SURVEY OF IDENTIFIED ELIGIBLE STUDIES
In all, 28eligible trials were identified, of which eight were identified only as meeting reports. Two studies were too small for further consideration [30,31]. Targeted agents might be growth stabilizing rather than cytoreductive, and three studies randomly discontinued the active agent to placebo in patients with stable disease during an initial ‘run-in’ period (randomised discontinuation trials) [4,5,32]. The most frequent stratification was by performance status, nephrectomy status, and prognostic risk category. Five trials of four agents with non-specific anti-angiogenic activity were tested in the earlier years of this series and none showed clinical benefits [4,6–9]. We here divide the studies of target-specific agents into three groups based on the molecular target: specific VEGF pathway inhibitors (15 studies), mammalian target of rapamycin (mTOR) inhibitors (three studies), and other (three studies). Most studies required RCC with a clear cell component; consequently the following results are for clear cell RCC (ccRCC) unless stated otherwise. Presented statistics of time-dependent outcomes are based on the authors' reports of the two-sided log-rank test on an intent-to-treat basis. Quantitative subset analysis is considered for stratified variables only.
VEGF/VEGF RECEPTOR (VEGFR) INHIBITORS
BEV is a monoclonal antibody against VEGF, blocking access to its receptor and inhibiting downstream angiogenesis that is amplified in ccRCC. In a randomised phase II study, BEV at 3 mg/kg and 10 mg/kg i.v. biweekly was compared with placebo in 116 patients previously treated with, or unsuitable for, high-dose interleukin-2 . The ORR was <10% in any arm but PFS was prolonged with BEV 10 mg/kg (median 4.8 vs 2.5 months, hazard ratio [HR] 0.39, P < 0.001). This dose and schedule of BEV was reported to be tolerable when added to IFNα (9 million IU, s.c., three-times weekly). Two studies compared BEV + IFNα vs IFNα alone with similar results [11,12]. Unlike CALGB 90206, the AVOREN trial also included a placebo control and conducted independent ‘blinded’ imaging assessment for response and progression endpoints. The ORR was substantially improved (28.4 vs 12.9% for BEV + IFNα vs IFNα or IFNα+ placebo, combined data for the two studies), as well as PFS, the HRs for progression were 0.71 and 0.61, respectively. The primary endpoint for both studies was OS (median survivals for CALGB 90206 were 18.3 vs 17.4 months, and for AVOREN 23.2 vs 21.3 months for BEV + IFNα vs IFNα or IFNα+ placebo, respectively). Survival differences were not significant in either study alone. However, the stratified HRs for survival indicated a 14% risk reduction for death in favour of the BEV + IFNα combination. On both studies, more than half of all patients received post-protocol therapies such as VEGFR inhibitors that may have diluted any survival benefit of the first-line treatment. The relative contributions of BEV and IFNα to these benefits is unknown, but each agent has shown efficacy over inactive therapy [1,10].
The intracellular kinase terminal of the VEGF receptor family can be blocked by orally available small molecule inhibitors developed over the past decade, beginning with sorafenib. A small randomised discontinuation trial of sorafenib showed prolonged PFS in patients stable during the run-in phase . The TARGET phase III study evaluated sorafenib vs placebo in the second-line setting after IFNα progression, finding few RECIST-defined responses but prolonged PFS (median 5.5 vs 2.8 months, HR 0.44, P < 0.001) . Improvement in the primary endpoint of OS did not reach significance in the intent-to-treat analysis but nearly half of the placebo-assigned patients crossed over to sorafenib at study closure. Overall health-related quality of life (HRQL) scores were not significantly improved . Sorafenib has been the best-evidenced second-line option after cytokine failure, until the AXIS study discussed below. A randomised phase II study of sorafenib in the first-line setting reported no significant advantage in remissions or PFS for sorafenib over IFNα at the standard sorafenib dose of 400 mg twice daily . Subsequent emphasis has been on attempted enhancement of activity by combining sorafenib with other agents, including low dose IFNα[15,16], low dose interleukin-2 , and AMG 386 (an investigational fusion protein that sequesters angiopoietin-1 and -2) . Thus far, no clinically useful advance with these combinations has been identified.
