European Journal of Cancer (2014) 50, 1321– 1329

Available at www.sciencedirect.com

ScienceDirect journal homepage: www.ejcancer.com

Review

Controversies in renal cell carcinoma: Treatment choice after progression on vascular endothelial growth factor-targeted therapy Emiliano Calvo a,⇑, Viktor Gru¨nwald b, Joaquim Bellmunt c a

Centro Integral Oncolo´gico Clara Campal and START Madrid, Madrid, Spain Clinic for Hematology, Hemostasis, Oncology and Stemcell Transplantation, Medical School Hannover, Germany c University Hospital del Mar, Barcelona, Spain b

Available online 1 March 2014

KEYWORDS Quality of life Renal cell carcinoma Second-line Sequencing Treatment planning

Abstract The mammalian target of rapamycin inhibitor (mTORI) everolimus and the tyrosine kinase inhibitor (TKI) axitinib are the only two post-first-line treatment options for metastatic renal cell carcinoma (mRCC) licensed at present. Extrapolation of robust phase III studies suggests that median progression-free survival (PFS) is similar between agents. This presents a dilemma for the physician planning treatment for their patients with mRCC: should they be treated with a TKI–mTORI or a TKI–TKI sequence? The lack of direct comparison between axitinib and everolimus leaves the clinician without clear guidance on the optimal choice in second-line therapy. In phase III studies, both post first-line everolimus and axitinib have been shown to delay disease progression; however, cumulative toxicity with sequential use of TKIs may result in more treatment interruptions or dose reductions or increased likelihood of adverse events. While everolimus exerts a tolerability advantage, axitinib is associated with higher response rate and a similar PFS benefit. Proven superiority cannot be used to guide treatment sequence selection in mRCC. Instead, therapeutic planning requires us to take a long-term view of our patient’s treatment that includes quality of life and a balance between symptom control, adverse event management and avoidance of unnecessary drug interruptions or dose reductions. In the absence of curative therapies, sustaining a patient’s quality of life is a major goal throughout the course of treatment and choosing a second-line agent that is able to adequately achieve this by limiting adverse events should be a priority. Ó 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author: Address: START Madrid, Centro Integral Oncolo´gico Clara Campal, Hospital Madrid Norte Sanchinarro, Calle On ˜ a, 10, 28050 Madrid, Spain. Tel.: +34 91 7567825; fax: +34 91 7567931. E-mail address: [email protected] (E. Calvo).

http://dx.doi.org/10.1016/j.ejca.2014.02.007 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.

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1. Introduction Seven molecularly-targeted agents have been licensed for the treatment of metastatic renal cell carcinoma (mRCC), including the humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (used in combination with interferon [IFN]-a); the multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and sorafenib; and the mammalian target of rapamycin inhibitors (mTORIs) everolimus and temsirolimus. In each line of mRCC therapy, the molecularly-targeted agents specifically approved for that setting have demonstrated similar efficacy, requiring oncologists to rely on factors other than clinical efficacy alone to select the optimal therapy for their mRCC patient and generating debate on the optimal therapy sequence in mRCC. It is without doubt that initial treatment of low- or intermediate-risk mRCC patients with a VEGF-targeted agent significantly improves clinical outcomes compared with conventional immunotherapy [1–3], as reflected in current evidence-based guidelines (Table 1) [4,5]. A recent randomised non-inferiority trial (COMPARZ) suggested that pazopanib is non-inferior to sunitinib in the first-line setting, and may be more favourable than sunitinib in terms of safety and quality of life [6]. First-line temsirolimus has demonstrated efficacy in patients with poor prognosis [7]. Despite the clear benefits of targeted therapies in mRCC, most patients experience disease progression while on treatment [8]. Approved post first-line treatment options include everolimus [9,10] and axitinib [11,12], which are both active after treatment with VEGF-targeted therapy and are associated with median progression-free survival (PFS) durations in the range of 4–5 months. This presents a dilemma for the physician planning the treatment sequence for their patient with mRCC:

