Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: Optimizing patient benefit

Cancer Treatment Reviews 38 (2012) 981–987

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Anti-Tumour Treatment

Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: Optimizing patient benefit Stéphane Oudard a,⇑, Reza-Thierry Elaidi b a b

Department of Medical Oncology, Hôpital Européen Georges-Pompidou, AP-HP, René Descartes University Paris 5, 20 Rue Leblanc, 75015 Paris, France ARTIC (Association pour la Recherche sur les Thérapeutique en Cancérologie), Hôpital Européen Georges-Pompidou, 20 rue Leblanc, Paris 75015, France

a r t i c l e

i n f o

Article history: Received 19 October 2011 Received in revised form 16 December 2011 Accepted 20 December 2011

Keywords: Kidney cancer Metastatic disease Anticancer therapy Resistance Sequential therapy Mechanism of action

a b s t r a c t Multiple targeted agents are now available for the treatment of patients with metastatic renal cell carcinoma (mRCC). Although targeted agents offer improvements over previous treatments and significantly prolong progression-free survival, most patients eventually experience disease progression. For these patients, sequential treatment with multiple lines of therapy may afford sustained clinical benefit. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) are recommended as first-line therapy for most patients with mRCC. Current clinical practice guidelines uniformly recommend treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus after initial VEGFr-TKI failure. Recent results of the AXIS phase 3 trial demonstrated improved efficacy with second-line axitinib compared with sorafenib in patients who progressed on a variety of first-line therapies, including the VEGFr-TKI sunitinib. Available clinical evidence, individual patient profile, and toxicity concerns should be carefully evaluated when deciding whether to administer an mTOR inhibitor or a second VEGFr-TKI after progression on a first-line VEGFr-TKI. In patients who progress on a VEGFr-TKI and an mTOR inhibitor, retrospective analyses indicate that treatment with a second VEGFr-TKI in the third-line setting provides additional clinical benefit. Recent results from a prospective phase 1/2 trial indicate that third-line therapy with the investigational TKI, dovitinib, may have promising efficacy in patients who progress on a VEGFr-TKI and an mTOR inhibitor; a phase 3 trial of dovitinib versus sorafenib in this patient population is ongoing. This review discusses and evaluates current clinical evidence for sequential therapy with targeted agents in patients with mRCC. Ó 2011 Elsevier Ltd. All rights reserved.

Introduction Until recently, cytokine therapy, i.e., interferon (IFN)-a or interleukin (IL)-2, was the only treatment option for patients with metastatic renal cell carcinoma (mRCC). However, cytokines are associated with significant toxicity and in most patients have little effect on survival.1 Research directed towards determining the underlying causes of RCC has facilitated the development of more effective therapeutic options. Patients with von HippelLindau (VHL) disease, which is caused by an inherited autosomal dominant mutation in the VHL gene, have a >70% risk of developing RCC.2 VHL inactivation via sporadic mechanisms, such as gene mutation or methylation, has also been reported in up to 91% of noninherited clear cell RCC.3 When the VHL protein is absent, the hypoxia inducible factors (HIF), HIF-1a, and HIF-2a, are not

⇑ Corresponding author. Tel.: +33 1 56 09 34 47; fax: +33 1 56 09 24 31. E-mail address: [email protected] (S. Oudard). 0305-7372/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2011.12.009

degraded and therefore accumulate in the nucleus.4 Activation of the mammalian target of rapamycin (mTOR) pathway also increases HIF levels.4 This leads to increased transcription of genes such as vascular endothelial growth factor (VEGF) and plateletderived growth factor (PDGF) that control cell proliferation, glucose uptake, and angiogenesis.4 Thus, increased HIF expression can promote angiogenesis in tumors. Six novel therapies targeting the VEGF or mTOR signaling pathways are currently approved for use in patients with mRCC (Fig. 1). These agents include the VEGF receptor-tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib, sorafenib, and pazopanib, the VEGF-targeted antibody bevacizumab, and the mTOR inhibitors temsirolimus and everolimus. Although these targeted agents demonstrate antitumor activity and prolonged progression-free survival (PFS) in patients with mRCC, patients eventually experience disease progression, and sequential lines of therapy are typically required to maintain clinical benefit. This review will discuss current clinical evidence of sequential treatment with targeted therapies in patients with mRCC, with a focus on optimal treatment selection in patients who have failed initial VEGF-targeted therapy.

