REVIEW URRENT C OPINION
The role of rechallenge with targeted therapies in metastatic renal-cell carcinoma Ste´phane Oudard a,b and Yann Vano a,b
Purpose of review To explore the accumulating evidence and feasibility of rechallenge with agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways for incorporation into the evolving management algorithm for metastatic renal-cell carcinoma (mRCC). Recent findings The current standard of care after the development of resistance to first-line targeted therapies in mRCC is sequential treatment with subsequent lines of alternative anti-VEGF agents or mTOR inhibitors, with optimal sequencing being the focus of ongoing research. Recent evidence from case study and retrospective reports suggests that mRCC patients can achieve important clinical benefits from rechallenge at later lines of therapy with the same targeted therapy used for previous line treatment. Further, the results of REchallenge with SUnitinib in MEtastatic, the first study of sunitinib rechallenge to include a prospective component, reinforce the potential for prolonged survival with this treatment approach for mRCC patients. Summary Rechallenge represents an important and feasible therapeutic option for the future treatment of mRCC patients. The results of ongoing prospective studies are expected to further evaluate the benefits of rechallenge and better inform wherein this approach fits in the treatment algorithm for mRCC. Keywords metastatic renal-cell carcinoma, rechallenge, targeted therapy, vascular endothelial growth factor
INTRODUCTION The treatment of metastatic renal-cell carcinoma (mRCC) has advanced significantly since the era of cytokine therapy, when patient prognosis was poor with 5-year survival rates estimated at 10% [1]. The last decade has seen the advent of therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, heralding significant improvements in progression-free survival (PFS) and overall survival (OS) for patients with mRCC [2–4]. Multiple-targeted agents are now approved for the treatment of mRCC, including tyrosine kinase inhibitors (TKIs) of the VEGF receptor (VEGFR; axitinib, pazopanib, sorafenib, and sunitinib), antiVEGF antibodies (bevacizumab in combination with interferon-a) and inhibitors of the mTOR pathway (temsirolimus and everolimus). Although these therapies have undoubtedly provided considerable survival benefits for patients with mRCC, most tumors will develop acquired or adaptive resistance to targeted agents, with resistance to first-line VEGFR-TKIs developing within 6–11 months of www.co-urology.com
treatment initiation in the majority of patients [5,6]. When resistance develops, a recognized treatment strategy is the sequential use of different targeted agents, with optimal sequencing being the focus of considerable ongoing research [3]. Growing evidence also suggests that rechallenge with the same agent could be considered in this sequential treatment approach, as resistant tumors can regain sensitivity to first-line (or previous-line) therapy after subsequent lines of alternative treatments. The purpose of this review is to explore the current evidence for rechallenge with targeted therapies in mRCC.
a
Oncology Department, European Hospital Georges Pompidou and Oncology Department, Paris Descartes University, Paris, France
b
Correspondence to Ste´phane Oudard, MD, PhD, Oncology Department, European Hospital Georges Pompidou, 20 rue Leblanc, Paris 75015, France. Tel: +33 1 56 09 34 76; fax: +33 1 56 09 20 39; e-mail: [email protected] Curr Opin Urol 2015, 25:402–410 DOI:10.1097/MOU.0000000000000206 Volume 25 Number 5 September 2015
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Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano &
KEY POINTS Targeted therapies have dramatically improved the prognosis for patients with mRCC; however, resistance to these agent will inevitably develop in the majority of patients. The standard of care for patients with mRCC who develop resistance is the sequential use of alternative targeted therapies, a strategy that has been shown to provide clinical benefit. Determining the optimal sequencing of targeted therapies is the focus of ongoing research with the aim of further improving the outlook for patients with mRCC. Accumulating data suggests that rechallenge with the same targeted therapy at a later line of treatment is a feasible strategy to include in this sequential treatment approach. The results of ongoing prospective evaluations will help further inform on how rechallenge can be incorporated into the current treatment algorithm for mRCC.
SEQUENTIAL TARGETED THERAPY AFTER THE DEVELOPMENT OF RESISTANCE Sequential treatment with as many targeted therapies as a patient is likely to benefit from is the current standard of care in mRCC, with the potential to considerably extend patient survival and maximize the duration of disease control [7,8 –10 ]. On progression of a first-line agent, the European Society for Molecular Oncology (ESMO), European Association of Urology (EAU), and National Comprehensive Cancer Network (NCCN) guidelines recommend alternative VEGFR-TKIs or mTOR inhibitors as second-line treatment (Table 1) [11 –13 ]. However, specific guidance on the order in which these agents should be selected is less clear, with sequences often determined by treatment availability, the toxicity profile of previous therapies, physician familiarity with specific drugs, treatment costs, and patient comorbidities [4]. As different VEGFR-TKIs essentially target the same signaling pathway, subsequent therapy with an mTOR inhibitor would seem to be the most logical treatment approach for patients who are refractory to a first-line agent [14 ]. However, as each VEGFR-TKI has a distinct molecular target profile and specific binding affinities for shared molecular targets (Fig. 1), successive treatment with an alternative VEGFR-TKI is also a plausible strategy to counteract resistance [7]. Indeed, there is no evidence to suggest cross-resistance between VEGFR-TKIs, and meaningful clinical benefits are observed in patients refractory to firstline VEGFR-TKIs receiving sequential therapy with a &
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second VEGFR-TKI [8 –10 ]. Furthermore, in a headto-head, randomized controlled trial, second-line treatment with sorafenib was associated with significantly longer median OS compared with temsirolimus after progression on first-line sunitinib (16.6 versus 12.3 months, respectively; P ¼ 0.01) [15 ]. Limited data are available from randomized studies assessing the comparative efficacy of different VEGFR-TKIs as second-line or third-line agents for mRCC. The AXIS trial was the first phase 3, randomized trial to directly compare second-line treatment of mRCC with two VEGF-targeted agents, axitinib, and sorafenib [16]. Axitinib was associated with improved median PFS compared with sorafenib (6.7 versus 4.7 months, respectively; P < 0.0001), although this did not translate into improved median OS. A longer duration of prior treatment and a smaller tumor burden following initial therapy was generally associated with longer OS for both agents second line [17 ]. In the third-line setting, the phase three GOLD study was conducted to compare the efficacy of dovitinib (a fibroblast growth factor receptor, platelet-derived growth factor receptor, and VEGFR inhibitor) and sorafenib after previous VEGF-targeted therapies and mTOR inhibitors [10 ]. Although both agents provided clinical benefits, no significant differences in efficacy outcomes were noted between groups. Real world, observational data may also help inform on the optimal sequencing of targeted therapies. In a systematic review and meta-analysis of observational studies comparing sequential treatment strategies for mRCC, some survival benefit was observed with second-line mTOR inhibitors over second-line VEGFR-TKIs among a subset of studies with more controlled design [18 ]. However, data for axitinib were limited at the time of this analysis. In contrast, in a retrospective multicenter analysis, a longer duration of response to first-line TKI therapy and receiving a TKI rather than an mTOR inhibitor second line were associated with a longer duration of response and PFS with secondline therapy [19 ]. &
&
&
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RATIONALE FOR RECHALLENGE: PRECLINICAL EVIDENCE The precise mechanisms by which resistance to targeted therapies for RCC develops are yet to be fully elucidated. VEGF-targeted therapies are proposed to cause tumor hypoxia, leading to the accumulation of hypoxia-inducible factor 1, which in turn leads to upregulation of factors that stimulate angiogenesis, tumor invasiveness, and epithelial-to-mesenchymal transition [20 ]. Accumulating evidence suggests that these effects are reversible, and that changes in the
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403
404
www.co-urology.com Clinical trial Sunitinib
NCCN [13 ]
Good or intermediate risk
Temsirolimus
Sorafenib
High-dose IL-2
Axitinib
Pazopanib
After cytokines Sorafenib, axitinib or pazopanib
After VEGFR Axitinib, sorafenib or everolimus
Sunitinib Sorafenib
Sorafenib
Sunitinib
Options
Rechallenge
Other TKIs
Options
Sorafenib
Post-TKI and mTOR
Everolimus
Post-2 TKIs
Standard
Third-line
High-dose IL-2
Axitinib, sorafenib, sunitinib, pazopanib, temsirolimus or bevacizumab
After cytokines
Everolimus, axitinib, sorafenib, sunitinib, pazopanib, temsirolimus or bevacizumab
After TKIs
Clinical trial
Any targeted agent
After mTOR Sorafenib
After VEGFR Everolimus
Axitinib or everolimus
Post-TKIs
Axitinib, sorafenib or pazopanib
Postcytokines
Standard
Second-line
EAU, European Association of Urology; IFN-a, interferon-a; IL, interleukin; NCCN, National Comprehensive Cancer Network; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor; VEGFR, vascular & & endothelial growth factor receptor. Adapted with permission from [11 –13 ]. For selected patients.