should they be treated with a TKI or an mTORI after failure of a VEGF-targeted therapy? In other tumour types, it is common practice to avoid cross-resistance by switching to a drug with a different mechanism of action after treatment failure. Do the same rules apply in mRCC? This review evaluates current evidence to guide post first-line drug selection in mRCC and considers how to optimise clinical outcome, patient quality of life and survival through therapy selection. 2. Treatment sequencing: what is the evidence from direct comparisons? Until recently, there has been little evidence to guide treatment sequencing in mRCC, with most data generated from retrospective or non-comparative studies [13–26]. While these analyses indicate that some level of second-line activity is achieved when a TKI–mTORI or a TKI–TKI sequence is used, the quality of data makes it difficult to draw any greater conclusions. We need to extrapolate the robust data that we do have on individual agents into thoughtful and rational treatment decisions. One prospective study (INTORSECT) has recently been presented that directly compared agents with different mechanisms of action (temsirolimus and sorafenib) in mRCC patients who had progressed on first-line sunitinib [27]. There was no significant difference between treatments in the primary end-point of PFS (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.71–1.07); however, sorafenib afforded a significant overall survival (OS) advantage to temsirolimus (HR 1.31; 95% CI 1.05–0.63). The reasons for the discrepancy in PFS and OS are unclear. Data on post-second-line therapies were not collected, meaning that any potential contribution of between-group imbalances in salvage therapy cannot be elucidated. Irrespective of the findings of this study, it may be a red herring in unravelling the controversy surrounding

Table 1 ESMO recommendations for systemic treatment in clear-cell metastatic renal cell carcinoma (mRCC) [5]. Treatment line

Risk group

Previous therapy

First

Good/ intermediate

None

Poor

None

All

Second

Third

All

Standard treatment

Alternative treatment

   

Sunitinib Bevacizumab + IFN Pazopanib Temsirolimus

 Cytokines  Sorafenib

Vascular endothelial growth factor (VEGF)-targeted therapy Cytokines

    

Everolimus Axitinib Sorafenib Pazopanib Axitinib

 Sorafenib

Two VEGF-targeted therapies VEGF-targeted therapy and mammalian target of rapamycin inhibitor (mTORI)

 Everolimus  Tyrosine kinase inhibitor (TKI)

 Sunitinib  Sorafenib

 Sunitinib

Adapted from Escudier B, Eisen T, Porta C, Patard JJ, Khoo V, Algaba F, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl. 7:vii65–71.

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post-first-line mRCC treatment selection as it compares two therapies that do not have a current role in the second-line setting and raises the question as to whether temsirolimus is in fact detrimental as a second-line therapy. 3. Efficacy in the post-first line setting Both everolimus and axitinib have been evaluated in separate phase III randomised controlled trials in the post first-line mRCC setting [9–12]. The phase III RECORD-1 study provides high-level evidence that everolimus after failure of a VEGF-targeted therapy gives a clear clinical benefit [9,10]. In this double-blind study, patients with disease progression on sunitinib and/or sorafenib were randomised to everolimus or placebo. Prior therapy with cytokines and/or VEGF inhibitors (including bevacizumab) was permitted. At the time this study was conducted, no standard RCC treatment option was approved for patients who had progressed on TKIs, making placebo the only appropriate comparator. In the whole study population, everolimus more than doubled PFS compared with placebo (median PFS of 4.9 months and 1.9 months, respectively; HR 0.32; 95% CI 0.25–0.41). Interestingly, in a preplanned subanalysis of the study, everolimus showed an apparent longer median PFS when used after one TKI (5.4 months) than after two TKIs (4.0 months), although the reduction in risk of progression was similar relative to placebo irrespective of treatment line (Fig. 1) [28]. Of particular relevance to this discussion is the efficacy of everolimus in patients who had not received any previous anti-neoplastic therapy other than

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sunitinib: in this group, everolimus reduced the risk of disease progression by 78% compared with placebo (median PFS 4.6 months versus 1.8 months, respectively; HR 0.22; 95% CI 0.09–0.55). Approval for axitinib as second-line treatment for mRCC was based on the phase III AXIS study [11,12], which compared axitinib and sorafenib (one acceptable second-line TKI therapy at the time of the study initiation). The AXIS population was notably different from RECORD-1 in that participants were strictly in the second-line setting; however, only 54% of patients had received first-line sunitinib (the most common first-line targeted therapy when the study was launched), with other patients receiving first-line cytokines (35%), bevacizumab (8%) or temsirolimus (3%). Axitinib was associated with significantly longer PFS than sorafenib (HR 0.67; 95% CI 0.54–0.81); however, in a preplanned subanalysis, median PFS with both axitinib and sorafenib was shorter in patients who had received sunitinib as first-line treatment than those who received first-line cytokines (Fig. 2). This suggests that the major gain in overall PFS in the AXIS trial was largely driven by the subgroup of patients receiving first-line cytokines, which is now largely irrelevant in clinical practice. Interestingly, if the data are compared across studies, the median PFS duration with axitinib and everolimus is almost numerically identical (within 6 days difference) in the subgroup of patients who progressed on first-line sunitinib and who we are now most likely to be treating in our clinics. No OS advantage was detected in either trial. It is unlikely that an OS benefit would have ever been detected in RECORD-1 because of the high cross-over rate from placebo to everolimus (80%). In

Fig. 1. RECORD-1: Kaplan–Meier estimates of progression-free survival (PFS) in patients treated with everolimus after progressing on treatment with one or two previous vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs) [28]. Reprinted from, Eur J Cancer, 48, Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, et al., Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study, 333–9 (2012), with permission from Elsevier.

