 of 13 in the >6-month group (P = .01). The 2 groups also looked different with respect to MSKCC risk group—38% favorable, 63% intermediate in the <6-month group compared with 92% intermediate and 8% unfavorable in the >6-month group (P = .03) (Table 3). Furthermore, 5 of the 6 patients with a longer PFS at rechallenge compared with initial sunitinib had a greater than 6-month interval. With regard to PFS on rechallenge compared with initial objective response, patients who achieved an initial partial response with sunitinib (n = 15) had a median PFS of 8 months versus 6 months for patients (n = 7) with a best response of stable disease to initial sunitinib (P = 0.1).

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Figure 2. Progression-free survival with initial sunitinib and sunitinib rechallenge.

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Figure 3. Progression-free survival (PFS) with initial sunitinib compared with PFS with sunitinib rechallenge.

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Table 3. Characteristics of Patients with <6-Month and >6-Month Interval Between Sunitinib Treatmentsa
Factor<6-Mo. Lag (n=9)>6-Mo. Lag (n=14)Pb
  • a

    MSKCC, Memorial Sloan-Kettering Cancer Center; KPS, Karnofsky Performance Scale; mets, metastases; CCF, Cleveland Clinic Foundation; PR, partial response.

  • b

    Cochran-Armitage trend test

  • c

    Liver, lymph node, and lung metastases not shown as the rates were similar in both groups.

MSKCC risk group
 Good3(38%)0.03c
 Intermediate5(63%)12(92%) 
 Poor01(8%) 
KPS
 90-100%2(22%)0.21
 80-90%7(78%)14(100%) 
Bone metsd
 No4(44%)10(71%).38
 Yes5(56%)4(29%) 
Brain metsd
 No6(67%)13(93%).26
 Yes3(33%)1(7%) 
No. metastatic sites
 1-24(44%)6(43%)1.0
 >25(56%)8(57%) 
CCF risk group
 Favorable3(38%)7(54%)1.0c
 Intermediate4(50%)3(23%) 
 Unfavorable1(13%)3(23%) 
PR with initial sunitinib
 No5(56%)3(21%).18
 Yes4(44%)11(79%) 

Table 4 compares the toxicities of initial treatment and rechallenge for patients (n = 20) with complete data available. The most common toxicities experienced on both initial treatment and at rechallenge were fatigue, diarrhea, and hand-foot syndrome. Noting the limitations of toxicity recording outside of a clinical trial and the shorter duration of therapy with rechallenge, sunitinib rechallenge does not appear to be associated with an increased risk of toxicity. Substantial new toxicity or significantly increased severity of prior toxicity was not seen during rechallenge in this cohort.

Table 4. Toxicity on First Sunitinib Treatment and Sunitinib Rechallenge
Toxicity (n=20)No toxicity with either sunitinib treatmentNo toxicity with initial sunitinib but present at rechallengeToxicity present with initial sunitinib but not at rechallengeToxicity present with both treatments and same or less severe with rechallengeToxicity present with both treatments and more. severe with rechallenge
Fatigue7 (35%)2 (10%)4 (20%)4 (20%)2 (10%)
Diarrhea10 (50%)06 (30%)4 (20%)0
Hand-foot7 (35%)2 (10%)5 (25%)5 (25%)0
Hypothyroidism16 (80%)1 (5%)3 (15%)00
Neutropenia17 (85%)02 (10%)01 (5%)
Thrombocytopenia16 (80%)1 (5%)2 (10%)1 (5%)0
Mucositis13 (65%)1 (5%)3 (15%)1 (5%)0

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

This study demonstrates that patients with metastatic RCC can demonstrate antitumor effect to sunitinib rechallenge after failure of prior sunitinib therapy, as evidenced by objective responses and a median PFS of over 7 months. Although the clinical effects observed were less than initial sunitinib treatment, rechallenge may be a viable therapeutic strategy in the select subset of patients who are able to receive further therapy. In addition, sunitinib rechallenge was associated with expected and acceptable toxicity.