Poor risk
Temsirolimus
Poor risk
Bevacizumab and IFN-a
Bevacizumab and IFN-a Pazopanib
Good or intermediate risk
&
Sunitinib
EAU [12 ]
&
Temsirolimus
Poor risk
Bevacizumab and low-dose IFN-a
High-dose IL-2 Sorafenib
Sunitinib Bevacizumab and IFN-a Pazopanib
Good or intermediate risk
Options
Standard
&
ESMO [11 ]
First-line
Table 1. Guidelines and recommendations for the treatment of metastatic renal-cell carcinoma (clear-cell histology)
The future of kidney cancer: quo vadis
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Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano
Axitinib
Dovitinib
Motesanib
TKL
TKL
TKL
TK
TK
CMGC
AGC
Other
CMGC
CAMK
Sorafenib
1 nM 10 nM 100 nM 11 µM
CMGC
CAMK
Vatalanib
TKL
AGC
Other
CAMK
CMGC
Vandetanib
TKL TK STE
CK1
CK1
AGC
Other
CAMK
STE
AGC
CK1
TK
STE
Kd
CMGC
CAMK
TK
CMGC
AGC
Other
TKL
TKL
STE
CK1
Sunitinib
TK
Other
TK STE
CK1
CK1
AGC
TKL
TK STE
STE
Other
Pazopanib
STE
CK1
AGC
Other
CMGC
CAMK
CAMK
CK1
AGC
Other
CMGC
CAMK
TK = tyrosine kinase; TKL= tyrosine kinase-like; STE = STE family protein kinase; CK1 = casein kinase I; AGC = protein kinase A, G, and C families; CAMK = calcium/calmodulin-dependent protein kinase; CMGC = cyclin-dependent kinases (CDK), mitogen-activated protein kinases, glycogen synthase kinases and CDK-like kinases Images generated using TREE spot software tool and reprinted with permission from KINOME scan, a division of discoveRx corporation, discoverx corporation 2010.
FIGURE 1. Interaction of targeted therapies with specific molecular targets. AGC, protein kinase A, G, and C families; CAMK, calcium/calmodulin-dependent protein kinase; CK1, casein kinase I; CMGC, cyclin-dependent kinases (CDK), mitogen-activated protein kinases, glycogen synthase kinases and CDK-like kinases; STE, STE family protein kinase; TK, tyrosine kinase; TKL, tyrosine kinase-like; Images generated using TREEspot Software Tool and reprinted with permission from KINOMEscan, a division of DiscoveRx Corporation, ß DISCOVERX CORPORATION 2010.
tumor microenvironment may restore tumor sensitivity to targeted therapies [7]. Preclinical evidence supporting this hypothesis comes from a study in which tumor tissue was transplanted from sunitinibresistant metastatic skin lesions into nude mice [21]. Interestingly, xenograft tumors regained sensitivity to sunitinib and demonstrated the clear cell phenotype, whereas evidence of epithelial-to-mesenchymal transition was observed in the sunitinib-resistant metastatic tumor tissue [21]. In a clinical setting, the same effect of altering the tumor environment may be affected by switching to a different targeted therapy or with a treatment break followed by rechallenge with the same agent [14 ]. Recent research has investigated the impact of the tumor microenvironment on the clinical outcome for patients with RCC. Molecular subtypes of clear cell RCC with poor sensitivity to sunitinib exhibit sarcomatoid differentiation and a suppressive immune microenvironment, with high expression of the immune checkpoint protein, PD-1, and its ligands [22 ]. Similarly, high expression of &&
&
immune checkpoint proteins and the absence of fully functional mature dendritic cells have been observed in primary or metastatic tumors from RCC patients with a poor prognosis [23 ]. Conversely, low expression of immune checkpoints and mature dendritic cells located in tertiary lymphoid structures were observed in tumors from patients with prolonged survival. &
RECHALLENGE IN OTHER TUMOR TYPES Drug rechallenge has provided meaningful clinical benefits in retrospective studies of other tumor types. In 270 patients with metastatic castrationresistant prostate cancer who progressed after an initial good response to first-line docetaxel, improved rates of symptom relief and stable disease were achieved with docetaxel rechallenge compared with nontaxane-based second-line therapies [24 ]. Similarly, the reintroduction of docetaxel to 72 patients with metastatic breast cancer resulted in a substantial proportion achieving a partial response
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(42.5%) or stable disease (33.5%) [25]. The survival benefits of rechallenge in this heavily pretreatedpatient population needs to be balanced against the risk of exacerbation of chronic toxicities and impaired quality of life. Key considerations determining whether a patient may be suitable for rechallenge include the length of time that has passed between completion of initial therapy and subsequent rechallenge [26], and the duration of the progressionfree interval (PFI) achieved with first-line chemotherapy [27,28]. In patients with advanced ovarian cancer who achieve a PFI of more than 6 months with first-line paclitaxel in combination with a platinum analogue can achieve response rates of 30–50% on retreatment with a platinum-based therapy after progression [27]. Similarly, for patients with advanced small-cell lung cancer and a PFI of at least 3 months after the discontinuation of first-line treatment may be considered for platinum-based rechallenge [28].