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Fig. 2. AXIS: Kaplan–Meier estimates of PFS in patients treated with axitinib or sorafenib after progressing on first-line therapy. Subanalyses in (A) patients pre-treated with cytokines and (B) patients pre-treated with sunitinib [11]. Reprinted from the Lancet, 378, Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al., Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial, 1931–9 (2011), with permission from Elsevier.

the AXIS study, although cross-over between study drugs was not permitted, the magnitude of PFS gain with axitinib does not suggest an increase in OS. How do these data influence our decision making in mRCC? When the findings of each of these studies are extrapolated to the context of current therapy, where most patients receive sunitinib (or increasingly pazopanib) as first-line therapy, there is little indirect difference between second-line everolimus and axitinib in terms of median PFS. Furthermore, it remains unknown as to whether an OS difference exists between axitinib and everolimus. In the absence of any direct comparison, considerations beyond efficacy need to come into play when considering drug sequencing.

4. Quality of life and tolerability in the post first-line setting Current therapies for mRCC are non-curative; therefore, delay in the worsening of symptoms is a primary treatment goal [29], particularly given the very real burden of disease associated with RCC [30]. Indeed, the PFS benefit gained with any particular therapy diminishes in value if quality of life is not maintained or improved over the course of treatment [31]. The recent COMPARZ and PISCES studies showed that quality of life is a very important parameter for patients when differentiating between the quasi-equally efficacious first-line pazopanib and sunitinib [6,32]; this factor is

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also of considerable importance in discriminating between second-line therapies where efficacy is also generally equivalent. Performance status and quality of life parameters were evaluated in both the RECORD-1 and the AXIS trials. Both studies utilised the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, Disease Related Symptoms (FKSI-DRS) scale, while the FKSI-15 scale was also used in the AXIS study. In the RECORD-1 study, patients treated with everolimus had a delayed time to definitive deterioration in Karnofsky Performance Status (KPS) by 10% (p = 0.004) and FKSI-DRS by two score units (p = 0.053) compared with placebo [9], indicating that everolimus had a beneficial impact on delaying the worsening of disease symptoms and quality of life. In the AXIS study, FKSI-15 and FKSI-DRS scores were similar during treatment with axitinib and sorafenib and decreased over the finalisation of the course of therapy, probably as a result of tumour progression. Somewhat unexpectedly, however, quality of life scores actually improved after treatment discontinuation, possibly owing to amelioration of treatment-related toxicity with cessation of therapy and benefit from a coping strategy for disease progression [33]. In addition, the AXIS study included an a priori statistical analysis of time to deterioration (TTD), defined as a composite end-point of death/progression/worsening of FKSI-15. In the whole study population, axitinib was associated with a significantly greater TTD compared with sorafenib; however, in a subgroup analysis of patients pre-treated with sunitinib, this treatment difference was not evident [34]. Tolerability is also an important consideration in treating patients with advanced disease. In RECORD1 [9], dose interruptions and reductions were reported in 38% and 7% of patients treated with everolimus, respectively. Everolimus was discontinued in 13% of patients as a result of adverse events. In the AXIS study [11], the overall incidence of adverse events was higher in patients receiving prior sunitinib than those receiving prior cytokines, suggesting a cumulative toxicity effect in patients receiving sequential TKIs (Fig. 3). Other studies using sequential TKIs have also found a higher than expected rate of adverse events with second-line therapy [20,23]. In AXIS, axitinib was discontinued in 10% of patients as a result of adverse events, while dose interruptions and reductions were required in 77% and 31% of axitinib recipients, respectively. This may have been a partial consequence of the AXIS study protocol allowing dose escalation in the absence of grade 2 adverse events or hypertension, which may then have increased the later dose-reduction rate; nevertheless, it is of considerable clinical significance, as one of the goals of oral mRCC therapy is to maintain the full dose of the drug for the duration of treatment so that outcomes may be optimised [35]. The large variation

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Fig. 3. AXIS: Toxicity in patients treated with (A) axitinib and (B) sorafenib after progressing on first-line cytokines or sunitinib [56]. Adverse events shown are those with a >10% difference in incidence between first-line subgroups in either treatment arm.