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Fig. 1. Signaling pathways and therapeutic targets in renal cell carcinoma. 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor 2; HIF, hypoxia-inducible factor; IGF, insulin-like growth factor; IGF-1R, insulin-like growth factor receptor; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide3kinase; PTEN, phosphatase and tensin homolog; S6K, S6 kinase; VEGF, vascular endothelial growth factor; VEGFr, vascular endothelial growth factor receptor; VHL, von Hippel-Lindau.

Evidence for first-line VEGF- and mTOR-targeted therapies in patients with mRCC Clinical evidence supporting the use of the orally administered VEGFr-TKIs sunitinib, sorafenib, and pazopanib, the humanized monoclonal VEGF antibody bevacizumab and the mTOR inhibitor temsirolimus in patients with mRCC has been previously reviewed.5 In a phase 3 trial, temsirolimus demonstrated increased PFS and overall survival (OS) compared with interferon-a (IFN-a) alone in treatment-naive patients with mRCC with poor prognosis (PFS, 3.8 months vs 1.9 months; OS, 10.9 months vs 7.3 months for temsirolimus and IFN-a, respectively).6 Based on these results, temsirolimus is the recommended first-line therapy for this patient population; however, for the majority of patients with mRCC, VEGF-targeted therapies are generally prescribed in the first-line setting.7–10 In a randomized, phase 3 trial, median PFS was significantly longer for sunitinib versus IFN-a (11 months vs 5 months; P < .001) in patients with mRCC who had not received prior treatment.11,12 Similarly, bevacizumab, in combination with IFN-a, led to a significantly longer PFS compared with IFN-a plus placebo (10.4 months vs 5.5 months; P < .001) in a randomized phase 3 trial (AVOREN).13 The VEGFr-TKI sorafenib was compared with IFN-a as first-line therapy in a phase 2 trial, and no significant difference was observed in PFS between the 2 groups (5.7 months vs 5.6 months, respectively), though sorafenib-treated patients did report better quality of life and tolerability than those receiving IFN-a.14 Sorafenib has also been evaluated in a randomized phase 3 study in cytokine-refractory patients with clear cell mRCC. In this setting, sorafenib afforded a median PFS of 5.5 months, compared with 2.8 months with placebo (P < .001).15 Pazopanib was evaluated in a randomized, double-blind, phase 3 trial of 233 treatment-naive patients and 202 cytokine-refractory patients.16 Median PFS of patients receiving first-line pazopanib was 11.1 months, compared with 2.8 months with placebo (P < .001).16 Among cytokine-pretreated patients receiving pazopanib, median PFS was 7.4 months compared with 4.2 months with placebo (P < .001).16 Although VEGF-targeted agents offer significant improvement over cytokine therapy, resistance and disease

progression eventually occur in the majority of patients. An understanding of potential resistance mechanisms and knowledge of currently available clinical data in patients refractory to initial VEGF-targeted therapy is critical to inform decisions regarding subsequent treatment.

Mechanisms of resistance to VEGFr-TKI treatment In most patients, resistance to first-line VEGFr-TKI therapy develops within 6–11 months of starting treatment.11,15 Several preclinical studies provide insight into possible mechanisms of resistance to VEGFr-TKIs, including the reemergence of tumorassociated vasculature, the potential to reverse VEGF-targeted resistance, and the contribution of proangiogenic factors.17–19 In a mouse model of pancreatic islet carcinogenesis, a function-blocking antibody to VEGFr2 was used to model phenotypic resistance to VEGFr. This resistance involved reemergence of tumor-associated vasculature associated with VEGF-independent, hypoxiamediated induction of proangiogenic factors, including members of the fibroblast growth factor (FGF) family, suggesting this as a possible mechanism for VEGFr-TKI resistance.20 In an in vitro study using CAKI1 and 786-0 (renal carcinoma) cells exposed to stepwise increasing doses of sunitinib or sorafenib for >6 months, resistance to sunitinib and/or sorafenib was frequently associated with activation of AKT.21 In a separate study, Hammers and colleagues grafted skin metastases from a patient with clear cell RCC who had become resistant to sunitinib subcutaneously in athymic nude mice.22 Surprisingly, these established xenografts regained sensitivity and responded to subsequent treatment with sunitinib. Histologic comparison of the original skin tumor with the xenografts suggested that a reversible epithelial-to-mesenchymal transition may be partially responsible for acquired resistance to sunitinib.22 The phenomenon of reversible VEGFr resistance has also been investigated by Zhang et al., who demonstrated that, on reimplantation into treatment-naive mice, sorafenib-resistant RCC tumors regained sensitivity to sorafenib.19 The authors hypothesized that acquired resistance to VEGFr inhibitors in RCC is partially mediated