EVIDENCE FOR RECHALLENGE IN METASTATIC RENAL-CELL CARCINOMA: RETROSPECTIVE STUDIES AND CASE REPORTS Recent ESMO guidelines for RCC include rechallenge with the same TKI used for initial treatment as an option for patients requiring third-line therapies (Table 1) [11 ], although this recommendation is based on limited evidence from retrospective cohort or case–control studies. A summary of studies evaluating rechallenge either with agents from the same class or the same agent are provided in Table 2 [16,29–35]. The majority of studies exploring rechallenge with the same agent have focused on sunitinib, and have been summarized in a recent review by Porta et al. [14 ]. Initial case report data reported symptomatic relief and disease stabilization with sunitinib rechallenge in patients with mRCC who had progressed on first-line sunitinib [36,37]. Similarly, in a small retrospective analysis, 12 of 13 patients rechallenged with sunitinib experienced a partial response or stable disease, with median PFS of 6.9 months compared with 21 months after first-line sunitinib treatment [34]. In a further study, five of 23 patients experiencing disease progression or intolerance to first-line sunitinib (and 1 subsequent agent) achieved a partial response to sunitinib rechallenge [33]. Median PFS first line was 13.7 months compared with 7.2 months on sunitinib rechallenge, with the length of the interval between first-line sunitinib and rechallenge influencing the duration of PFS. A retreatment interval greater than 6 months was &
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associated with longer median PFS compared with rechallenge within 6 months (16.5 versus 6.0 months, respectively). The type or number of intervening treatments had no significant effect on outcomes and no new toxicities or exacerbation of prior toxicities was noted. Similarly, in another study, sunitinib rechallenge in nine patients who had failed at least two previous targeted therapies was associated with median PFS of 6.8 months compared with 13.7 months for initial sunitinib treatment [35]. The evidence for rechallenge in mRCC is not limited to sunitinib. In a case series of 12 patients who had failed first-line sorafenib and subsequent anti-VEGF therapies or mTOR inhibitors, eight (67%) achieved stable disease upon sorafenib rechallenge, with median PFS of 5.4 months [32]. In contrast to sunitinib rechallenge, the duration of PFS with sorafenib rechallenge did not correlate with the PFS duration observed with initial sorafenib treatment or with the length of the interval between initial treatment and rechallenge. In a retrospective analysis of 12 patients with mRCC who progressed on treatment with their first mTOR inhibitor (temsirolimus or everolimus; after 1 line of prior VEGFR-TKIs), and then underwent rechallenge with the other agent, a longer median treatment duration was observed with the everolimus–temsirolimus sequence compared with the temsirolimus–everolimus sequence (10.3 versus 5.8 months; respectively) [31]. Of the seven patients treated with everolimus before temsirolimus, 57 and 29% responded to everolimus or temsirolimus only, and 14% responded to both mTOR inhibitors. Among the five patients treated with temsirolimus before everolimus, 20% responded to temsirolimus only, 20% responded to everolimus only, and 60% did not respond to either mTOR inhibitor. Despite the limited number of patients included in this study, the results again highlight the potential feasibility of rechallenge as a sequential therapy option in mRCC.
RECHALLENGE WITH SUNITINIB IN METASTATIC: THE LARGEST STUDY OF RECHALLENGE IN MRCC CONDUCTED TO DATE REchallenge with SUnitinib in MEtastatic renal-cell carcinoma (RESUME) was a multicenter, observational, prospective, and retrospective study of sunitinib rechallenge in the third line or more. The primary objective was to examine the effect of sunitinib rechallenge on PFS in 52 patients with mRCC who received first-line sunitinib followed by one or more lines of different therapies (temsirolimus, Volume 25 Number 5 September 2015
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Sunitinib Sunitinib
Axitinib [16,30]
Sorafenib [16,30]
Everolimus
Temsirolimus [31]
0963-0643 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. Retrospective analysis Retrospective analysis
Gru¨nwald et al. [34]
Nagyivanyi et al. [35]
9
12
23
12
5
7
723
723
55
Number of patients
IV,B
IV,B
IV,B
V,B
IV,B
IV,B
I,A
I,A
II,A
Evidence level
Median PFS on rechallenge: 6.8 months
Median PFS on initial therapy: 13.7 months
Stable disease: 55%
Partial response: 11%
Median PFS on rechallenge: 6.9 months
Median PFS on initial therapy: 21 months
Median PFS on rechallenge: 7.2 months
Median PFS on initial therapy: 13.7 months
Partial response: 22%
Median PFS overall: 21.3 months (95% CI: 18.1–24.5)
Median PFS on rechallenge: 5.4 months (95% CI: 3.8–7.0)
Median treatment duration: 5.8 months (95% CI: 2.9–19.3)
Median treatment duration: 10.3 months (95% CI: 8.8–19.2)
Median PFS: 4.7 months (95% CI: 4.6–5.6)
Median OS: 19.2 months (95% CI: 175–223)
Median PFS: 6.7 months (95% CI: 6.3–8.6)
Median OS: 20.1 months (95% CI: 167–234)
Median survival: 24.2 months (95% CI: 14.7–NR)
Median PFS: 7.5 months (95% CI: 5.4–9.4)
Efficacy data on rechallenge
CI, confidence interval; mTOR, mammalian target of rapamycin; NR, not reached; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
Retrospective review
Sunitinib
Sunitinib
Case series
Retrospective analysis
Retrospective analysis
Phase 3
Phase 3
Phase 2
Study type
Zama et al. [33]
Sorafenib
Sorafenib [32]
Rechallenge with the same agent (third-line or more)
Temsirolimus
Everolimus [31]
Rechallenge with an alternative mTOR inhibitor
Sunitinib
Pazopanib [29]
Rechallenge with an alternative TKI (second-line)
Previous therapy
Table 2. Evidence for rechallenge in of metastatic renal-cell carcinoma from clinical trials and retrospective studies
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everolimus, sorafenib, pazopanib, axitinib, or bevacizumab) [38 ]. On first-line sunitinib, 28 patients (54%) achieved an objective response and median PFS was 18.4 months (Table 3). The median duration of therapy was 14.9 months, with the majority of patients (82%) discontinuing due to disease progression rather than tolerability issues. Rechallenge began a median of 14.6 months after discontinuation of initial sunitinib treatment and constituted fourth-line therapy in the majority of patients (65%). On sunitinib rechallenge, median OS was 55.9 months with 61% of patients (n ¼ 32) experiencing clinical benefit (Table 3) [38 ]. Median PFS was 7.9 months, which is in line with the duration of PFS observed in the smaller retrospective studies of sunitinib rechallenge [33–35]. A shorter duration of PFS with later lines of therapy would be expected compared with first-line therapy as these patients are more likely to have a poorer performance status. Subgroup analyses also revealed significantly improved median PFS on rechallenge in patients who achieved median PFS at least 18.4 months and had a median duration of treatment at least 14.9 months with first-line sunitinib therapy (P < 0.05). Eight patients (15%) achieved a partial response on rechallenge, with six of these patients having experienced a prior response to first-line sunitinib [38 ]. These patients who had achieved a complete or partial response to first-line sunitinib also achieved longer PFS with sunitinib rechallenge compared with first-line nonresponders (15.0 versus 5.0 months, respectively; P ¼ 0.05). As would be expected for this heavily pretreated patient population, the proportion of patients &&
&&
&&
experiencing serious adverse events was higher on rechallenge compared with on first-line sunitinib (19 versus 4%, respectively; Table 3). Importantly, no new adverse events were reported either at first line or on rechallenge [38 ]. Although the results of RESUME provide convincing evidence for the potential clinical benefit of rechallenge in mRCC, there may have been some positive selection bias toward patients more likely to achieve longer OS in this study. Patients with mRCC who are able to receive multiple lines of targeted therapy are often likely to live longer, with a greater duration of PFS [39 ]. Additionally, 80% of patients had a dose reduction when receiving first-line sunitinib, and therefore may not have been truly resistant to the recommended dose of sunitinib. Another key consideration is that as the RESUME study was partly retrospective, adverse event data were only available for some patients (n ¼ 27), meaning that the tolerability profile of sunitinib rechallenge may not have been fully characterized. To further explore the potential clinical benefits of sunitinib rechallenge in mRCC, two prospective phase 2 studies have been initiated. A Dutch trial (NTR3711) will assess the ability of sunitinib rechallenge to improve PFS in patients who achieved stable disease for at least 6 months on first-line sunitinib but subsequently progressed on sunitinib and second-line therapies [mTOR inhibitors or another therapy (excluding VEGFR TKIs)]. A second Italian study will assess the ability of third-line sunitinib rechallenge after second-line everolimus to provide freedom from disease progression (EudraCT 2012–000473–23/RETRY). It is hoped that the results of these studies will help better inform wherein rechallenge fits in the current &&
&
Table 3. Key efficacy and safety outcomes from the REchallenge with SUnitinib in MEtastatic study [38 ] &&
First-line sunitinib
Rechallenge sunitinib (i.e. third-line or later)
Key efficacy data (n ¼ 52 pts) Best response, n (%) Objective response Complete response
28 (54)
8 (15)
1 (2)
0
Partial response
27 (52)
8 (15)
Stable disease
21 (40)
24 (46)
Clinical benefit rate
49 (94)
32 (61)
Progressive disease
3 (6)
Median PFS (95% CI), months
20 (38)
18.4 (12.5–23.7)
Median OS (95% CI), months
7.9 (5.4–13.2) 55.9 (48.0–63.7)
Key safety data At least 1 adverse event, n (%)
5 (19)
At least 1 serious adverse event, n (%)
1 (4)
10 (37) 5 (19)
CI, confidence interval; OS, overall survival; PFS, progression-free survival.