in relative axitinib dose intensity in the AXIS trial makes it difficult to determine the most clinically effective dose. Furthermore, these data may understate the impact that toxicity-driven dose interruptions and reductions have on patient quality of life. Interestingly, the incidences of dose interruptions and reductions with sorafenib in the AXIS trial (80% and 52%, respectively) were considerably higher than those seen in the phase III randomised, placebo-controlled TARGET study [36] (21% and 13%, respectively), where sorafenib was administered second-line to non-TKI therapies (primarily cytokines or IFN-a). This further suggests the possibility of cumulative toxicity when two TKIs are administered sequentially, although it may also be that increased experience

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with TKIs at the time of the AXIS trial meant that investigators were notably more proactive and effective at implementing dose interruption or reduction strategies than during the earlier TARGET study.

5. Using past response to guide treatment selection Historically, a commonly-used strategy to guide second-line therapy in mRCC was to consider how the patient responded to first-line therapy. However, recent retrospective reviews did not find any obvious correlation between initial and subsequent outcomes in patients who received a second-line VEGF-targeted therapy after failing a first-line VEGF-targeted therapy, [37–39]. Furthermore, prospective studies have suggested that treatment with a second-line TKI or mTORI after first-line TKI failure is associated with few (if any) patients achieving an objective response [10,11,20,23,27]. However, the response rate for axitinib remains higher (11%) than for everolimus (2%), which renders axitinib a preferred choice for patients who need rapid tumour reduction for palliation. Interestingly, however, a recent German multicentre non-interventional study documented time to progression in mRCC patients starting everolimus after failure of initial VEGF-targeted therapy, with results suggesting that a patient who responds well to initial VEGR blockade may also respond well to second-line mTOR inhibition [24]. Of course, the noninterventional design of this study precludes definitive conclusions from being drawn. Taken together, these findings indicate that response to specific second-line therapy is dependent upon tumour biology and not the efficacy of specific first-line treatment. This is in keeping with most tumour types where patients who respond to first-line therapy tend to respond to any subsequent therapy while patients with refractory tumours at the outset are less prone to respond to sequential treatment, irrespective of the specific drugs that are used. This finding is not entirely surprising, given that none of the existing VEGFR-TKIs completely block all angiogenic signalling pathways [40] and resistance to treatment typically develops through various mechanisms, including upregulation of alternative pro-angiogenic factors, invasion without angiogenesis and mutation [41,42]. Interestingly, however, there is growing evidence that TKIs have activity in the third-line setting in patients treated with a first-line VEGFR inhibitor followed by everolimus [43–45], suggesting that some TKI resistance is transient in nature and that mechanism of action changes may re-introduce treatment susceptibility, offering a valid sequencing pathway to manage mRCC. For example, in a small subanalysis of the RECORD-1 study, 75% of the 36 patients who received a third-line TKI after a prior TKI and everolimus achieved disease control [43]. This sequencing pathway concept is further

illustrated in the recent GOLD study, which compared sorafenib with the investigational multi-targeted TKI dovitinib in patients who had progressed on first-line VEGF-targeted therapy and a second-line mTORI (92%) or vice versa (8%) [46]. While no significant differences in the primary end-point of PFS were noted between the two agents (median 3.6 and 3.7 months, respectively), the observation that median PFS in both treatment groups was notably longer than in the placebo arm of the RECORD-1 study (median 1.8–1.9 months consistently across subgroups) suggests that sorafenib and dovitinib are both active in this setting. This is noteworthy in the context of this discussion, as it provides further evidence that the TKI–mTORI–TKI treatment sequence is effective in advanced RCC and continuation of sequential therapy should be a therapeutic goal. Preliminary results of the recently-reported phase II RECORD-3 trial further support the standard treatment pathway of first-line sunitinib followed by everolimus at progression and provide crucial insight into the importance of appropriate drug sequencing [47]. Treatment-naı¨ve mRCC patients were randomised to sunitinib followed by everolimus at disease progression or vice versa. While the use of first-line everolimus was not supported by the study, the results reassured the relevance of sequential sunitinib–everolimus therapy. In the preliminary OS analysis, an unprecedented median OS of 32.0 months was reported with sunitinib followed by everolimus compared with 22.4 months with the reverse sequence (HR 1.24; 95% CI 0.94–1.64). It will be interesting to note whether OS is extended beyond a median of 32 months in the subgroup of patients who receive another TKI after the sunitinib–everolimus sequence; conventional wisdom would suggest that this will be the case, as those patients who continue to third-line therapy are likely to be those with better performance status and, according to GOLD study [46], there appears to be antitumor activity with a third-line TKI after progression on a TKI–mTORI sequence. However, definitive conclusions cannot be drawn until the final analysis is presented.