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by reversible changes in gene expression within the tumor cells and/or their microenvironment.19 The role of IL-8 upregulation has also been evaluated in RCC. In a xenograft RCC model mimicking clinical resistance to sunitinib, reactivation of tumor angiogenesis coincided with increased secretion of IL-8 from tumors, and administration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment, suggesting that IL-8 secretion also plays a role in resistance to sunitinib.17 In further support of this hypothesis, IL-8 expression was elevated in clear cell RCC tumors from patients who were refractory to sunitinib treatment.17 IL-8 is also suggested to play an important role in the regulation of angiogenesis and tumorigenicity in bladder cancer,23 and a phase 2 clinical study in this tumor type found low IL-8 baseline levels to be significantly associated with increased time to progression.24 Overcoming resistance to initial VEGF-targeted therapy with a second VEGF-targeted agent: current evidence One approach to treating patients who have developed resistance to initial VEGF-targeted therapy is sequential treatment with a different VEGF-targeted agent. Although using a second agent from the same class in resistant patients may seem counterintuitive, variations in kinase targets and interactions may circumvent resistance.25 Efficacy of sequential VEGFr-TKI therapy has been evaluated in numerous retrospective and prospective studies (Tables 1–3). Clinical benefit associated with a second-line VEGFrTKI may be dependent on its relative potency and selectivity profile compared with the first-line agent, e.g., the sequence sorafenib-sunitinib is more frequently associated with a longer secondline PFS than the sequence sunitinib-sorafenib. Though their safety profiles may differ slightly, all VEGF-targeted agents exhibit class effect toxicities, such as hypertension, hand-foot syndrome, and rash42,43; thus, patients who receive two successive VEGFr-TKIs may be at increased risk for these adverse events. A retrospective study by Porta et al. analyzed 99 patients treated with sunitinib followed by sorafenib (SuSo) and 90 patients treated with sorafenib followed by sunitinib (SoSu).29 Median PFS of the second agent was longer in the SoSu group than the SuSo group (7.9 months vs 4.2 months, respectively). In a prospective

phase 2 study of 52 sunitinib-refractory patients treated with sorafenib (Di Lorenzo et al.), median PFS was 3.7 months and the disease control rate was 19%.38 Grade 3 adverse events included diarrhea (11.5%), neutropenia (9.6%), nausea/vomiting (9.6%), and hypertension (9.6%).38 The recently reported AXIS phase 3 trial directly compared the efficacy and safety of axitinib, an investigational VEGFr-TKI, with the active comparator sorafenib, in patients with mRCC who had failed 1 previous systemic therapy.41 Axitinib was shown to be more effective than sorafenib in patients who had progressed after previous treatment with sunitinib, bevacizumab + IFN-a, temsirolimus, or cytokines.41 Median PFS was 6.7 months (95% CI, 6.3– 8.6 months; n = 361) for axitinib and 4.7 months (95% CI, 4.6– 5.6 months; n = 362) for sorafenib (HR = 0.665; 95% CI, 0.544– 0.812; P < .0001).41 Overall, approximately 35% of patients had received cytokine therapy as their only previous treatment, meaning that the AXIS trial was their first exposure to a VEGFr-TKI, while 54% of patients had received previous sunitinib.41 Among cytokine-refractory patients, median PFS was 12.1 months with axitinib and 6.5 months with sorafenib (P < .0001).41 In the subpopulation of AXIS patients who had received previous sunitinib, median PFS was 4.8 months with axitinib and 3.4 months with sorafenib (P = .011).41 The shorter median PFS observed in both treatment arms in sunitinib-refractory patients relative to those who received cytokines is suggestive of at least partial cross-resistance with sequential VEGF-targeted therapy. Axitinib displayed a similar, yet distinct safety profile to sorafenib; axitinib-treated patients more commonly reported hypertension and hypothyroidism, and sorafenib-treated patients had higher incidence of hand-foot syndrome, rash, and alopecia.41 Overcoming resistance to initial VEGF-targeted therapy with an mTOR inhibitor: current evidence Another approach for treating patients after progression on initial VEGF-targeted therapy is to switch to a second-line agent with a different mechanism of action, such as an mTOR inhibitor. Currently, two mTOR inhibitors are approved for use in patients with mRCC; everolimus is approved for use in patients who are refractory to previous VEGFr-TKI therapy, and temsirolimus is indicated