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Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano
treatment algorithm for mRCC, further optimizing the sequential-targeted therapy approach.
CONCLUSION Adaptive or acquired resistance to targeted therapies for mRCC is the main barrier preventing patients from achieving maximal survival benefits with these agents. The sequential use of different targeted therapies is a promising approach to bypassing this resistance, potentially by providing continual inhibition of the signaling pathways implicated in tumor angiogenesis, thereby stabilizing disease progression. The accumulated data from case reports, retrospective studies, and the recent RESUME study supports the validity of rechallenge as an additional strategy to be included in this sequential therapy approach for the management of tumor progression in mRCC. Key factors that may be linked to the degree of clinical benefit likely to be observed with rechallenge include a longer duration of response to initial treatment and a greater interval between firstline therapy and rechallenge. The results of ongoing prospective studies of sunitinib rechallenge should further characterize the clinical benefits that could be expected with targeted therapy rechallenge. Future research should also focus on characterizing, which patients are most likely to benefit from rechallenge or other sequential therapy options, with the goal of further enhancing survival outcomes for mRCC patients. Acknowledgements None. Financial support and sponsorship Medical writing support was provided by Farah Dalwai at Litmus MME (London, UK). Funding for medical writing support was provided by Pfizer Inc. Conflicts of interest S.O. has received honoraria from Novartis, Pfizer, Bayer, Bristol-Myers, Squibb and GlaxoSmithKline.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17:2530–2540. 2. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27:3584–3590.
3. Oudard S, Elaidi RT. Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: optimizing patient benefit. Cancer Treat Rev 2012; 38:981–987. 4. Hutson TE, Bukowski RM, Cowey CL, et al. Sequential use of targeted agents in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol 2011; 77:48–62. 5. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renalcell carcinoma. N Engl J Med 2007; 356:125–134. 6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115–124. 7. Porta C, Tortora G, Linassier C, et al. Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement. Med Oncol 2012; 29:1896–1907. 8. Bellmunt J, Pons F, Foreshew A, et al. Sequential targeted therapy after & pazopanib therapy in patients with metastatic renal cell cancer: efficacy and toxicity. Clin Genitourin Cancer 2014; 12:262–269. Retrospective study of sequential-targeted therapy following first-line pazopanib in patients with mRCC. 9. Richter S, Seah JA, Pond GR, et al. Evaluation of second-line and subsequent & targeted therapies in metastatic renal cell cancer (mRCC) patients treated with first-line cediranib. Can Urol Assoc J 2014; 8:398–402. Retrospective study of sequential-targeted therapy following first-line cediranib in patients with mRCC. 10. Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third& line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15:286–296. Phase 3 clinical trial comparing third-line therapy with dovitinib and sorafenib in patients with mRCC showing no significant difference between therapies. 11. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO & Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 (Suppl 3):iii49–iii56. Recent clinical practice guidelines from ESMO for the management of mRCC. 12. Ljungberg B, Bensalah K, Canfield S, et al. EAU Guidelines on Renal Cell & Carcinoma: 2014 Update. Eur Urol 2015. [Epub ahead of print] Recent clinical practice guidelines from the EAU for the management of mRCC. 13. National Comprehensive Cancer Network (NCCN). NCCN clinical practice & guidelines in Oncology. Kidney Cancer. Version 3. 2015. Available at: http:// www.nccn.org/professionals/physician_gls/pdf/kidney.pdf [Accessed March 2015]. Recent update to the NCCN guidelines for the management of RCC. 14. Porta C, Paglino C, Grunwald V. Sunitinib re-challenge in advanced renal-cell && carcinoma. Br J Cancer 2014; 111:1047–1053. Systematic review and meta-analyses of retropective studies and case reports of sunitinib rechallenge in mRCC demonstrating clinical benefits with rechallenge. 15. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of & temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2014; 32:760–767. Phase 3 trial demonstrating survival benefits with second-line TKIs versus mTOR inhibitors after first-line sunitinib. 16. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931–1939. 17. Escudier B, Michaelson MD, Motzer RJ, et al. Axitinib versus sorafenib in & advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer 2014; 110:2821–2828. Subanalyses of a phase 3 trial comparing second-line axitinib and sorafenib demonstrating that a longer duration of the first-line therapy generally yields better outcome with the second-line therapy in mRCC. 18. Heng DY, Signorovitch J, Swallow E, et al. Comparative Effectiveness of && Second-Line Targeted Therapies for Metastatic Renal Cell Carcinoma: A systematic review and meta-analysis of real-world observational studies. PLoS One 2014; 9:e114264. Sytematic review of observational studies of second-line therapies for mRCC demonstrating a potential survival benefit with second-line mTOR inhibitors compared with VEGFR-TKIs in a subset of studies. 19. Elaidi R, Harbaoui A, Beuselinck B, et al. Outcomes from second-line therapy && in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma. Ann Oncol 2015; 26:378–385. Retrospective multicenter analysis demonstrating that mRCCpatients who remain on first-line TKI for longer experience clinical benefit with TKI rechallenge rather than second-line mTOR inhibitors. 20. Joosten SC, Hamming L, Soetekouw PM, et al. Resistance to sunitinib in renal & cell carcinoma: From molecular mechanisms to predictive markers and future perspectives. Biochim Biophys Acta 2015; 1855:1–16. Review providing insights on the mechanisms of resistance to first-line targeted therapies. 21. 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; 9:1525–1535. 22. Beuselinck B, Job S, Becht E, et al. Molecular subtypes of clear cell renal cell & carcinoma are associated with sunitinib response in the metastatic setting. Clin Cancer Res 2015; 21:1329–1339. Molecular analysis identifying specific subtypes of mRCC that are resistant to suntinib and the potential link with the tumor microenviroment.