6. Can mTORIs be used interchangeably in mRCC? Everolimus and temsirolimus are both functional analogues of rapamysin (sirolimus) and members of the mTORI class of drugs. Everolimus is an active drug, while temsirolimus is a pro-drug of rapamysin, which is formed following hepatic metabolism [48]. Each agent has been separately assessed in the treatment of mRCC, with treatment guidelines and licensing approvals assigning them different positions within the treatment armamentarium (Table 1) [4,5]. Furthermore, they have different administration regimens, with everolimus administered orally on a daily basis and temsirolimus administered by intravenous (IV) injection on a weekly

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basis [48,49]. Everolimus is rapidly absorbed following oral administration, has a bioavailability of around 30% and is metabolised by the CYP3A4, CYP3A4 and CYP2C8 pathways to form six main metabolites. The mean terminal half-life of everolimus is approximately 30 h with the drug mainly excreted in the bile. This half-life duration allows once-daily administration, which also achieves continuous drug exposure and less fluctuation in drug concentration. As temsirolimus is administered intravenously, its bioavailability is not affected by food intake or variability in gastrointestinal absorption. Temsirolimus is rapidly metabolised by CYP3A4 to form rapamysin, which has a mean terminal half-life of 56 h (allowing weekly dosing) and is mainly eliminated in the faeces [48]. Despite differences in administration, toxicity profiles of everolimus and temsirolimus remain relatively similar [50–52]. Interestingly, the recommended dose and schedule developed for everolimus in phase I studies (10 mg/day by oral administration) [49,50,53] is the same as the licenced dose, whereas the optimal dose of IV temsirolimus in phase I and II studies (220 mg/m2/ week) [51,54] is considerably higher than the licenced dose (25 mg/week). Despite these differences between drugs, prescribing pattern analyses from the United States indicates that everolimus and temsirolimus are often used outside of guideline recommendations [55]. This may be driven in the United States by financial incentives for administration of IV medication; however, these incentives are not replicated in the European Union and it is important that these two agents are used in the appropriate line of treatment for the appropriate patient group. On the basis of current evidence, licensing and clinical guidelines, everolimus is the preferred mTORI in the post first-line setting.

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exploring novel therapeutic agents in mRCC, including nivolumab, a PD-1 inhibitor, and cabozantinib, a TKI dually targeting the VEGFR and MET axes. These agents may add additional flavour to this debate in the near future, perhaps optimising our use of agents and bringing novel aspects of toxicity management to the field of RCC. As clinicians, it is important to discuss treatment options with our mRCC patients using more than just PFS data. Therapeutic planning requires us to take a long-term view of our patient’s treatment, including quality of life and a balance between symptom control, adverse event management and avoidance of unnecessary drug interruptions or dose reductions. In the absence of curative treatments, sustaining a patient’s quality of life is a major goal throughout the course of anticancer therapies and choosing a second-line agent that is able to adequately achieve this by limiting adverse events and providing consistency of dosing should be a priority. Conflict of interest statement Joaquim Bellmunt has received, before April 2013, honoraria from Astellas, Bayer, GlaxoSmithKline, J&J, Novartis, Pfizer and Roche and has served on advisory boards for GlaxoSmithKline and Astellas. Emiliano Calvo has received research grants from Astellas, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer and Roche and has served on advisory boards for Astellas, GlaxoSmithKline, Novartis and Pfizer. Viktor Gru¨nwald has received honoraria from Astellas, Bayer, GlaxoSmithKline, Novartis, Pfizer and Roche and has served on advisory boards for Astellas, Bayer, GlaxoSmithKline, Novartis and Pfizer. Financial support

7. Implications for therapy Everolimus was licensed in August 2009 for mRCC that has progressed on VEGF-targeted therapy and has been prescribed in more than 100,000 patients world-wide across multiple indications. Axitinib was approved in Europe for second-line mRCC in September 2012. Current data for either agent build the basis for sequential therapy, with RECORD-3 representing contemporary data for a TKI–mTORI sequence with a remarkable OS duration in mRCC [47]. Given that fewer than 20% of patients in Europe actually receive third-line therapy in mRCC [8,26], it seems a false economy to save an efficacious drug like everolimus for third-line use, potentially decreasing its impact. Furthermore, the recent GOLD study suggests that a TKI may be effective in the third-line setting [46], providing an appropriate treatment pathway for our patients (TKI–mTORI–TKI). Current studies are

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