Table 1 Efficacy and safety of second-line VEGFr-TKI therapy in patients refractory to first-line VEGFr-TKI treatment, as reported in retrospective studies of sequencing with sunitinib and sorafenib. Sequence

n

Median PFS with second VEGFr-TKI, months

DCR with second VEGFr-TKI, %a

Median OS, of overall sequence, months

Most common grade 3/4 AEs with second VEGFr-TKI, %

Reference

SO ? SU SO ? SU SU ? SO

22 30 23

4.9 10.3 NR

73 50 70b

Not reached NR 8.5c

Zimmermann et al.26 Eichelberg et al.27 Sepulveda et al.28

SU ? SO Or SO ? SU SO ? SU Or SU ? SO SO ? SU Or SU ? SO SO ? SU Or SU ? SO SO ? SU SU ? SO

99 90 31 7 29 20 68 22 96 13

4.2 7.9 5.8 2.6 17.9d 8.5d 6.4 3.9 8 4

NR

NR

NR NR Asthenia, 17% Mucositis, 9% Hypertension, 9% Hand-foot syndrome, 4% NR

NR

23.3 10.3 23.4 10.3 NR

NR

Choueiri et al.30

NR

Dudek et al.31

Patients with grade 3/4 toxicities: 38% (SU); 27% (SO) Patients with grade 3/4 toxicities: 19% (SU); 17% (SO)

Sablin et al.32

59 35 66 66 NR NR

NR NR

Porta et al.29

Procopio et al.33

AE, adverse event; CR, complete response; DCR, disease control rate; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; SO, sorafenib; SU, sunitinib; VEGFr-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor. a For the purposes of this review, DCR was calculated as follows: DCR = %CR + %PR + %SD. b DCR in patients evaluable for efficacy (n = 20). c From start of sorafenib treatment. d TTP (time to progression) instead of PFS.

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Table 2 Efficacy of second-line VEGFr-TKI or mTOR inhibitor therapy in patients refractory to first-line VEGFr-TKI treatment, as reported in retrospective studies evaluating patients treated with either a VEGF-targeted agent or an mTOR inhibitor following initial VEGF-targeted therapy. Sequence

n

Median PFS with second VEGFr-TKI, months

DCR with second VEGFr-TKI, %a

Median OS from start of second VEGFr-TKI, months

Reference

VEGFr-TKI ? SO VEGFr-TKI ? SU VEGFr-TKI ? TEM VEGF-targeted ? VEGF-targeted VEGF-targeted ? mTOR inhibitor

5 5 10 216 24

8.9 9.8 NR 4.9b 2.5b

60 100 20 NR NR

NR NR NR 14.2 10.6

Richter et al.34 Richter et al.34 Richter et al.34 Vickers et al.35 Vickers et al.35

CR, complete response; DCR, disease control rate; mTOR, mammalian target of rapamycin; NR, not reported; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; SO, sorafenib; SU, sunitinib; TEM, temsirolimus; VEGFr-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor. a For the purposes of this review, DCR was calculated as follows: DCR = %CR + %PR + %SD. b TTF (time to treatment failure) instead of PFS.

Table 3 Efficacy and safety of second-line VEGFr-TKI or mTOR inhibitor therapy in patients who have failed initial VEGF-targeted therapy, as reported in prospective studies. Sequence

n

Median PFS with second VEGFr-TKI, months

DCR with second VEGFr-TKI, %a

Median OS from start of second VEGFr-TKI, months

Most common grade 3/4 AEs with second-line treatment, %

Reference

SU/PAZ ? SO

18

4.3 (n = 14);>8 (n = 4)

72

NR

Mancuso et al.36

Bev/SU ? SO

47

4.4

45

16.0

SU ? SO

52

3.7b

19

7.4

SU/SO ? EVE

19

5.5

90

8.0

SU/SO ? EVE

277

4.9

68.6

14.8

SU ? SO/AX

390

3.4 (SO) 4.8 (AX)

NR

NR

Hand-foot syndrome, 38.8% Mucositis, 5% Hand-foot syndrome, 31% Fatigue, 18% Diarrhea, 9% Hypertension, 9% Diarrhea, 11.5% Neutropenia, 9.6% Nausea/vomiting, 9.6% Hypertension, 9.6% Pneumonitis, 27% Anemia, 19% Stomatitis, 8% Lymphopenia, 18% Hyperglycemia,<16% Anemia, 13% Infections, 10% NR

Garcia et al.37

Di Lorenzo et al.38

Jac et al.39

Motzer et al.40

Rini et al.41

AE, adverse event; AX, axitinib; Bev, bevacizumab; CR, complete response; DCR, disease control rate; EVE, everolimus; mTOR, mammalian target of rapamycin; NR, not reported; ORR, overall response rate; OS, overall survival; PAZ, pazopanib; PFS, progression-free survival; PR, partial response; SD, stable disease; SO, sorafenib; SU, sunitinib; VEGFr-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor. a For the purposes of this review, DCR was calculated as follows: DCR = %CR + %PR + %SD. b TTP (time to progression) instead of PFS.

for first-line use in treatment-naive, poor prognosis patients with mRCC. Toxicity profiles for mTOR inhibitors and VEGFr-TKIs do not overlap40; thus, class-effect toxicities associated with VEGFr inhibition may be alleviated when following VEGFr-TKI therapy with an mTOR inhibitor. The efficacy and safety of everolimus in patients who have failed initial VEGFr-TKI therapy has been evaluated in phase 2 (Jac et al.) and phase 3 (Motzer et al.) clinical trials (Table 3). The randomized, placebo-controlled phase 3 RECORD-1 trial demonstrated the clinical benefit of everolimus in patients who had progressed on previous VEGFr-TKI therapy.40 Median PFS was 4.9 months with everolimus compared with 1.9 months for placebo (HR = 0.33; 95% CI, 0.25–0.43; P < .001) by independent central review. The most commonly reported grade 3/4 AEs in the everolimus arm included: infections (10%), dyspnea (7%), fatigue (5%), and stomatitis (<5%).40 Results from a preplanned, prospective subanalysis demonstrated that everolimus provided clinical benefit over placebo in patients who received previous treatment with either 1 VEGFr-TKI or 2 previous VEGFr-TKIs.44 In the subgroup of patients who had received 1 previous VEGFr-TKI (n = 308), median PFS was 5.4 months in the everolimus group and 1.9 months in the placebo group (HR = 0.32; 95% CI, 0.24– 0.43; P < .001), and in the subgroup of patients who had received 2 previous VEGFr-TKIs (n = 108), median PFS was 4.0 months in

the everolimus group and 1.8 months in the placebo group (HR = 0.32; 95% CI, 0.19–0.54; P < .001).44 Available evidence suggests that everolimus serves as an effective, well-tolerated therapy option in patients who have failed initial VEGFr-TKI therapy. Current clinical practice guidelines in the European Union and the United States recommend category level 1 use of everolimus in this patient population.7–10

Comparison of VEGFr-TKIs and mTOR inhibitors in the secondline setting To date, no head-to-head, prospective clinical studies have been conducted to compare the safety and efficacy of a VEGFr-TKI and an mTOR inhibitor in patients who failed initial VEGFr-TKI therapy. An indirect comparison study by Di Lorenzo and colleagues demonstrated that the estimated median OS benefit in patients with VEGFr-TKI-refractory mRCC was 81.5 weeks (95% CI, 78–86 weeks) for everolimus, compared with 32.0 weeks (95% CI, 22–64 weeks) for sorafenib.45 The investigational VEGFr-TKI axitinib has also demonstrated efficacy in this patient population.41 In the absence of prospective data enabling direct comparisons, the decision on whether to administer an mTOR inhibitor or a second VEGFr-TKI following progression on a first-line VEGFr-TKI necessitates careful

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consideration of factors such as the distinct safety profiles of each agent, patient history, and comorbidities. No available agents appear to significantly improve clinical efficacy among patients who exhibit early disease progression after first-line VEGF-targeted therapy.46–48 In a retrospective analysis of patients with mRCC who experienced rapid disease progression with first-line sunitinib (n = 86), median second-line survival and second-line PFS were not significantly different between treatment with VEGFr-TKIs or mTOR inhibitors (OS, 6.6 months vs 5.0 months, P = .157; PFS, 2.0 months vs 0.9 months, P = .536, for VEGFr-TKIs and mTOR inhibitors, respectively).46 Similar results were reported in a larger retrospective study of patients (n = 272) who had progressive disease as best response to first-line VEGFtargeted therapy.47 The response rate, PFS, and OS of those receiving second-line VEGF-targeted therapy compared with mTOR inhibitors were 10% vs 6% (P value not significant), 2.8 months vs 2.0 months (P = .069) and 7.9 months vs 4.7 months (P = .40), respectively. Overall, current evidence suggests that intrinsic resistance to first-line VEGF-targeted agents is associated with low second-line response rate and subsequently poor patient prognosis, regardless of which class of agent is administered in secondline.46–48

VEGFr-TKI resensitization after mTOR inhibitor therapy Currently, no therapies are approved for the third-line treatment of mRCC; however, in clinical practice, a strategy that is seeing increased use is the reintroduction of a VEGFr-TKI following progression on a VEGFr-TKI and an mTOR inhibitor. Over the last two years, a number of retrospective studies evaluating the efficacy of a second VEGFr-TKI following a VEGFr-TKImTOR inhibitor treatment sequence have been reported, with encouraging results (Tables 4 and 5). Di Lorenzo et al. evaluated 34 patients with mRCC who received first-line sunitinib, second-line everolimus or temsirolimus, and third-line sorafenib.49 In the third-line setting, an overall disease control rate of 44%, PFS of 4 months, and OS of 7 months from start of sorafenib treatment were reported.49 Of the patients who responded to first-line treatment with sunitinib, 47% responded to third-line sorafenib; patients who did not respond to first-line sunitinib had a 0% response rate to third-line sorafenib (P = .0027). The most commonly reported grade 3/4 AEs with third-line sorafenib were hand-foot syndrome (14.7%), anemia (11.7%), fatigue (8.8%), diarrhea (8.8%), and neutropenia (8.8%).49 Another study reported by Blesius et al. analyzed subsequent therapy in 105 patients from French sites of the RECORD-1 phase 3 trial; 36 patients received a VEGFr-TKI after receiving everoli-

Table 5 Safety of treatment with a third-line TKI following treatment with sequential VEGFrTKI ? mTOR inhibitor therapy, as reported in retrospective and prospective studies. Grade 3/4 AE incidence,a%

Di Lorenzo et al. (thirdline sorafenib; n = 34)49

Angevin et al. (third-line dovitinib; n = 59b)53

Hand-foot syndrome Anemia Fatigue Diarrhea Neutropenia Decreased appetite Hypertension Nausea/vomiting Asthenia Hypertriglyceridemia

14.7 11.7 8.8 8.8 8.8 NR 5.8 2.9 NR NR

NR 0 13.6 10.2 NR 8.5 10.2 15.3 13.6 11.9

AE, adverse event; mTOR, mammalian target of rapamycin; NR, not reported; TKI, tyrosine kinase inhibitor; VEGFr, vascular endothelial growth factor receptor. a Grade 3/4 adverse events reported in P8% of patients in either study are shown. b Incidences of grade 3/4 AEs in the full analysis set (FAS) are shown. The FAS also included patients treated with other therapies (e.g., interleukin-2, interferon-a).

mus.50 An evaluation of this subgroup by specific agent showed that median PFS was 8.0 months, 5.3 months, and 12.0 months with sunitinib, sorafenib, and the investigational TKI, dovitinib, respectively.50 A partial response was reported in 8.6% of patients and 68.6% of patients had stable disease. Median OS was 29.1 months; patients who received sunitinib after everolimus had an apparently longer median survival than patients who received sorafenib after everolimus (30.5 months vs 17.6 months, P = .102).50 Grünwald et al. examined antitumor activity of VEGF-targeted therapies in everolimus-resistant patients who had progressed on a previous VEGFr-TKI (N = 40).55 Patients received sunitinib (n = 19), sorafenib (n = 8), dovitinib (n = 10), or bevacizumab/IFNa (n = 3) after failure of everolimus.55 Among these patients, 10% had a partial response and 55% had stable disease, and median PFS was 5.5 months.55 In a related study by the same group, 13 patients who were rechallenged with sunitinib after previous progression on sequential sunitinib and either temsirolimus or everolimus had a median PFS of 6.9 months; 15% of patients had partial response and 77% had stable disease.52 The overall PFS benefit of an entire VEGFr-TKImTOR inhibitorVEGFr-TKI treatment sequence has been retrospectively evaluated and recently reported by Porta et al.54 The clinical benefit of sequential sorafenib-mTOR inhibitor-sunitinib (n = 14) was compared with sequential sunitinib-mTOR inhibitor-sorafenib (n = 26), and no significant difference in overall median PFS was noted between the two regimens (21.9 months vs 22.8 months, respec-

Table 4 Efficacy of treatment with a third-line TKI following treatment with sequential VEGFr-TKI ? mTOR inhibitor therapy, as reported in retrospective and prospective studies. Sequence

n

Median PFS with first-line VEGFr-TKI, months

Median PFS with second-line mTORi, months

Median PFS with third-line TKI, months

Median OS of overall sequence, months

Reference

SU ? mTOR inhibitor? SO

34

10

4

7a

Di Lorenzo et al.49

TKI ? EVE ? TKI TKI ? EVE ? TKI TKI ? mTOR inhibitor ? TKI TKI ? mTOR inhibitor ? DOV SO ? mTOR inhibitor ? SU SU ? mTOR inhibitor ? SO VEGF-targeted ? mTOR inhibitor ? VEGF-targeted

36 14 13 31 14 26 40

11.4 10.7 21 NR 11.7 14.4 11.3

4 (EVE) 2 (TEM) 8.9 4.7 NR NR 5.1 4.3 5.9

8.2 5.1 6.9 6.1 9.1 3.9 5.5

29.1 28.2 NR 10.2b 21.9 22.8 NR

Blesius et al.50 Gruenwald et al.51 Grunwald et al.52 Angevin et al.53 Porta et al.54 Grunwald et al.55

DOV, dovitinib; EVE, everolimus; mTOR, mammalian target of rapamycin; NR, not reported; OS, overall survival; PFS, progression-free survival; SO, sorafenib; SU, sunitinib; TKI, tyrosine kinase inhibitor; VEGFr, vascular endothelial growth factor receptor. a From start of sorafenib treatment. b From start of dovitinib treatment.

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tively).54 The sorafenib-mTOR inhibitor-sunitinib group experienced median PFS of 11.7 months, 5.1 months, and 9.1 months with first-, second-, and third-line treatment, respectively. Those receiving sunitinib-mTOR inhibitor-sorafenib had median PFS of 14.4 months, 4.3 months, and 3.9 months, for each treatment, respectively.54 Taken together, these results suggest that reintroduction of a VEGFr-TKI following progression on a VEGFr-TKImTOR inhibitor treatment sequence is an effective strategy. However, patients appear to derive a lesser degree of clinical benefit from VEGFr-TKI rechallenge than that obtained in the first-line setting, suggesting at least partial cross-resistance. One strategy currently being evaluated to address such cross-resistance is introduction of a thirdline agent with the ability to broadly inhibit multiple angiogenic pathways, in addition to VEGF signaling. The investigational TKI dovitinib is an oral, multitargeted inhibitor of FGF receptors 1–3, the PDGF receptor, VEGFrs 1–3, and cKIT.56–58 Hypoxia-mediated induction of FGF signaling has been implicated as a key mechanism of resistance to VEGF-targeted therapy.20 Dovitinib has shown promising antitumor efficacy in a phase 2 trial of patients with mRCC who failed prior treatment with a VEGFr-TKI and/or an mTOR inhibitor (n = 31) or other therapies (e.g., interferon-a, interleukin-2; n = 59, full analysis set) (Tables 4 and 5).53 In the full analysis set, the best overall responses per central review included partial response, 2 patients (3.4%); stable disease P2 months, 29 patients (49.2%); stable disease P4 months, 16 patients (27.1%); and progressive disease, 11 patients (18.6%).53 Median PFS and OS were 5.5 months and 11.8 months, respectively, in the full analysis set, and 6.1 months and 10.2 months, respectively, in patients previously treated with a VEGFr-TKI and an mTOR inhibitor. In the full analysis set, the most common grade 3 adverse events were nausea/vomiting (15.3%), fatigue (13.6%), asthenia (13.5%), diarrhea (10.2%), and hypertension (10.2%); grade 4 hypertriglyceridemia occurred in 8.5% of patients.53 Dovitinib is currently under evaluation in a phase 3 trial (GOLD) as a third-line treatment for use in patients who have progressed on 1 prior VEGFr-TKI and 1 prior mTOR inhibitor (http://www.clinicaltrials.gov; NCT01223027). Clinical efficacy of fourth-line targeted therapy has been recently reported in a 52-year-old male patient with mRCC, treated sequentially with sunitinib, everolimus, sorafenib, and temsirolimus.59 A progression-free period of 48 months was achieved and each treatment was well tolerated, with no evidence of cumulative toxicity, suggesting that patients can continue to derive clinical benefit from multiple lines of therapy. As resistance to both mTOR inhibitors and VEGFr-TKIs appear to be at least partially transient, resensitization might be able to be further exploited in patients who exhibit good tolerability to treatment, allowing sustained disease control through multiple iterations of therapy.