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The future of kidney cancer: quo vadis 23. Giraldo N, Becht E, Pages F, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res 2015. [Epub ahead of print] Study examining the link between the tumor microenviroment and disease progression in mRCC. 24. Oudard S, Kramer G, Caffo O, et al. Docetaxel rechallenge after an initial good & response in patients with metastatic castration-resistant prostate cancer. BJU Int 2014. [Epub ahead of print] Study highlighting the potential of chemotherapy rechallenge in castration resistant prostate cancer. 25. Toulmonde M, Madranges N, Brouste V, et al. Docetaxel rechallenge after a first response in nonresistant metastatic breast cancer: significant activity with manageable toxicity. Breast Cancer Res Treat 2012; 134:325–332. 26. Gradishar WJ. Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl) 2012; 6:159–171. 27. Harries M, Gore M. Part II: chemotherapy for epithelial ovarian cancertreatment of recurrent disease. Lancet Oncol 2002; 3:537–545. 28. Huisman C, Postmus PE, Giaccone G, et al. Second-line chemotherapy and its evaluation in small cell lung cancer. Cancer Treat Rev 1999; 25:199– 206. 29. Hainsworth JD, Rubin MS, Arrowsmith ER, et al. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium Phase II Trial. Clin Genitourin Cancer 2013; 11:270–275. 30. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as secondline treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14:552–562. &
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31. Maj-Hes A, Medioni J, Scotte F, et al. Rechallenge with mTOR inhibitors in metastatic renal cell carcinoma patients who progressed on previous mTOR inhibitor therapy. Oncology 2013; 85:8–13. 32. Nozawa M, Yamamoto Y, Minami T, et al. Sorafenib rechallenge in patients with metastatic renal cell carcinoma. BJU Int 2012; 110:E228–E234. 33. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010; 116:5400–5406. 34. Grunwald V, Weikert S, Seidel C, et al. Efficacy of sunitinib re-exposure after failure of an mTOR inhibitor in patients with metastatic RCC. Onkologie 2011; 34:310–314. 35. Nagyivanyi K, Biro K, Gyergyay F, et al. Sunitinib rechallange in metastatic renal cell carcinoma patients. Ann Oncol 2012; 23:; Abstract 849P. 36. Shablak A, O’Dwyer J, Hawkins R, et al. Management of a new isolated metastasis during sunitinib treatment in renal cell carcinoma patients: a lesson from two cases. Urol Int 2011; 86:245–248. 37. Paule B, Brion N. Sunitinib re-challenge in metastatic renal cell carcinoma treated sequentially with tyrosine kinase inhibitors and everolimus. Anticancer Res 2011; 31:3507–3510. 38. Oudard S, Goupil MG, Geoffrois L, et al. Clinical activity of sunitinib rechal&& lenge in metastatic renal cell carcinoma (mRCC) - Results of the RESUME study (Poster 816PD). Ann Oncol 2014; 25:iv283–iv284. The first study to include a prospective component of rechallenge with the same TKI in mRCC, demonstrating the clinical benefits of rechallenge. 39. Ko JJ, Choueiri TK, Rini BI, et al. First-, second-, third-line therapy for mRCC: & benchmarks for trial design from the IMDC. Br J Cancer 2014; 110:1917– 1922. Study highlighting the extended survival of patients with mRCC who are able to withstand multiple lines of treatment with targeted therapies.
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The role of rechallenge with targeted therapies in metastatic renal-cell carcinoma Ste´phane Oudard a,b and Yann Vano a,b
Purpose of review To explore the accumulating evidence and feasibility of rechallenge with agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways for incorporation into the evolving management algorithm for metastatic renal-cell carcinoma (mRCC). Recent findings The current standard of care after the development of resistance to first-line targeted therapies in mRCC is sequential treatment with subsequent lines of alternative anti-VEGF agents or mTOR inhibitors, with optimal sequencing being the focus of ongoing research. Recent evidence from case study and retrospective reports suggests that mRCC patients can achieve important clinical benefits from rechallenge at later lines of therapy with the same targeted therapy used for previous line treatment. Further, the results of REchallenge with SUnitinib in MEtastatic, the first study of sunitinib rechallenge to include a prospective component, reinforce the potential for prolonged survival with this treatment approach for mRCC patients. Summary Rechallenge represents an important and feasible therapeutic option for the future treatment of mRCC patients. The results of ongoing prospective studies are expected to further evaluate the benefits of rechallenge and better inform wherein this approach fits in the treatment algorithm for mRCC. Keywords metastatic renal-cell carcinoma, rechallenge, targeted therapy, vascular endothelial growth factor
INTRODUCTION The treatment of metastatic renal-cell carcinoma (mRCC) has advanced significantly since the era of cytokine therapy, when patient prognosis was poor with 5-year survival rates estimated at 10% [1]. The last decade has seen the advent of therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, heralding significant improvements in progression-free survival (PFS) and overall survival (OS) for patients with mRCC [2–4]. Multiple-targeted agents are now approved for the treatment of mRCC, including tyrosine kinase inhibitors (TKIs) of the VEGF receptor (VEGFR; axitinib, pazopanib, sorafenib, and sunitinib), antiVEGF antibodies (bevacizumab in combination with interferon-a) and inhibitors of the mTOR pathway (temsirolimus and everolimus). Although these therapies have undoubtedly provided considerable survival benefits for patients with mRCC, most tumors will develop acquired or adaptive resistance to targeted agents, with resistance to first-line VEGFR-TKIs developing within 6–11 months of www.co-urology.com
treatment initiation in the majority of patients [5,6]. When resistance develops, a recognized treatment strategy is the sequential use of different targeted agents, with optimal sequencing being the focus of considerable ongoing research [3]. Growing evidence also suggests that rechallenge with the same agent could be considered in this sequential treatment approach, as resistant tumors can regain sensitivity to first-line (or previous-line) therapy after subsequent lines of alternative treatments. The purpose of this review is to explore the current evidence for rechallenge with targeted therapies in mRCC.
a
Oncology Department, European Hospital Georges Pompidou and Oncology Department, Paris Descartes University, Paris, France
b
Correspondence to Ste´phane Oudard, MD, PhD, Oncology Department, European Hospital Georges Pompidou, 20 rue Leblanc, Paris 75015, France. Tel: +33 1 56 09 34 76; fax: +33 1 56 09 20 39; e-mail: [email protected] Curr Opin Urol 2015, 25:402–410 DOI:10.1097/MOU.0000000000000206 Volume 25 Number 5 September 2015
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Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano &
KEY POINTS Targeted therapies have dramatically improved the prognosis for patients with mRCC; however, resistance to these agent will inevitably develop in the majority of patients. The standard of care for patients with mRCC who develop resistance is the sequential use of alternative targeted therapies, a strategy that has been shown to provide clinical benefit. Determining the optimal sequencing of targeted therapies is the focus of ongoing research with the aim of further improving the outlook for patients with mRCC. Accumulating data suggests that rechallenge with the same targeted therapy at a later line of treatment is a feasible strategy to include in this sequential treatment approach. The results of ongoing prospective evaluations will help further inform on how rechallenge can be incorporated into the current treatment algorithm for mRCC.