There are other examples within solid tumor oncology of drug rechallenge with clinical benefit. Ovarian cancer is an example in which the majority of women with advanced ovarian cancer with initial response to cisplatin-based regimens and subsequent recurrence demonstrate a second response to re-treatment with a platinum-based regimen. Patients who recurred more than 6 months after complete clinical response with a platinum-based regimen have the best response to re-treatment.17-20 Successful retreatment of lung cancer with gefitinib, a tyrosine kinase inhibitor targeting endothelial growth factor receptor, has been reported in several case reports. Of interest, after the development of acquired resistance to gefitinib, the lung cancer patients in these reports regained sensitivity to gefitinib after a several month gefitinib-free interval.21-24 Similar effect was observed in this RCC cohort in regards to a greater time off prior sunitinib associated with a better response, but response to prior sunitinib did not appear to impact response at rechallenge within the limitations of this small study.

The biology of tumor susceptibility to a drug after previous exposure is unknown. In RCC, this is largely due to the ill-defined biology of sunitinib resistance. If resistance involved a fundamental shift to an alternative tumor-promoting pathway not targeted by sunitinib, clinical effect of re-treatment would not be expected. However, the greater antitumor effect seen in patients with a longer time off sunitinib suggests that, RCC may revert to a greater VEGF reliance with increasing time off prior VEGF-inhibiting therapy. Alternatively, resistance may involve inadequate target inhibition either due to enhanced receptor signaling or reduced drug levels from physiologic changes. This resistance mechanism indeed could be overcome with time off therapy and re-dosing. Given the lack of data regarding sunitinib drug levels at time of first resistance, this hypothesis would require prospective testing.

Another possible explanation is that metastatic renal cancer, like other cancers, has been demonstrated to have significant intratumoral heterogeneity.25-27 This heterogeneity creates an opportunity for Darwinian selection of tumor subclones.28, 29 In this model, selective pressure from sunitinib causes drug-resistant clones to expand. However, during treatment interruptions, the selective pressure from sunitinib is removed. Without the selective pressure from sunitinib, the drug-resistant clones no longer have a selective advantage and are outgrown by faster growing drug-sensitive clones. This type of clonal selection has been observed in HIV where drug resistant viruses frequently have poor “replicative fitness” compared with wild-type HIV.30, 31 Although this model is speculative, shifting populations of resistant and sensitive tumor cells has been observed during imatinib treatment in chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia as well as in gefitinib treatment in lung cancer.32-34

This study has several limitations. The retrospective nature of this review and the small number of patients, even though from multiple centers, introduces several biases. All tumor assessments were made by the investigators, limiting reliability and consistency of objective response assessment and progression. There were heterogeneous treatments received between the initial and rechallenge that might have affected the biology of the tumors. This patient cohort is clearly highly selected as evidenced by the high initial sunitinib objective response rate and long PFS. Furthermore, toxicity recording outside of a clinical trial is imprecise; thus, the full toxicity profile of sunitinib rechallenge remains to be defined.

Notably, the objective response rate and PFS with sunitinib rechallenge were nearly identical to those in 2 separate trials, 1 of sunitinib in bevacizumab-refractory RCC patients10 and axitinib in sorafenib-refractory RCC patients.11 Collectively, these data support that metastatic RCC remains to a greater or lesser extent VEGF driven through the disease course. The biologic impact of prior therapy as it relates to clinical outcome with subsequent therapy is at present poorly understood. Thus, the optimal clinical approach to the treatment-resistant RCC patient is unknown, and will require careful prospective trials for further insight. Sunitinib rechallenge has potential benefits in metastatic RCC patients. Prospective studies to evaluate this strategy are needed. A prospective trial of sunitinib rechallenge versus everolimus in sunitinib refractory patients is being planned. Other trials in sunitinib-refractory patients may consider a sunitinib rechallenge control arm as a comparator.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Brian Rini is a consultant to and on the advisory board of Pfizer. Toni K. Choueiri is a consultant to and on the advisory boards of Pfizer, Novartis, Genentech, Glaxo Smith Kline, Abbot, Bayer/Onyx, and Ei Lilly. Thomas Hutson is a consultant to, on the advisory boards of, a speaker for, and receives research funds from Pfizer, Glaxo Smith Kline, Genentech, Aveo, and Novartis. Bernard Escudier has received honoraria from Bayer, Pfizer, Novartis, and Roche.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES