- Email: [email protected]
Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma
Original Study
Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma Sebastian Nachbargauer,1 Andreas Bruchbacher,1 Harun Fajkovic,2 Mesut Remzi,2 Manuela Schmidinger1 Abstract We performed a retrospective study of patients with metastatic renal cell carcinoma treated with sunitinib in 2 different treatment lines at the Medical University of Vienna. The approach to rechallenge with sunitinib after the development of resistance appears to be a feasible strategy and might be especially important in areas where novel agents are not yet available. Background: Sunitinib has been the standard of care for patients with metastatic renal cell carcinoma (mRCC). However, nearly all patients will eventually develop resistance. Before the introduction of novel agents, few treatment options remained after sunitinib failure. Sunitinib rechallenge is a strategy based on the presumption that resistance might be only temporary. The aim of this analysis was to evaluate the efficacy and safety of sunitinib rechallenge in patients with mRCC. Patients and Methods: Patients who had undergone sunitinib rechallenge (SU2) at the Medical University of Vienna from 2010 to 2017 were identified for the present retrospective study. The primary endpoint was the treatment duration with rechallenge (TDSU2). The secondary endpoints included the treatment duration with upfront sunitinib (TDSU1), progression-free survival (PFSSU1 and PFSSU2), overall survival (OSSU1 and OSSU2), the objective response rate in both settings (ORRSU1 and ORRSU2), and toxicity. Results: A total of 31 patients were eligible. The median TDSU2 was 7.2 months, and the median TDSU1 was 17.8 months. The median OSSU1 and OSSU2 was 57.9 months and 14.7 months, respectively. The median PFSSU1 and PFSSU2 was 14.2 months and 5.6 months, respectively. The ORRSU1 and ORRSU2 was 34% and 16%, and another 48% and 42% achieved stable disease (SD), respectively. Fatigue and hypertension were the most common adverse events. Conclusions: Sunitinib rechallenge appears to benefit patients in later treatment lines. With the abundance of novel treatment options available, this approach might appear less relevant. However, novel agents are not yet available everywhere. Thus, sunitinib rechallenge could be an additional strategy to improve the outcomes of patients with mRCC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: mRCC, Rechallenge, Resistance, Sunitinib, Tyrosine kinase inhibitors
Introduction Sunitinib is an oral tyrosine kinase inhibitor (TKI) targeting several growth factor receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), KIT, and FLT3. This agent has been the standard of care for first-line treatment of metastatic renal cell 1 Clinical Division of Oncology and Comprehensive Cancer Center, Department of Medicine I 2 Department of Urology, Medical University of Vienna, Vienna, Austria
Submitted: Sep 9, 2019; Revised: Nov 2, 2019; Accepted: Nov 27, 2019 Address for correspondence: Sebastian Nachbargauer, MD, Clinical Division of Oncology and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Waehringer Gürtel 18e20, Vienna 1090, Austria E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2019.11.006
carcinoma (mRCC) for more than a decade. However, tumors will ultimately acquire secondary resistance after a median treatment period of 11 months.1-3 First, VEGFR inhibitors induce a loss of vasculature, resulting in tumor stasis or regression. However, eventually, the hypoxic microenvironment induces an epithelial-tomesenchymal transition and resistance to anti-VEGFetargeted therapy. At this stage, other non-VEGFedependent pathways become relevant (eg, angiopoietin, fibroblast growth factor [FGF], MET).4,5 Newer TKIs that address the mechanisms of resistance such as the MET/AXL and VEGFR inhibitor cabozantinib or the FGF and VEGFR TKI lenvatinib have been shown to optimize the outcomes in patients with disease resistant to sunitinib.6,7 Moreover, the introduction of immune checkpoint inhibitors has contributed considerably to the longer overall survival (OS) of patients with mRCC.8 However, despite this therapeutic revolution,
Clinical Genitourinary Cancer Month 2019
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Sunitinib Rechallenge in Patients With mRCC Table 1 Patient Baseline Characteristics Characteristic All patients
Table 2 Sunitinib Rechallenge: Treatment Characteristics n (%)
Characteristic
31 (100)
All patients
Male
21 (68)
Sunitinib rechallenge starting dose, mg
Female
10 (32)
Gender
50
Age at rechallenge, y Median Range
59.1 42.8-84.9 27 (87)
Papillary
1 (3)
Other
3 (10)
Previous surgical procedure Nephrectomy Nephron-sparing surgery
37.5
29 (94) 2 (6)
3 (10) 23 (74) 5 (16)
Rechallenge line Third
Histologic subtype Clear cell
62.5
n (%) 31 (100)
10 (32)
Fourth
10 (32)
Fifth or later
11 (35)
Dose modifications during rechallenge Dose escalation
8 (26)
Dose reduction
6 (19)
Treatment break required
9 (29)
Local treatment Radiotherapy
11 (35)
Metastasectomy
12 (39)
MSKCC risk group Favorable Intermediate Poor
5 (16) 13 (42) 1 (3)
Unknown
12 (39)
Metastatic sites, n 1
2 (6)
2
8 (26)
3
9 (29)
4
12 (39)
Metastatic site Lung
26 (84)
Liver
13 (42)
Lymph nodes
20 (65)
Bone
8 (26)
Central nervous system
2 (6)
Soft tissue
5 (16)
a
Other
21 (68)
Treatments between SU1 and SU2 Tyrosine kinase inhibitorsb mTOR inhibitorsc Both tyrosine kinase and mTOR inhibitorsd
2
-
9 (29) 3 (10) 12 (39)
Nivolumab
2 (6)
Other agentse
5 (16)
Abbreviations: MSKCC ¼ Memorial Sloan Kettering Cancer Center; SU1 ¼ upfront sunitinib; SU2 ¼ sunitinib rechallenge. a Pancreas, 8 patients (26%); adrenal gland, 4 patients (13%); thyroid gland, 2 patients (6%); pleura, 3 patients (10%); kidney, 4 patients (13%); peritoneal, 1 patient (3%); retroperitoneal, 3 patients (10%); intestinal, 2 patients (6%); chest wall, 1 patient (3%); colon, 1 patient (3%); tumor thrombus in splenic vein, 1 patient (3%). b Seven patients (23%) had received axitinib and two (6%) had received pazopanib. c Everolimus was used in 3 patients (10%). d Axitinib and everolimus were used in 7 patients (23%), axitinib, everolimus, and pazopanib in 2 (6%), pazopanib and everolimus in 2 (6%), and sorafenib and everolimus in 1 patient (3%). e Bevacizumab and interferon-alfa were used in 2 patients (6%), axitinib and nivolumab in 1 (3%), temsirolimus, sorafenib, and bevacizumab in 1 (3%), and sorafenib, everolimus, temsirolimus, bevacizumab, pazopanib, interferon-alfa, and axitinib in 1 patient (3%).
Clinical Genitourinary Cancer Month 2019
most patients will eventually develop progression. At a certain point during the disease course, physicians and patients could face the situation in which no more new treatment options remain. Little evidence is available for the optimal treatment of patients who have undergone multiple lines of treatment. The approach to rechallenge with sunitinib has been based on the observation that the epithelial-to-mesenchymal transition is a reversible phenomenon. When transplanted into a xenograft model, a sunitinib-resistant tumor was shown to respond again to sunitinib.9 We hypothesized that this phenomenon might translate into clinical practice by withholding the VEGFR TKI for a certain period and that the mRCC might regain sensitivity to sunitinib during the treatment break. Small clinical studies have shown that heavily pretreated patients might benefit from sunitinib rechallenge after the occurrence of resistance to various previous agents, including mTOR inhibitors, monoclonal antibodies, cytokines, and other TKIs.10-12 The aim of the present analysis was to investigate the outcomes of patients who had undergone sunitinib rechallenge at the Medical University of Vienna.
Patients and Methods The present study was a retrospective and noninterventional single-center analysis of patients with mRCC who had undergone sunitinib rechallenge from 2010 to 2017. Out of 298 patients who had received sunitinib during the study period, 31 (10.4%) were eligible for the present analysis. The inclusion criteria were the receipt of sunitinib in 2 different treatment lines (upfront sunitinib [SU1] and sunitinib rechallenge [SU2]) after treatment with mTOR inhibitors, other TKIs, or immune checkpoint inhibitors. Tumor assessments were performed in accordance with the RECIST (response evaluation criteria in solid tumors), version 1.1, if available.13 The primary endpoint was the treatment duration (TD) of the sunitinib rechallenge (TDSU2), defined as the interval from initiation of the rechallenge until treatment discontinuation for any cause. The secondary endpoints included progression-free survival (PFS) of both upfront treatment (PFSSU1) and rechallenge (PFSSU2) and the treatment duration of upfront sunitinib (TDSU1). OS was
Sebastian Nachbargauer et al Figure 1 (A) Treatment Duration With Sunitinib Rechallenge (TDSU2): Median, 7.2 Months (95% Confidence Interval, 4.1-10.3 Months; n [ 31). (B) Progression-free Survival During Sunitinib Rechallenge (PFSSU2): Median, 5.6 Months (95% Confidence Interval, 3.0-8.2 Months; n [ 31)
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Sunitinib Rechallenge in Patients With mRCC Figure 2 Treatment Duration and Progression-free Survival During Upfront Sunitinib (TDSU1 and PFSSU1, Respectively)
measured from upfront sunitinib to death (OSSU1) and from the beginning of the rechallenge to death (OSSU2). The objective response rate in both settings (ORRSU1 and ORRSU2) was also measured. Toxicity during SU1 and SU2 was an additional secondary endpoint. The Kaplan-Meier method was used to estimate the TD, PFS, and OS. The observation interval was censored at the last follow-up examination. All statistical analyses were performed using IBM SPSS Statistics, version 24.0.
Results Patient Characteristics and Initial Treatment A total of 31 patients were included in the present study. All patients had experienced progression during SU1 and subsequently underwent rechallenge with sunitinib after treatment with 1 different agents approved for mRCC treatment. Three patients were still undergoing SU2 at analysis. The baseline characteristics at rechallenge are outlined in Table 1. The median patient age at rechallenge was 59.1 years (range, 42.8-84.9 years). Most patients (87%) had had clear cell tumors, and all had undergone either previous nephrectomy (94%) or nephron-sparing surgery (6%). The disease of most patients (42%) had been classified as intermediate risk using the Memorial Sloan Kettering Cancer Center risk group classification. Of the 31 patients, 39% had had 4 metastatic sites. The lung (84%), liver (42%), and lymph nodes (65%) were among the most common sites. SU1 had mostly been offered in the first-line setting (68%). Seven patients (23%) had been treated with cytokines, and three (10%) with other TKIs or mTOR inhibitors before SU1.
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Sunitinib Rechallenge The treatment characteristics of SU2 are listed in Table 2. SU2 was offered in the setting of third-, fourth-, or fifth-line or later treatment for 32%, 32%, and 35% of patients, respectively. Most patients (74%) had started SU2 at a dose of 50 mg. Dose escalations to 75 mg were performed for 26% of patients, 19% required dose reductions, and 9 patients (29%) required temporary treatment breaks.
Efficacy The median TDSU2 was 7.2 months (95% confidence interval [CI], 4.1-10.3 months; Figure 1A), and the median PFSSU2 was 5.6 months (95% CI, 3.0-8.2 months; Figure 1B). Three patients (10%) were censored for TDSU2 and PFSSU2, respectively. The median TDSU1 was 17.8 months, and the median PFSSU1 was 14.2 months (Figure 2). The median OSSU1 was 57.9 months (95% CI, 48.8-66.9 months; Figure 3A), and the median OSSU2 was 14.7 months (95% CI, 9.4-20.0 months; Figure 3B). At the time of data collection, 12 patients (39%) were alive and thus were censored for the OS estimations. An objective response with SU1 and SU2 was achieved in 10 (34%) and 5 (16%) patients, respectively (Table 3).
Safety Analysis The toxicity occurring during both SU1 and SU2 is outlined in Table 4. The most common adverse events during both treatment lines were fatigue and hypertension. The comparison of the incidence and severity of toxicities in SU1 and SU2 revealed that fatigue was more pronounced during SU2 but hypertension was more severe during SU1.
Sebastian Nachbargauer et al Figure 3 (A) Overall Survival During Upfront Sunitinib (OSSU1): Median, 57.9 Months (95% Confidence Interval, 48.8-66.9 Months; n [ 30). (B) Overall Survival During Sunitinib Rechallenge (OSSU2): Median, 14.7 Months (95% Confidence Interval, 9.4-20.0 Months; n [ 31)
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Sunitinib Rechallenge in Patients With mRCC Table 3 Efficacy of Upfront Sunitinib and Sunitinib Rechallenge Characteristic All patients
n (%) 31 (100)
Best response to initial sunitinib (n ¼ 29) Stable disease
14 (48)
Partial response
8 (28)
Complete response
2 (7)
Progressive disease
5 (17)
TDSU1 (n ¼ 29) Median
17.8
Range
5.2-47.3
PFSSU1 (n ¼ 30), mo Median
14.2
Range
1.6-35.8
OSSU1 (n ¼ 30), mo Median
57.9
95% CI
48.8-66.9
Best response (sunitinib rechallenge) Stable disease
13 (42)
Partial response
5 (16)
Complete response
0 (0)
Progressive disease
13 (42)
TDSU2 (n ¼ 31), mo Median
7.2
95% CI
4.1-10.3
PFSSU2 (n ¼ 31), mo Median
5.6
95% CI
3.0-8.2
OSSU2 (n ¼ 31), mo Median
14.7
95% CI
9.4-20.0
Interval between initial sunitinib and rechallenge (n ¼ 29), mo Median
8.9
Range
2.1-42.5
Abbreviations: CI ¼ confidence interval; OSSU1 ¼ overall survival measured from upfront sunitinib to death; OSSU2 ¼ overall survival measured from the beginning of the rechallenge to death; PFSSU1 ¼ progression-free survival measured from upfront sunitinib to progression; PFSSU2 ¼ progression-free survival measured from the beginning of the rechallenge to progression or death; TDSU1 ¼ treatment duration of upfront sunitinib; TDSU2 ¼ treatment duration of sunitinib rechallenge.
The aim of the present study was to analyze the safety and efficacy of sunitinib rechallenge at the Medical University of Vienna. Most patients (58%) had experienced either a partial response or stable disease at rechallenge, with a median TDSU2 of 7.2 months, median PFSSU2 of 5.6 months, and median OSSU2 of 14.7 months. The median OS from the beginning of initial sunitinib was 57.9 months. Our results support the hypothesis that resistance to sunitinib might represent a temporary phenomenon. Sunitinib-resistant cells might be prone to increase expression of hypoxia-inducible factor1a or to rely on alternative pathways for angiogenesis, such as MET, AXL, or angiopoietin.4,5,17 Moreover, intratumor heterogeneity was found to be an important driver of treatment failure in patients with mRCC. In 2012, Gerlinger et al18 reported on branched evolutionary tumor growth, with most mutations not detectable across different metastatic sites. This might explain why responses will not occur at all metastatic sites.18 Despite the complexity of the biology of tumor progression, our data suggest that rechallenge with sunitinib after previous resistance could be beneficial. In kidney cancer, sunitinib rechallenge has been previously studied. Oudard et al12 reported a median PFS of 7.9 months in the RESUME (results of the rechallenge with sunitinib in metastatic RCC) study. Zama et al11 reported a median PFS of 7.2 months. By indirect comparison, our patients derived slightly less PFS benefit. This most likely resulted from differences in the patient populations. First, documented progression during SU1 was crucial for inclusion in our analysis. In contrast, 19% of patients included in the RESUME study had had treatment discontinuation for reasons other than disease progression. Hence, resistance to sunitinib had not necessarily developed before the rechallenge had been started. Second, only 6% of patients in the RESUME study had been classified as having primary resistant disease (progressive disease as best response). In contrast, 17% of our patients had had disease progression as the best response during SU1. This supports the assumption that our analysis included a greater number of individuals with primary resistance to anti-VEGF treatment. Third, the patients in the RESUME study had been required to have a life expectancy of 3 months and a minimum of 2 computed tomography scans performed during the rechallenge. In contrast, all patients in whom sunitinib had been initiated a second time were considered eligible for our study. Finally, in terms of safety, fatigue was the most common side effect during SU2. This might have been a result of the advanced stage of the disease rather than the treatment itself.19,20 The limitations of the present analysis were its retrospective design and the small number of patients. In addition, because we had performed the tumor assessments, the response rates and estimated PFS might be biased.
Discussion The strategy to rechallenge a patient with an agent on which progression had occurred in a previous treatment line has been previously studied for other malignancies. Analogous approaches with EGFR-targeting agents have been used in metastatic colorectal cancer. Also, re-exposure with platinum-based chemotherapy has been established in recurrent ovarian carcinoma. Similar concepts were also evaluated in studies of small cell lung cancer.14-16
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Clinical Genitourinary Cancer Month 2019
Conclusions Sunitinib rechallenge was efficient in several patients, with an acceptable safety profile. The main reason for the strategy of rechallenge was that fewer therapeutic alternatives were available during the study period. Rechallenge could still be an option to improve outcomes in regions where novel agents, such as nivolumab, ipilimumab, pembrolizumab, and cabozantinib, are not yet available and/or reimbursed.
Sebastian Nachbargauer et al Table 4 Adverse Events During Upfront Sunitinib and Sunitinib Rechallenge SU1 Adverse Event (n [ 25) Diarrhea Nausea Emesis Stomatitis Hypertension Fatigue Hand-foot syndrome Rash
All Grades 10 6 3 11 17 17 7 3
(40) (24) (12) (44) (68) (68) (28) (12)
SU2 Grade 3-4 1 0 0 2 11 4 0 0
(4) (0) (0) (8) (44) (16) (0) (0)
All Grades 7 10 5 10 17 19 7 3
(28) (40) (20) (40) (68) (76) (28) (12)
Grade 3-4 1 1 0 2 5 11 0 0
(4) (4) (0) (8) (20) (44) (0) (0)
Data presented as n (%). Abbreviations: SU1 ¼ upfront sunitinib; SU2 ¼ sunitinib rechallenge.
Clinical Practice Points Sunitinib, a TKI targeting VEGFR, PDGFR, KIT, and FLT3,
has been a mainstay in the treatment of mRCC. However, its long-term application will ultimately lead to the
development of resistance through upregulation of alternative pathways, such as MET or FGF. Some small clinical studies have previously demonstrated the efficacy of sunitinib rechallenge (ie, reinduction of this TKI after treatment had been withheld for a period). The aim of the present analysis was to evaluate efficacy and safety of SU2 in patients treated at the Medical University of Vienna. The TD, PFS, OS, toxicity, and ORR were evaluated for both SU1 and SU2. SU2 appears to be a feasible and safe option for patients in later treatment lines, especially when novel agents, such as ipilimumab, nivolumab, pembrolizumab, and cabozantinib, are not yet available. However, further investigation is needed to determine the relevance of this approach among the currently available alternatives.
Disclosure A.B. has received a research grant from Pfizer and travel grant from EUSA Pharma. H.F. has received honoraria for lectures from Pfizer, Jansen, Ipsen, and Astellas. M.R. has received honoraria for lectures and congress support from Pfizer. M.S. has received honoraria for lectures and participating on advisory boards from Pfizer, Roche, Novartis, BMS, Ipsen, Eisai, Astellas, and EUSA Pharma. The remaining authors declare that they have no competing interests.
References 1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115-24.
2. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019; 30:706-20. 3. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res 2003; 9:327-37. 4. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 2009; 10:992-1000. 5. Zhou L, Liu X, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2015; 35:2687-97. 6. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; 16:1473-82. 7. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, openlabel, phase 3 trial. Lancet Oncol 2016; 17:917-27. 8. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373:1803-13. 9. Hammers HJ, Verheul HM, Salumbides B, et al. Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 2010; 9:1525-35. 10. Oudard S, Vano Y. The role of rechallenge with targeted therapies in metastatic renal-cell carcinoma. Curr Opin Urol 2015; 25:402-10. 11. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010; 116:5400-6. 12. Oudard S, Geoffrois L, Guillot A, et al. Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma—results of the rechallenge with sunitinib in metastatic RCC (RESUME) study. Eur J Cancer 2016; 62:28-35. 13. Eisenhauer E, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-47. 14. Sartore-Bianchi A, Siena S, Tonini G, Bardelli A, Santini D. Overcoming dynamic molecular heterogeneity in metastatic colorectal cancer: multikinase inhibition with regorafenib and the case of rechallenge with anti-EGFR. Cancer Treat Rev 2016; 51:54-62. 15. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6):Vi24-32. 16. Genestreti G, Tiseo M, Kenmotsu H, et al. Outcomes of platinum-sensitive smallcell lung cancer patients treated with platinum/etoposide rechallenge: a multiinstitutional retrospective analysis. Clin Lung Cancer 2015; 16:e223-8. 17. Lai X, Liu S, Tsai Y, et al. HAF mediates the evasive resistance of anti-angiogenesis TKI through disrupting HIF-1a and HIF-2a balance in renal cell carcinoma. Oncotarget 2017; 8:49713-24. 18. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366:883-92. 19. Anand D, Escalante CP. Ongoing screening and treatment to potentially reduce tyrosine kinase inhibitor-related fatigue in renal cell carcinoma. J Pain Symptom Manage 2015; 50:108-17. 20. Kwon YC, Yun YH, Lee KH, et al. Symptoms in the lives of terminal cancer patients: which is the most important? Oncology 2006; 71:69-76.
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Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma Sebastian Nachbargauer,1 Andreas Bruchbacher,1 Harun Fajkovic,2 Mesut Remzi,2 Manuela Schmidinger1 Abstract We performed a retrospective study of patients with metastatic renal cell carcinoma treated with sunitinib in 2 different treatment lines at the Medical University of Vienna. The approach to rechallenge with sunitinib after the development of resistance appears to be a feasible strategy and might be especially important in areas where novel agents are not yet available. Background: Sunitinib has been the standard of care for patients with metastatic renal cell carcinoma (mRCC). However, nearly all patients will eventually develop resistance. Before the introduction of novel agents, few treatment options remained after sunitinib failure. Sunitinib rechallenge is a strategy based on the presumption that resistance might be only temporary. The aim of this analysis was to evaluate the efficacy and safety of sunitinib rechallenge in patients with mRCC. Patients and Methods: Patients who had undergone sunitinib rechallenge (SU2) at the Medical University of Vienna from 2010 to 2017 were identified for the present retrospective study. The primary endpoint was the treatment duration with rechallenge (TDSU2). The secondary endpoints included the treatment duration with upfront sunitinib (TDSU1), progression-free survival (PFSSU1 and PFSSU2), overall survival (OSSU1 and OSSU2), the objective response rate in both settings (ORRSU1 and ORRSU2), and toxicity. Results: A total of 31 patients were eligible. The median TDSU2 was 7.2 months, and the median TDSU1 was 17.8 months. The median OSSU1 and OSSU2 was 57.9 months and 14.7 months, respectively. The median PFSSU1 and PFSSU2 was 14.2 months and 5.6 months, respectively. The ORRSU1 and ORRSU2 was 34% and 16%, and another 48% and 42% achieved stable disease (SD), respectively. Fatigue and hypertension were the most common adverse events. Conclusions: Sunitinib rechallenge appears to benefit patients in later treatment lines. With the abundance of novel treatment options available, this approach might appear less relevant. However, novel agents are not yet available everywhere. Thus, sunitinib rechallenge could be an additional strategy to improve the outcomes of patients with mRCC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: mRCC, Rechallenge, Resistance, Sunitinib, Tyrosine kinase inhibitors
Introduction Sunitinib is an oral tyrosine kinase inhibitor (TKI) targeting several growth factor receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), KIT, and FLT3. This agent has been the standard of care for first-line treatment of metastatic renal cell 1 Clinical Division of Oncology and Comprehensive Cancer Center, Department of Medicine I 2 Department of Urology, Medical University of Vienna, Vienna, Austria
Submitted: Sep 9, 2019; Revised: Nov 2, 2019; Accepted: Nov 27, 2019 Address for correspondence: Sebastian Nachbargauer, MD, Clinical Division of Oncology and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Waehringer Gürtel 18e20, Vienna 1090, Austria E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2019.11.006
carcinoma (mRCC) for more than a decade. However, tumors will ultimately acquire secondary resistance after a median treatment period of 11 months.1-3 First, VEGFR inhibitors induce a loss of vasculature, resulting in tumor stasis or regression. However, eventually, the hypoxic microenvironment induces an epithelial-tomesenchymal transition and resistance to anti-VEGFetargeted therapy. At this stage, other non-VEGFedependent pathways become relevant (eg, angiopoietin, fibroblast growth factor [FGF], MET).4,5 Newer TKIs that address the mechanisms of resistance such as the MET/AXL and VEGFR inhibitor cabozantinib or the FGF and VEGFR TKI lenvatinib have been shown to optimize the outcomes in patients with disease resistant to sunitinib.6,7 Moreover, the introduction of immune checkpoint inhibitors has contributed considerably to the longer overall survival (OS) of patients with mRCC.8 However, despite this therapeutic revolution,
Clinical Genitourinary Cancer Month 2019
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Sunitinib Rechallenge in Patients With mRCC Table 1 Patient Baseline Characteristics Characteristic All patients
Table 2 Sunitinib Rechallenge: Treatment Characteristics n (%)
Characteristic
31 (100)
All patients
Male
21 (68)
Sunitinib rechallenge starting dose, mg
Female
10 (32)
Gender
50
Age at rechallenge, y Median Range
59.1 42.8-84.9 27 (87)
Papillary
1 (3)
Other
3 (10)
Previous surgical procedure Nephrectomy Nephron-sparing surgery
37.5
29 (94) 2 (6)
3 (10) 23 (74) 5 (16)
Rechallenge line Third
Histologic subtype Clear cell
62.5
n (%) 31 (100)
10 (32)
Fourth
10 (32)
Fifth or later
11 (35)
Dose modifications during rechallenge Dose escalation
8 (26)
Dose reduction
6 (19)
Treatment break required
9 (29)
Local treatment Radiotherapy
11 (35)
Metastasectomy
12 (39)
MSKCC risk group Favorable Intermediate Poor
5 (16) 13 (42) 1 (3)
Unknown
12 (39)
Metastatic sites, n 1
2 (6)
2
8 (26)
3
9 (29)
4
12 (39)
Metastatic site Lung
26 (84)
Liver
13 (42)
Lymph nodes
20 (65)
Bone
8 (26)
Central nervous system
2 (6)
Soft tissue
5 (16)
a
Other
21 (68)
Treatments between SU1 and SU2 Tyrosine kinase inhibitorsb mTOR inhibitorsc Both tyrosine kinase and mTOR inhibitorsd
2
-
9 (29) 3 (10) 12 (39)
Nivolumab
2 (6)
Other agentse
5 (16)
Abbreviations: MSKCC ¼ Memorial Sloan Kettering Cancer Center; SU1 ¼ upfront sunitinib; SU2 ¼ sunitinib rechallenge. a Pancreas, 8 patients (26%); adrenal gland, 4 patients (13%); thyroid gland, 2 patients (6%); pleura, 3 patients (10%); kidney, 4 patients (13%); peritoneal, 1 patient (3%); retroperitoneal, 3 patients (10%); intestinal, 2 patients (6%); chest wall, 1 patient (3%); colon, 1 patient (3%); tumor thrombus in splenic vein, 1 patient (3%). b Seven patients (23%) had received axitinib and two (6%) had received pazopanib. c Everolimus was used in 3 patients (10%). d Axitinib and everolimus were used in 7 patients (23%), axitinib, everolimus, and pazopanib in 2 (6%), pazopanib and everolimus in 2 (6%), and sorafenib and everolimus in 1 patient (3%). e Bevacizumab and interferon-alfa were used in 2 patients (6%), axitinib and nivolumab in 1 (3%), temsirolimus, sorafenib, and bevacizumab in 1 (3%), and sorafenib, everolimus, temsirolimus, bevacizumab, pazopanib, interferon-alfa, and axitinib in 1 patient (3%).
Clinical Genitourinary Cancer Month 2019
most patients will eventually develop progression. At a certain point during the disease course, physicians and patients could face the situation in which no more new treatment options remain. Little evidence is available for the optimal treatment of patients who have undergone multiple lines of treatment. The approach to rechallenge with sunitinib has been based on the observation that the epithelial-to-mesenchymal transition is a reversible phenomenon. When transplanted into a xenograft model, a sunitinib-resistant tumor was shown to respond again to sunitinib.9 We hypothesized that this phenomenon might translate into clinical practice by withholding the VEGFR TKI for a certain period and that the mRCC might regain sensitivity to sunitinib during the treatment break. Small clinical studies have shown that heavily pretreated patients might benefit from sunitinib rechallenge after the occurrence of resistance to various previous agents, including mTOR inhibitors, monoclonal antibodies, cytokines, and other TKIs.10-12 The aim of the present analysis was to investigate the outcomes of patients who had undergone sunitinib rechallenge at the Medical University of Vienna.
Patients and Methods The present study was a retrospective and noninterventional single-center analysis of patients with mRCC who had undergone sunitinib rechallenge from 2010 to 2017. Out of 298 patients who had received sunitinib during the study period, 31 (10.4%) were eligible for the present analysis. The inclusion criteria were the receipt of sunitinib in 2 different treatment lines (upfront sunitinib [SU1] and sunitinib rechallenge [SU2]) after treatment with mTOR inhibitors, other TKIs, or immune checkpoint inhibitors. Tumor assessments were performed in accordance with the RECIST (response evaluation criteria in solid tumors), version 1.1, if available.13 The primary endpoint was the treatment duration (TD) of the sunitinib rechallenge (TDSU2), defined as the interval from initiation of the rechallenge until treatment discontinuation for any cause. The secondary endpoints included progression-free survival (PFS) of both upfront treatment (PFSSU1) and rechallenge (PFSSU2) and the treatment duration of upfront sunitinib (TDSU1). OS was
Sebastian Nachbargauer et al Figure 1 (A) Treatment Duration With Sunitinib Rechallenge (TDSU2): Median, 7.2 Months (95% Confidence Interval, 4.1-10.3 Months; n [ 31). (B) Progression-free Survival During Sunitinib Rechallenge (PFSSU2): Median, 5.6 Months (95% Confidence Interval, 3.0-8.2 Months; n [ 31)
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Sunitinib Rechallenge in Patients With mRCC Figure 2 Treatment Duration and Progression-free Survival During Upfront Sunitinib (TDSU1 and PFSSU1, Respectively)
measured from upfront sunitinib to death (OSSU1) and from the beginning of the rechallenge to death (OSSU2). The objective response rate in both settings (ORRSU1 and ORRSU2) was also measured. Toxicity during SU1 and SU2 was an additional secondary endpoint. The Kaplan-Meier method was used to estimate the TD, PFS, and OS. The observation interval was censored at the last follow-up examination. All statistical analyses were performed using IBM SPSS Statistics, version 24.0.
Results Patient Characteristics and Initial Treatment A total of 31 patients were included in the present study. All patients had experienced progression during SU1 and subsequently underwent rechallenge with sunitinib after treatment with 1 different agents approved for mRCC treatment. Three patients were still undergoing SU2 at analysis. The baseline characteristics at rechallenge are outlined in Table 1. The median patient age at rechallenge was 59.1 years (range, 42.8-84.9 years). Most patients (87%) had had clear cell tumors, and all had undergone either previous nephrectomy (94%) or nephron-sparing surgery (6%). The disease of most patients (42%) had been classified as intermediate risk using the Memorial Sloan Kettering Cancer Center risk group classification. Of the 31 patients, 39% had had 4 metastatic sites. The lung (84%), liver (42%), and lymph nodes (65%) were among the most common sites. SU1 had mostly been offered in the first-line setting (68%). Seven patients (23%) had been treated with cytokines, and three (10%) with other TKIs or mTOR inhibitors before SU1.
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Sunitinib Rechallenge The treatment characteristics of SU2 are listed in Table 2. SU2 was offered in the setting of third-, fourth-, or fifth-line or later treatment for 32%, 32%, and 35% of patients, respectively. Most patients (74%) had started SU2 at a dose of 50 mg. Dose escalations to 75 mg were performed for 26% of patients, 19% required dose reductions, and 9 patients (29%) required temporary treatment breaks.
Efficacy The median TDSU2 was 7.2 months (95% confidence interval [CI], 4.1-10.3 months; Figure 1A), and the median PFSSU2 was 5.6 months (95% CI, 3.0-8.2 months; Figure 1B). Three patients (10%) were censored for TDSU2 and PFSSU2, respectively. The median TDSU1 was 17.8 months, and the median PFSSU1 was 14.2 months (Figure 2). The median OSSU1 was 57.9 months (95% CI, 48.8-66.9 months; Figure 3A), and the median OSSU2 was 14.7 months (95% CI, 9.4-20.0 months; Figure 3B). At the time of data collection, 12 patients (39%) were alive and thus were censored for the OS estimations. An objective response with SU1 and SU2 was achieved in 10 (34%) and 5 (16%) patients, respectively (Table 3).
Safety Analysis The toxicity occurring during both SU1 and SU2 is outlined in Table 4. The most common adverse events during both treatment lines were fatigue and hypertension. The comparison of the incidence and severity of toxicities in SU1 and SU2 revealed that fatigue was more pronounced during SU2 but hypertension was more severe during SU1.
Sebastian Nachbargauer et al Figure 3 (A) Overall Survival During Upfront Sunitinib (OSSU1): Median, 57.9 Months (95% Confidence Interval, 48.8-66.9 Months; n [ 30). (B) Overall Survival During Sunitinib Rechallenge (OSSU2): Median, 14.7 Months (95% Confidence Interval, 9.4-20.0 Months; n [ 31)
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Sunitinib Rechallenge in Patients With mRCC Table 3 Efficacy of Upfront Sunitinib and Sunitinib Rechallenge Characteristic All patients
n (%) 31 (100)
Best response to initial sunitinib (n ¼ 29) Stable disease
14 (48)
Partial response
8 (28)
Complete response
2 (7)
Progressive disease
5 (17)
TDSU1 (n ¼ 29) Median
17.8
Range
5.2-47.3
PFSSU1 (n ¼ 30), mo Median
14.2
Range
1.6-35.8
OSSU1 (n ¼ 30), mo Median
57.9
95% CI
48.8-66.9
Best response (sunitinib rechallenge) Stable disease
13 (42)
Partial response
5 (16)
Complete response
0 (0)
Progressive disease
13 (42)
TDSU2 (n ¼ 31), mo Median
7.2
95% CI
4.1-10.3
PFSSU2 (n ¼ 31), mo Median
5.6
95% CI
3.0-8.2
OSSU2 (n ¼ 31), mo Median
14.7
95% CI
9.4-20.0
Interval between initial sunitinib and rechallenge (n ¼ 29), mo Median
8.9
Range
2.1-42.5
Abbreviations: CI ¼ confidence interval; OSSU1 ¼ overall survival measured from upfront sunitinib to death; OSSU2 ¼ overall survival measured from the beginning of the rechallenge to death; PFSSU1 ¼ progression-free survival measured from upfront sunitinib to progression; PFSSU2 ¼ progression-free survival measured from the beginning of the rechallenge to progression or death; TDSU1 ¼ treatment duration of upfront sunitinib; TDSU2 ¼ treatment duration of sunitinib rechallenge.
The aim of the present study was to analyze the safety and efficacy of sunitinib rechallenge at the Medical University of Vienna. Most patients (58%) had experienced either a partial response or stable disease at rechallenge, with a median TDSU2 of 7.2 months, median PFSSU2 of 5.6 months, and median OSSU2 of 14.7 months. The median OS from the beginning of initial sunitinib was 57.9 months. Our results support the hypothesis that resistance to sunitinib might represent a temporary phenomenon. Sunitinib-resistant cells might be prone to increase expression of hypoxia-inducible factor1a or to rely on alternative pathways for angiogenesis, such as MET, AXL, or angiopoietin.4,5,17 Moreover, intratumor heterogeneity was found to be an important driver of treatment failure in patients with mRCC. In 2012, Gerlinger et al18 reported on branched evolutionary tumor growth, with most mutations not detectable across different metastatic sites. This might explain why responses will not occur at all metastatic sites.18 Despite the complexity of the biology of tumor progression, our data suggest that rechallenge with sunitinib after previous resistance could be beneficial. In kidney cancer, sunitinib rechallenge has been previously studied. Oudard et al12 reported a median PFS of 7.9 months in the RESUME (results of the rechallenge with sunitinib in metastatic RCC) study. Zama et al11 reported a median PFS of 7.2 months. By indirect comparison, our patients derived slightly less PFS benefit. This most likely resulted from differences in the patient populations. First, documented progression during SU1 was crucial for inclusion in our analysis. In contrast, 19% of patients included in the RESUME study had had treatment discontinuation for reasons other than disease progression. Hence, resistance to sunitinib had not necessarily developed before the rechallenge had been started. Second, only 6% of patients in the RESUME study had been classified as having primary resistant disease (progressive disease as best response). In contrast, 17% of our patients had had disease progression as the best response during SU1. This supports the assumption that our analysis included a greater number of individuals with primary resistance to anti-VEGF treatment. Third, the patients in the RESUME study had been required to have a life expectancy of 3 months and a minimum of 2 computed tomography scans performed during the rechallenge. In contrast, all patients in whom sunitinib had been initiated a second time were considered eligible for our study. Finally, in terms of safety, fatigue was the most common side effect during SU2. This might have been a result of the advanced stage of the disease rather than the treatment itself.19,20 The limitations of the present analysis were its retrospective design and the small number of patients. In addition, because we had performed the tumor assessments, the response rates and estimated PFS might be biased.
Discussion The strategy to rechallenge a patient with an agent on which progression had occurred in a previous treatment line has been previously studied for other malignancies. Analogous approaches with EGFR-targeting agents have been used in metastatic colorectal cancer. Also, re-exposure with platinum-based chemotherapy has been established in recurrent ovarian carcinoma. Similar concepts were also evaluated in studies of small cell lung cancer.14-16
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Conclusions Sunitinib rechallenge was efficient in several patients, with an acceptable safety profile. The main reason for the strategy of rechallenge was that fewer therapeutic alternatives were available during the study period. Rechallenge could still be an option to improve outcomes in regions where novel agents, such as nivolumab, ipilimumab, pembrolizumab, and cabozantinib, are not yet available and/or reimbursed.
Sebastian Nachbargauer et al Table 4 Adverse Events During Upfront Sunitinib and Sunitinib Rechallenge SU1 Adverse Event (n [ 25) Diarrhea Nausea Emesis Stomatitis Hypertension Fatigue Hand-foot syndrome Rash
All Grades 10 6 3 11 17 17 7 3
(40) (24) (12) (44) (68) (68) (28) (12)
SU2 Grade 3-4 1 0 0 2 11 4 0 0
(4) (0) (0) (8) (44) (16) (0) (0)
All Grades 7 10 5 10 17 19 7 3
(28) (40) (20) (40) (68) (76) (28) (12)
Grade 3-4 1 1 0 2 5 11 0 0
(4) (4) (0) (8) (20) (44) (0) (0)
Data presented as n (%). Abbreviations: SU1 ¼ upfront sunitinib; SU2 ¼ sunitinib rechallenge.
Clinical Practice Points Sunitinib, a TKI targeting VEGFR, PDGFR, KIT, and FLT3,
has been a mainstay in the treatment of mRCC. However, its long-term application will ultimately lead to the
development of resistance through upregulation of alternative pathways, such as MET or FGF. Some small clinical studies have previously demonstrated the efficacy of sunitinib rechallenge (ie, reinduction of this TKI after treatment had been withheld for a period). The aim of the present analysis was to evaluate efficacy and safety of SU2 in patients treated at the Medical University of Vienna. The TD, PFS, OS, toxicity, and ORR were evaluated for both SU1 and SU2. SU2 appears to be a feasible and safe option for patients in later treatment lines, especially when novel agents, such as ipilimumab, nivolumab, pembrolizumab, and cabozantinib, are not yet available. However, further investigation is needed to determine the relevance of this approach among the currently available alternatives.
Disclosure A.B. has received a research grant from Pfizer and travel grant from EUSA Pharma. H.F. has received honoraria for lectures from Pfizer, Jansen, Ipsen, and Astellas. M.R. has received honoraria for lectures and congress support from Pfizer. M.S. has received honoraria for lectures and participating on advisory boards from Pfizer, Roche, Novartis, BMS, Ipsen, Eisai, Astellas, and EUSA Pharma. The remaining authors declare that they have no competing interests.
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