SEQUENTIAL TARGETED THERAPY AFTER THE DEVELOPMENT OF RESISTANCE Sequential treatment with as many targeted therapies as a patient is likely to benefit from is the current standard of care in mRCC, with the potential to considerably extend patient survival and maximize the duration of disease control [7,8 –10 ]. On progression of a first-line agent, the European Society for Molecular Oncology (ESMO), European Association of Urology (EAU), and National Comprehensive Cancer Network (NCCN) guidelines recommend alternative VEGFR-TKIs or mTOR inhibitors as second-line treatment (Table 1) [11 –13 ]. However, specific guidance on the order in which these agents should be selected is less clear, with sequences often determined by treatment availability, the toxicity profile of previous therapies, physician familiarity with specific drugs, treatment costs, and patient comorbidities [4]. As different VEGFR-TKIs essentially target the same signaling pathway, subsequent therapy with an mTOR inhibitor would seem to be the most logical treatment approach for patients who are refractory to a first-line agent [14 ]. However, as each VEGFR-TKI has a distinct molecular target profile and specific binding affinities for shared molecular targets (Fig. 1), successive treatment with an alternative VEGFR-TKI is also a plausible strategy to counteract resistance [7]. Indeed, there is no evidence to suggest cross-resistance between VEGFR-TKIs, and meaningful clinical benefits are observed in patients refractory to firstline VEGFR-TKIs receiving sequential therapy with a &
&
&&
&
&
&
second VEGFR-TKI [8 –10 ]. Furthermore, in a headto-head, randomized controlled trial, second-line treatment with sorafenib was associated with significantly longer median OS compared with temsirolimus after progression on first-line sunitinib (16.6 versus 12.3 months, respectively; P ¼ 0.01) [15 ]. Limited data are available from randomized studies assessing the comparative efficacy of different VEGFR-TKIs as second-line or third-line agents for mRCC. The AXIS trial was the first phase 3, randomized trial to directly compare second-line treatment of mRCC with two VEGF-targeted agents, axitinib, and sorafenib [16]. Axitinib was associated with improved median PFS compared with sorafenib (6.7 versus 4.7 months, respectively; P < 0.0001), although this did not translate into improved median OS. A longer duration of prior treatment and a smaller tumor burden following initial therapy was generally associated with longer OS for both agents second line [17 ]. In the third-line setting, the phase three GOLD study was conducted to compare the efficacy of dovitinib (a fibroblast growth factor receptor, platelet-derived growth factor receptor, and VEGFR inhibitor) and sorafenib after previous VEGF-targeted therapies and mTOR inhibitors [10 ]. Although both agents provided clinical benefits, no significant differences in efficacy outcomes were noted between groups. Real world, observational data may also help inform on the optimal sequencing of targeted therapies. In a systematic review and meta-analysis of observational studies comparing sequential treatment strategies for mRCC, some survival benefit was observed with second-line mTOR inhibitors over second-line VEGFR-TKIs among a subset of studies with more controlled design [18 ]. However, data for axitinib were limited at the time of this analysis. In contrast, in a retrospective multicenter analysis, a longer duration of response to first-line TKI therapy and receiving a TKI rather than an mTOR inhibitor second line were associated with a longer duration of response and PFS with secondline therapy [19 ]. &
&
&
&&
&&
RATIONALE FOR RECHALLENGE: PRECLINICAL EVIDENCE The precise mechanisms by which resistance to targeted therapies for RCC develops are yet to be fully elucidated. VEGF-targeted therapies are proposed to cause tumor hypoxia, leading to the accumulation of hypoxia-inducible factor 1, which in turn leads to upregulation of factors that stimulate angiogenesis, tumor invasiveness, and epithelial-to-mesenchymal transition [20 ]. Accumulating evidence suggests that these effects are reversible, and that changes in the
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403
404
www.co-urology.com Clinical trial Sunitinib
NCCN [13 ]
Good or intermediate risk
Temsirolimus
Sorafenib
High-dose IL-2
Axitinib
Pazopanib
After cytokines Sorafenib, axitinib or pazopanib
After VEGFR Axitinib, sorafenib or everolimus
Sunitinib Sorafenib
Sorafenib
Sunitinib
Options
Rechallenge
Other TKIs
Options
Sorafenib
Post-TKI and mTOR
Everolimus
Post-2 TKIs
Standard
Third-line
High-dose IL-2
Axitinib, sorafenib, sunitinib, pazopanib, temsirolimus or bevacizumab
After cytokines
Everolimus, axitinib, sorafenib, sunitinib, pazopanib, temsirolimus or bevacizumab
After TKIs
Clinical trial
Any targeted agent
After mTOR Sorafenib
After VEGFR Everolimus
Axitinib or everolimus
Post-TKIs
Axitinib, sorafenib or pazopanib
Postcytokines
Standard
Second-line
EAU, European Association of Urology; IFN-a, interferon-a; IL, interleukin; NCCN, National Comprehensive Cancer Network; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor; VEGFR, vascular & & endothelial growth factor receptor. Adapted with permission from [11 –13 ]. For selected patients.
Poor risk
Temsirolimus
Poor risk
Bevacizumab and IFN-a
Bevacizumab and IFN-a Pazopanib
Good or intermediate risk
&
Sunitinib
EAU [12 ]
&
Temsirolimus
Poor risk
Bevacizumab and low-dose IFN-a
High-dose IL-2 Sorafenib
Sunitinib Bevacizumab and IFN-a Pazopanib
Good or intermediate risk
Options
Standard
&
ESMO [11 ]
First-line
Table 1. Guidelines and recommendations for the treatment of metastatic renal-cell carcinoma (clear-cell histology)
The future of kidney cancer: quo vadis
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Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano
Axitinib
Dovitinib
Motesanib
TKL
TKL
TKL
TK
TK
CMGC
AGC
Other
CMGC
CAMK
Sorafenib
1 nM 10 nM 100 nM 11 µM
CMGC
CAMK
Vatalanib
TKL
AGC
Other
CAMK
CMGC
Vandetanib
TKL TK STE
CK1
CK1
AGC
Other
CAMK
STE
AGC
CK1
TK
STE
Kd
CMGC
CAMK
TK
CMGC
AGC
Other
TKL
TKL
STE
CK1
Sunitinib
TK
Other
TK STE
CK1
CK1
AGC
TKL
TK STE
STE
Other
Pazopanib
STE
CK1
AGC
Other
CMGC
CAMK
CAMK
CK1
AGC
Other
CMGC
CAMK
TK = tyrosine kinase; TKL= tyrosine kinase-like; STE = STE family protein kinase; CK1 = casein kinase I; AGC = protein kinase A, G, and C families; CAMK = calcium/calmodulin-dependent protein kinase; CMGC = cyclin-dependent kinases (CDK), mitogen-activated protein kinases, glycogen synthase kinases and CDK-like kinases Images generated using TREE spot software tool and reprinted with permission from KINOME scan, a division of discoveRx corporation, discoverx corporation 2010.
FIGURE 1. Interaction of targeted therapies with specific molecular targets. AGC, protein kinase A, G, and C families; CAMK, calcium/calmodulin-dependent protein kinase; CK1, casein kinase I; CMGC, cyclin-dependent kinases (CDK), mitogen-activated protein kinases, glycogen synthase kinases and CDK-like kinases; STE, STE family protein kinase; TK, tyrosine kinase; TKL, tyrosine kinase-like; Images generated using TREEspot Software Tool and reprinted with permission from KINOMEscan, a division of DiscoveRx Corporation, ß DISCOVERX CORPORATION 2010.