The oral VEGFR inhibitor sunitinib was introduced to phase I/II testing using a discontinuous 6-week cycle of 4 weeks ‘on’ and 2 weeks ‘off’ therapy (4/2 regimen). Sunitinib went directly into a phase III study in systemically untreated patients . At entry, patients were required to have pretreatment progression and measurable disease. The high rates of objective response in non-randomised phase II studies after cytokine failure were confirmed in the first-line phase III trial (independently assessed ORR 46.9 vs 12.3%, sunitinib vs IFNα). The primary endpoint of PFS was evaluated by independent imaging review and was substantially prolonged (median 11 vs 5 months, HR 0.54, P < 0.001), and was consistent across patient subsets, although only 7% were poor prognostic risk. Importantly, there was an improvement in patient-reported outcomes , although the validity of this evaluation is difficult to assess in the absence of a double-dummy placebo control. The secondary endpoint of OS was improved with borderline statistical significance (median 26.4 vs 21.8 months, HR 0.82, stratified P= 0.049). The survival benefit may have been diluted by crossover of ≈60% of placebo-assigned patients to sunitinib and/or other VEGFR inhibitor therapy. The phase II EFFECT trial in measurable treatment-naïve advanced disease compared the standard 4 weeks on/2 weeks off (4/2) 50 mg daily regimen with 37.5 mg daily taken continuously; compliance was better with the discontinuous regimen, patients appreciate the break in toxicities, and the primary outcome of PFS showed a trend in favour of the 4/2 regimen (median PFS 8.5 vs 7.0 months, HR 0.77, P= 0.07) .
Pazopanib is the third oral VEGFR inhibitor to achieve regulatory approval status in the USA and Europe. The study of pazopanib 800 mg daily vs placebo (2:1 randomisation)  included 202 patients after prior cytokine and was expanded soon after opening to include 233 treatment-naïve patients because of the emerging evidence of VEGFR inhibitor efficacy in the untreated setting. The intent-to-treat ORR was 30 vs 3% (pazopanib vs placebo, P < 0.001). The primary outcome of PFS was significantly improved in both cytokine-pretreated and treatment-naïve patients (all patients median PFS 9.2 vs 4.2 months, HR 0.46; cytokine-pretreated HR 0.54, and treatment-naïve patients HR 0.40; all P < 0.001, overlapping 95%CIs). OS was similar for pazopanib-assigned and placebo-assigned patients (median OS 22.9 vs 20.5 months, HR 0.91, P= 0.22) but 54% of the latter received pazopanib after progression. HRQL was neither better nor worse than placebo . The results of the COMPARZ phase III study comparing pazopanib with sunitinib are awaited with interest (NCT00720941).
Tivozanib 1.5 mg daily (orally), 3 weeks ‘on’ then 1 week ‘off’, has shown activity over placebo from a randomised discontinuation trial in treatment-naïve or cytokine-pretreated patients with stable disease after the 16-week run-in phase [22,32]. The primary endpoint of freedom from progression after a further 12 weeks was 49% for tivozanib vs 21% for placebo (P= 0.001). This agent is currently in phase III vs sorafenib (NCT01030783).
Axitinib is the most recently reported active oral VEGFR inhibitor from the second-line phase III AXIS study of 723 patients who had received one prior agent reflecting the range of current choices for first-line therapy (sunitinib 54%, cytokine 35%, other 11%) . Sorafenib 400 mg twice daily was compared with axitinib 5 mg twice daily dose-titrated up or down to tolerance. The primary outcome of PFS was significantly better for axitinib than sorafenib regardless of prior treatment (median PFS for all patients was 6.7 vs 4.7 months, HR 0.67, P < 0.001; HR 0.74 after prior sunitinib, HR 0.46 after cytokine). Partial responses were seen more often after axitinib than sorafenib (19.4 vs 9.4%, P < 0.001). Improved PFS in the AXIS study was confirmed by evaluation of patient-reported outcomes that was the same for the two agents during therapy but was better for axitinib in the post-treatment evaluation .
Adverse events with VEGFR inhibitors
The practical supervision and detailed monitoring of targeted agents in the clinic is central to the safety of the individual patient but beyond the scope of this article. Currently, the only direct comparison of two targeted agents is of the VEGFR inhibitors axitinib vs sorafenib in the AXIS trial, as yet only available as a meeting report [23,36]. Axitinib had more all-grade hypertension (40 vs 29%) and hypothyroidism (19 vs 8%) than sorafenib, considered on-target effects and consistent with axitinib having more selective action against VEGFRs. Axitinib also had more fatigue and dysphonia but less hand-foot syndrome, rash, and alopecia. Fewer axitinib patients discontinued therapy for adverse events (3.9 vs 8.2%) despite dose reductions or interruptions being allowed in either arm. Other toxicities seen with VEGFR inhibitors include cardiotoxicity, bleeding, impaired wound healing, sarcopenia, hepatotoxicity, stomatitis and diarrhoea.
Comparative efficacy of VEGFR inhibitors
These agents differ in their range of inhibition of the spectrum of VEGFRs and other similar receptor families, and at this time there is limited data to support the hypothesis that a narrower activity spectrum gives a superior therapeutic index of efficacy over toxicity. The AXIS trial is the first to provide comparative data and more trials are in progress.
mTOR inhibitors are semi-synthetic derivatives of the antifungal agent sirolimus, a product of a Streptomyces species discovered in a soil sample collected on Easter Island (now Rapa Nui, hence rapamycins or rapalogs). mTOR is a highly conserved kinase at a key regulatory locus on the PI3K-Akt-mTOR pathway with complex linkages to other pathways affecting cell cycle progression and angiogenesis. Temsirolimus, a prodrug of sirolimus, given by weekly i.v. infusion was examined in advanced RCC for dose-response , with the lowest dose of 25 mg projected from the in vitro inhibition of mTOR, the unique target for rapalogs. There was no advantage to the higher dose arms so the low dose was taken forward. An international phase III study of temsirolimus vs IFNα was conducted in 626 systemically untreated patients with at least three of six adverse prognostic factors, a minority group in which the then available treatment with cytokines was considered minimally effective . Despite a low ORR by RECIST criteria, other outcomes were superior for temsirolimus, including PFS, HRQL, and the primary endpoint of OS (median OS 10.9 vs 7.3 months, HR 0.73, P= 0.008). Lactate dehydrogenase was both prognostic and predictive for survival benefit .
Everolimus is the first oral mTOR inhibitor to be evaluated in RCC, and has a different active form from temsirolimus. RECORD-1 compared everolimus 10 mg daily with placebo in 410 patients with progressive disease ≤6 months of sunitinib and/or sorafenibtreatment . The primary endpoint of PFS by independent central review was improved (median PFS 4.9 vs 1.9 months, HR 0.33, P < 0.001). RECIST-defined responses were infrequent. Overall HRQL was neither impaired nor improved, but there was a delay in performance status decline . OS was the same in both arms, although everolimus was used in 76% of placebo-assigned patients after disease progression.
Adverse events with mTOR inhibitors
No direct toxicity comparisons are available for mTOR inhibitors. The parent drug sirolimus is in wide use for immunosuppression after organ transplantation, and lymphopenia and atypical infections are class effects, as is non-infectious pneumonitis. Fortunately these effects have been manageable and reversible in most patients. Other common toxicities include elevation of serum cholesterol, glucose, and triglycerides.
Epidermal growth factor receptor (EGFR) inhibitors
Lapatinib is an inhibitor of the EGFR and Her-2. As second-line treatment after cytokine failure, lapatinib was not superior to hormone therapy, considered a placebo equivalent . Interestingly, a pre-planned subset analysis of patients with tumours that strongly overexpressed EGFR showed a trend to improved OS (P < 0.012). We are not aware of current studies of lapatinib for RCC. Another phase II study of BEV with or without the EGFR inhibitor, erlotinib, reported no difference in response or progression for the combination .
Sorafenib combinations are discussed under VEGFR inhibitors above. Non-randomised studies are finding high rates of adverse events with targeted agent combinations. TORAVA, a three-arm phase II study, compared BEV plus temsirolimus to standard sunitinib and to BEV + IFNα and encountered troublesome toxicity in the investigational arm that prevented useful treatment delivery .
Three published studies with an IFNα control provide prospective data for ‘on-study’ nephrectomy status, that is, patients were stratified for this variable and outcomes are separately reported. Temsirolimus showed a survival benefit over IFNα for 138 poor-risk patients who had not undergone nephrectomy (HR 0.6, P < 0.05, values estimated from graph) . BEV + IFNα also improved survival in 112 patients that were not nephrectomised (HR 0.65, P= 0.04) . The same trend was seen for sunitinib (HR 0.79, P < 0.05) . Therefore prior nephrectomy does not appear to be essential for benefit from targeted therapy with either VEGFR or mTOR inhibitor therapies, although patients who did not undergo a nephrectomy could have different important characteristics from the group that had the nephrectomy. Randomised trials are currently examining the role and timing of nephrectomy for sunitinib-treated patients (NCT00930033, NCT01099423).