Conclusions Following first-line VEGFr-TKI failure, current clinical practice guidelines uniformly recommend everolimus.7–10 Recent results of the AXIS trial demonstrated that the novel VEGFr-TKI axitinib is also efficacious in this patient population, and may result in the introduction of a new agent into the mRCC treatment paradigm. Choice of second-line treatment following progression on a VEGFr-TKI should be made with consideration of factors such as the distinct safety profiles of each agent and patient history. For patients who receive second-line treatment with an mTOR inhibitor, a growing body of evidence suggests that subsequent treatment with a third-line VEGFr-TKI appears to be an effective and generally well-tolerated treatment strategy. The multitargeted TKI dovitinib has shown promising efficacy in patients who have

progressed on a VEGFr-TKI and an mTOR inhibitor in a prospective phase 2 study, and results of the ongoing phase 3 GOLD trial of dovitinib versus sorafenib in this population of patients are eagerly awaited. Several questions about the optimal sequencing of therapies in patients with mRCC remain to be answered. For instance, will patients gain enhanced clinical benefit from a second targeted therapy if it is initiated before they experience disease progression on first-line therapy? The ongoing EVERSUN trial was designed to address this question by evaluating the effect of alternating treatment with everolimus and sunitinib in patients with advanced RCC in the absence of disease progression (http://www.anzctr.org.au; ACTRN12609000643279). In addition, can response to specific targeted therapies be predicted in individual patients? Two ongoing clinical trials sponsored by the PREDICT Consortium are focused on the identification of predictive biomarkers for response to everolimus (E-PREDICT trial) and sunitinib (S-PREDICT trial).60 In these studies, paired pretreatment biopsies and on-treatment nephrectomy specimens from patients with previously untreated mRCC will be collected for use in molecular analyses and integration with clinical efficacy data.60 As therapeutic options currently available to patients with mRCC cannot yet deliver a cure, the balance of treatment-related quality of life with prolongation of disease progression must be individually considered. While prospective clinical data are limited and challenges remain, results discussed herein imply that, in many patients, maintaining this balance through successive lines of therapy is an attainable goal. Conflict of interest statement S Oudard has received honoraria from Bayer, Novartis, Pfizer, Roche, and Sanofi-Aventis. Acknowledgments Editorial assistance in the preparation of this manuscript was provided by ApotheCom (Yardley, PA, USA) and was funded by Novartis Pharmaceuticals Corporation. Novartis had no involvement in the collection, analysis, and interpretation of data for this manuscript, the writing of this manuscript, or the decision to submit it for publication. References 1. Coppin C. Immunotherapy for renal cell cancer in the era of targeted therapy. Exp Rev Anticancer Ther 2008;8:907–19. 2. Richards FM, Webster AR, McMahon R, et al. Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med 1998;243:527–33. 3. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von HippelLindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008;14:4726–34. 4. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005;353:2477–90. 5. Coppin C, Kollmannsberger C, Le L, Porzsolt F, Wilt TJ. Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int 2011;108:1556–63. 6. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–81. 7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer, V.2.2011. National Comprehensive Cancer Network Web site. Available at: ; 2011 accessed July 6, 2011. 8. Escudier B, Kataja V. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(suppl 5):v137–9. 9. de Reijke TM, Bellmunt J, van Poppel H, Marreaud S, Aapro M. EORTC-GU group expert opinion on metastatic renal cell cancer. Eur J Cancer 2009;45:765–73. 10. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol 2010;58:398–406. 11. 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. 12. 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;27:3584–90.

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