tumor microenvironment may restore tumor sensitivity to targeted therapies [7]. Preclinical evidence supporting this hypothesis comes from a study in which tumor tissue was transplanted from sunitinibresistant metastatic skin lesions into nude mice [21]. Interestingly, xenograft tumors regained sensitivity to sunitinib and demonstrated the clear cell phenotype, whereas evidence of epithelial-to-mesenchymal transition was observed in the sunitinib-resistant metastatic tumor tissue [21]. In a clinical setting, the same effect of altering the tumor environment may be affected by switching to a different targeted therapy or with a treatment break followed by rechallenge with the same agent [14 ]. Recent research has investigated the impact of the tumor microenvironment on the clinical outcome for patients with RCC. Molecular subtypes of clear cell RCC with poor sensitivity to sunitinib exhibit sarcomatoid differentiation and a suppressive immune microenvironment, with high expression of the immune checkpoint protein, PD-1, and its ligands [22 ]. Similarly, high expression of &&
&
immune checkpoint proteins and the absence of fully functional mature dendritic cells have been observed in primary or metastatic tumors from RCC patients with a poor prognosis [23 ]. Conversely, low expression of immune checkpoints and mature dendritic cells located in tertiary lymphoid structures were observed in tumors from patients with prolonged survival. &
RECHALLENGE IN OTHER TUMOR TYPES Drug rechallenge has provided meaningful clinical benefits in retrospective studies of other tumor types. In 270 patients with metastatic castrationresistant prostate cancer who progressed after an initial good response to first-line docetaxel, improved rates of symptom relief and stable disease were achieved with docetaxel rechallenge compared with nontaxane-based second-line therapies [24 ]. Similarly, the reintroduction of docetaxel to 72 patients with metastatic breast cancer resulted in a substantial proportion achieving a partial response
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(42.5%) or stable disease (33.5%) [25]. The survival benefits of rechallenge in this heavily pretreatedpatient population needs to be balanced against the risk of exacerbation of chronic toxicities and impaired quality of life. Key considerations determining whether a patient may be suitable for rechallenge include the length of time that has passed between completion of initial therapy and subsequent rechallenge [26], and the duration of the progressionfree interval (PFI) achieved with first-line chemotherapy [27,28]. In patients with advanced ovarian cancer who achieve a PFI of more than 6 months with first-line paclitaxel in combination with a platinum analogue can achieve response rates of 30–50% on retreatment with a platinum-based therapy after progression [27]. Similarly, for patients with advanced small-cell lung cancer and a PFI of at least 3 months after the discontinuation of first-line treatment may be considered for platinum-based rechallenge [28].
EVIDENCE FOR RECHALLENGE IN METASTATIC RENAL-CELL CARCINOMA: RETROSPECTIVE STUDIES AND CASE REPORTS Recent ESMO guidelines for RCC include rechallenge with the same TKI used for initial treatment as an option for patients requiring third-line therapies (Table 1) [11 ], although this recommendation is based on limited evidence from retrospective cohort or case–control studies. A summary of studies evaluating rechallenge either with agents from the same class or the same agent are provided in Table 2 [16,29–35]. The majority of studies exploring rechallenge with the same agent have focused on sunitinib, and have been summarized in a recent review by Porta et al. [14 ]. Initial case report data reported symptomatic relief and disease stabilization with sunitinib rechallenge in patients with mRCC who had progressed on first-line sunitinib [36,37]. Similarly, in a small retrospective analysis, 12 of 13 patients rechallenged with sunitinib experienced a partial response or stable disease, with median PFS of 6.9 months compared with 21 months after first-line sunitinib treatment [34]. In a further study, five of 23 patients experiencing disease progression or intolerance to first-line sunitinib (and 1 subsequent agent) achieved a partial response to sunitinib rechallenge [33]. Median PFS first line was 13.7 months compared with 7.2 months on sunitinib rechallenge, with the length of the interval between first-line sunitinib and rechallenge influencing the duration of PFS. A retreatment interval greater than 6 months was &
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associated with longer median PFS compared with rechallenge within 6 months (16.5 versus 6.0 months, respectively). The type or number of intervening treatments had no significant effect on outcomes and no new toxicities or exacerbation of prior toxicities was noted. Similarly, in another study, sunitinib rechallenge in nine patients who had failed at least two previous targeted therapies was associated with median PFS of 6.8 months compared with 13.7 months for initial sunitinib treatment [35]. The evidence for rechallenge in mRCC is not limited to sunitinib. In a case series of 12 patients who had failed first-line sorafenib and subsequent anti-VEGF therapies or mTOR inhibitors, eight (67%) achieved stable disease upon sorafenib rechallenge, with median PFS of 5.4 months [32]. In contrast to sunitinib rechallenge, the duration of PFS with sorafenib rechallenge did not correlate with the PFS duration observed with initial sorafenib treatment or with the length of the interval between initial treatment and rechallenge. In a retrospective analysis of 12 patients with mRCC who progressed on treatment with their first mTOR inhibitor (temsirolimus or everolimus; after 1 line of prior VEGFR-TKIs), and then underwent rechallenge with the other agent, a longer median treatment duration was observed with the everolimus–temsirolimus sequence compared with the temsirolimus–everolimus sequence (10.3 versus 5.8 months; respectively) [31]. Of the seven patients treated with everolimus before temsirolimus, 57 and 29% responded to everolimus or temsirolimus only, and 14% responded to both mTOR inhibitors. Among the five patients treated with temsirolimus before everolimus, 20% responded to temsirolimus only, 20% responded to everolimus only, and 60% did not respond to either mTOR inhibitor. Despite the limited number of patients included in this study, the results again highlight the potential feasibility of rechallenge as a sequential therapy option in mRCC.
RECHALLENGE WITH SUNITINIB IN METASTATIC: THE LARGEST STUDY OF RECHALLENGE IN MRCC CONDUCTED TO DATE REchallenge with SUnitinib in MEtastatic renal-cell carcinoma (RESUME) was a multicenter, observational, prospective, and retrospective study of sunitinib rechallenge in the third line or more. The primary objective was to examine the effect of sunitinib rechallenge on PFS in 52 patients with mRCC who received first-line sunitinib followed by one or more lines of different therapies (temsirolimus, Volume 25 Number 5 September 2015
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Sunitinib Sunitinib
Axitinib [16,30]
Sorafenib [16,30]
Everolimus
Temsirolimus [31]
0963-0643 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. Retrospective analysis Retrospective analysis
Gru¨nwald et al. [34]
Nagyivanyi et al. [35]
9
12
23
12
5
7
723
723
55
Number of patients
IV,B
IV,B
IV,B
V,B
IV,B
IV,B
I,A
I,A
II,A
Evidence level
Median PFS on rechallenge: 6.8 months
Median PFS on initial therapy: 13.7 months
Stable disease: 55%
Partial response: 11%
Median PFS on rechallenge: 6.9 months
Median PFS on initial therapy: 21 months
Median PFS on rechallenge: 7.2 months
Median PFS on initial therapy: 13.7 months
Partial response: 22%
Median PFS overall: 21.3 months (95% CI: 18.1–24.5)
Median PFS on rechallenge: 5.4 months (95% CI: 3.8–7.0)
Median treatment duration: 5.8 months (95% CI: 2.9–19.3)
Median treatment duration: 10.3 months (95% CI: 8.8–19.2)
Median PFS: 4.7 months (95% CI: 4.6–5.6)
Median OS: 19.2 months (95% CI: 175–223)
Median PFS: 6.7 months (95% CI: 6.3–8.6)
Median OS: 20.1 months (95% CI: 167–234)
Median survival: 24.2 months (95% CI: 14.7–NR)
Median PFS: 7.5 months (95% CI: 5.4–9.4)
Efficacy data on rechallenge
CI, confidence interval; mTOR, mammalian target of rapamycin; NR, not reached; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
Retrospective review
Sunitinib
Sunitinib
Case series
Retrospective analysis
Retrospective analysis
Phase 3
Phase 3
Phase 2
Study type
Zama et al. [33]
Sorafenib
Sorafenib [32]
Rechallenge with the same agent (third-line or more)
Temsirolimus
Everolimus [31]
Rechallenge with an alternative mTOR inhibitor
Sunitinib
Pazopanib [29]
Rechallenge with an alternative TKI (second-line)
Previous therapy
Table 2. Evidence for rechallenge in of metastatic renal-cell carcinoma from clinical trials and retrospective studies
Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano
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The future of kidney cancer: quo vadis
everolimus, sorafenib, pazopanib, axitinib, or bevacizumab) [38 ]. On first-line sunitinib, 28 patients (54%) achieved an objective response and median PFS was 18.4 months (Table 3). The median duration of therapy was 14.9 months, with the majority of patients (82%) discontinuing due to disease progression rather than tolerability issues. Rechallenge began a median of 14.6 months after discontinuation of initial sunitinib treatment and constituted fourth-line therapy in the majority of patients (65%). On sunitinib rechallenge, median OS was 55.9 months with 61% of patients (n ¼ 32) experiencing clinical benefit (Table 3) [38 ]. Median PFS was 7.9 months, which is in line with the duration of PFS observed in the smaller retrospective studies of sunitinib rechallenge [33–35]. A shorter duration of PFS with later lines of therapy would be expected compared with first-line therapy as these patients are more likely to have a poorer performance status. Subgroup analyses also revealed significantly improved median PFS on rechallenge in patients who achieved median PFS at least 18.4 months and had a median duration of treatment at least 14.9 months with first-line sunitinib therapy (P < 0.05). Eight patients (15%) achieved a partial response on rechallenge, with six of these patients having experienced a prior response to first-line sunitinib [38 ]. These patients who had achieved a complete or partial response to first-line sunitinib also achieved longer PFS with sunitinib rechallenge compared with first-line nonresponders (15.0 versus 5.0 months, respectively; P ¼ 0.05). As would be expected for this heavily pretreated patient population, the proportion of patients &&
&&
&&
experiencing serious adverse events was higher on rechallenge compared with on first-line sunitinib (19 versus 4%, respectively; Table 3). Importantly, no new adverse events were reported either at first line or on rechallenge [38 ]. Although the results of RESUME provide convincing evidence for the potential clinical benefit of rechallenge in mRCC, there may have been some positive selection bias toward patients more likely to achieve longer OS in this study. Patients with mRCC who are able to receive multiple lines of targeted therapy are often likely to live longer, with a greater duration of PFS [39 ]. Additionally, 80% of patients had a dose reduction when receiving first-line sunitinib, and therefore may not have been truly resistant to the recommended dose of sunitinib. Another key consideration is that as the RESUME study was partly retrospective, adverse event data were only available for some patients (n ¼ 27), meaning that the tolerability profile of sunitinib rechallenge may not have been fully characterized. To further explore the potential clinical benefits of sunitinib rechallenge in mRCC, two prospective phase 2 studies have been initiated. A Dutch trial (NTR3711) will assess the ability of sunitinib rechallenge to improve PFS in patients who achieved stable disease for at least 6 months on first-line sunitinib but subsequently progressed on sunitinib and second-line therapies [mTOR inhibitors or another therapy (excluding VEGFR TKIs)]. A second Italian study will assess the ability of third-line sunitinib rechallenge after second-line everolimus to provide freedom from disease progression (EudraCT 2012–000473–23/RETRY). It is hoped that the results of these studies will help better inform wherein rechallenge fits in the current &&
&
Table 3. Key efficacy and safety outcomes from the REchallenge with SUnitinib in MEtastatic study [38 ] &&
First-line sunitinib
Rechallenge sunitinib (i.e. third-line or later)
Key efficacy data (n ¼ 52 pts) Best response, n (%) Objective response Complete response
28 (54)
8 (15)
1 (2)
0
Partial response
27 (52)
8 (15)
Stable disease
21 (40)
24 (46)
Clinical benefit rate
49 (94)
32 (61)
Progressive disease
3 (6)
Median PFS (95% CI), months
20 (38)
18.4 (12.5–23.7)
Median OS (95% CI), months
7.9 (5.4–13.2) 55.9 (48.0–63.7)
Key safety data At least 1 adverse event, n (%)
5 (19)
At least 1 serious adverse event, n (%)
1 (4)
10 (37) 5 (19)
CI, confidence interval; OS, overall survival; PFS, progression-free survival.
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Targeted therapies in metastatic renal-cell carcinoma Oudard and Vano
treatment algorithm for mRCC, further optimizing the sequential-targeted therapy approach.
CONCLUSION Adaptive or acquired resistance to targeted therapies for mRCC is the main barrier preventing patients from achieving maximal survival benefits with these agents. The sequential use of different targeted therapies is a promising approach to bypassing this resistance, potentially by providing continual inhibition of the signaling pathways implicated in tumor angiogenesis, thereby stabilizing disease progression. The accumulated data from case reports, retrospective studies, and the recent RESUME study supports the validity of rechallenge as an additional strategy to be included in this sequential therapy approach for the management of tumor progression in mRCC. Key factors that may be linked to the degree of clinical benefit likely to be observed with rechallenge include a longer duration of response to initial treatment and a greater interval between firstline therapy and rechallenge. The results of ongoing prospective studies of sunitinib rechallenge should further characterize the clinical benefits that could be expected with targeted therapy rechallenge. Future research should also focus on characterizing, which patients are most likely to benefit from rechallenge or other sequential therapy options, with the goal of further enhancing survival outcomes for mRCC patients. Acknowledgements None. Financial support and sponsorship Medical writing support was provided by Farah Dalwai at Litmus MME (London, UK). Funding for medical writing support was provided by Pfizer Inc. Conflicts of interest S.O. has received honoraria from Novartis, Pfizer, Bayer, Bristol-Myers, Squibb and GlaxoSmithKline.
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31. Maj-Hes A, Medioni J, Scotte F, et al. Rechallenge with mTOR inhibitors in metastatic renal cell carcinoma patients who progressed on previous mTOR inhibitor therapy. Oncology 2013; 85:8–13. 32. Nozawa M, Yamamoto Y, Minami T, et al. Sorafenib rechallenge in patients with metastatic renal cell carcinoma. BJU Int 2012; 110:E228–E234. 33. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010; 116:5400–5406. 34. Grunwald V, Weikert S, Seidel C, et al. Efficacy of sunitinib re-exposure after failure of an mTOR inhibitor in patients with metastatic RCC. Onkologie 2011; 34:310–314. 35. Nagyivanyi K, Biro K, Gyergyay F, et al. Sunitinib rechallange in metastatic renal cell carcinoma patients. Ann Oncol 2012; 23:; Abstract 849P. 36. Shablak A, O’Dwyer J, Hawkins R, et al. Management of a new isolated metastasis during sunitinib treatment in renal cell carcinoma patients: a lesson from two cases. Urol Int 2011; 86:245–248. 37. Paule B, Brion N. Sunitinib re-challenge in metastatic renal cell carcinoma treated sequentially with tyrosine kinase inhibitors and everolimus. Anticancer Res 2011; 31:3507–3510. 38. Oudard S, Goupil MG, Geoffrois L, et al. Clinical activity of sunitinib rechal&& lenge in metastatic renal cell carcinoma (mRCC) - Results of the RESUME study (Poster 816PD). Ann Oncol 2014; 25:iv283–iv284. The first study to include a prospective component of rechallenge with the same TKI in mRCC, demonstrating the clinical benefits of rechallenge. 39. Ko JJ, Choueiri TK, Rini BI, et al. First-, second-, third-line therapy for mRCC: & benchmarks for trial design from the IMDC. Br J Cancer 2014; 110:1917– 1922. Study highlighting the extended survival of patients with mRCC who are able to withstand multiple lines of treatment with targeted therapies.
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