One of the initial VEGF-inhibiting approaches was a recombinant human monoclonal antibody against VEGF (bevacizumab, Avastin®; Genentech, South San Francisco, CA) which binds and neutralizes all biologically active isoforms of VEGF [29]. An initial randomized study identified that high dose (10 mg/kg) bevacizumab given intravenously every 2 weeks significantly prolonged time to progression in refractory metastatic RCC patients compared to placebo [30, 31]. Subsequently, two phase III trials randomized clear cell RCC patients to either low-dose interferon alpha 2b (Intron A, Schering-Plough, Kenilworth, NJ), 9 MU subcutaneously three times weekly (plus placebo infusion in one trial) or the same dose and schedule of interferon-alpha 2b in combination with bevacizumab, 10 mg/kg IV every 2 weeks [32, 33]. These trials collectively demonstrated an objective response rate and PFS advantage to the bevacizumab-containing regimen (Table 24.1).

The precise role of interferon in this regimen remains debated. Retrospective analyses suggest that dose-reduction of interferon improves tolerability without a compromise of efficacy [22]. Large-scale trials that would be needed to definitively answer this question are unlikely to be undertaken. Currently, the use and dose of interferon with bevacizumab is variable in clinical practice.

Sunitinib (Sutent®, Pfizer Inc. La Jolla, CA) is an orally bioavailable small molecule tyrosine kinase inhibitor of VEGFR-2 and related receptors [23, 24]. The efficacy of this agent as first-line treatment for metastatic RCC was demonstrated through a phase III clinical trial in which 750 treatment-naïve patients with metastatic clear cell RCC (largely good or intermediate risk groups per MSKCC model [42]) were randomized to receive interferon alpha (at a dose of 9 MU given subcutaneously three times weekly) or sunitinib (50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment; called ‘schedule 4/2’). Median PFS was 11 months for the sunitinib arm vs. 5 months for the interferon arm (Table 24.1) [34]. Sunitinib treatment was also associated with a higher objective response rate (31 % vs. 9 %). The overall survival was 26.4 months with sunitinib vs. 21.8 months with interferon (p = 0.051) [35]. Common adverse events related to sunitinib included fatigue, diarrhoea, hypertension, hand and foot syndrome and cytopenia. These data have established sunitinib as a standard of care front-line agent based on the highest response rate and longest PFS.

Attempts at combination therapy with sunitinib have largely not been tolerated, and none have proven more effective than monotherapy [43–45]. Further, attempts to deliver lower dose (37.5 mg), continuous sunitinib have resulted in reductions in clinical efficacy in a randomized comparison versus 50 mg 4/2. Retrospective data supports the importance of adequate daily drug levels of sunitinib, and thus 50 mg 4/2 remains the standard of care with dose reductions as needed for tolerability [46]. Alternative scheduling of sunitinib (e.g. 2 weeks on/1 week off) are also being explored.

Pazopanib is another VEGF-R inhibitor to receive regulatory approval. A phase III randomized double-blind clinical trial including 435 patients with treatment-naïve or cytokine-refractory clear cell metastatic RCC was conducted based on activity observed in previous phase II trials. Median PFS was longer with pazopanib vs. placebo in the overall population (median PFS 9.2 vs. 4.2 months), the treatment-naive subpopulation (median PFS 11.1 vs 2.8 months) and the cytokine-pretreated subpopulation (median PFS, 7.4 vs 4.2 months) [50]. Cross-over was permitted after PFS results became available and was widely employed. As such, the final OS analysis showed no significant OS advantage of pazopanib vs. placebo (22.9 versus 20.5 months, respectively = 0.224). Pazopanib has typical class effect toxicity including hypertension, fatigue and diarrhea. It is notable for a very low incidence of hand foot syndrome (6 % overall). Notably, however, there is an increased incidence of liver function abnormalities (grade 3 or higher ALT elevation in 12 %, AST elevation in 7 %). Pazopanib has been used in a refractory setting with increasing use in the front-line setting. The COMPARZ trial, a randomized trial of pazopanib versus sunitinib in previously untreated metastatic RCC demonstrated non-inferiority of pazopanib with some tolerability advantages, and thus pazopanib has also become a front-line standard of care [51].

Axitinib is a selective potent oral inhibitor of VEGFR1, 2 and 3, with greater potency against VEGFR compared to the other VEGFR inhibitors. Phase II studies data in refractory patients showed a high objective response arte and PFS [37, 38]. The subsequent phase III AXIS trial randomized clear cell mRCC patients who had progressive disease despite prior therapy with VEGF, mTOR inhibitors or cytokine-based therapy. Axitinib demonstrated a significantly longer PFS compared to sorafenib (6.7 months vs. 4.7 months; HR = 0.665; P < 0.0001) and a higher objective response rate (19.4 % vs. 9.4 %) [39]. These data support that more potent biochemical inhibition of VEGFR leads to enhanced clinical outcome. Common AEs including hypertension (40 %), fatigue (39 %), dysphonia (31 %), hypothyroidism (19 %) and hand-foot syndrome (27 %), typical for this class were observed. These data lead to regulatory approval of axitinib in refractory RCC.

The clinical activity of inhibitors of mammalian target of rapamycn (mTOR) in patients with a RCC demonstrates the relevance of this pathway. mTOR is an intra-cytoplasmic kinase regulated by a complex system of upstream and downstream elements including phosphoinositide 3-kinase (PI3K), Akt, and the tumor suppressor phosphatase and tensin homologue (PTEN). A serine/threonine kinase that regulates cell growth and metabolism in response to environmental factors, mTOR also regulates the angiogenic pathway through the HIF-1α and VEGF and is linked to endothelial proliferation [52, 53]. Thus, signal blockade of mTOR kinase will in interrupt stress response signals, prevent protein translation in cancer cells, and may also affect the VEGF-dependent angiogenic pathway. Aberrant activation of PI3K/Akt pathway has been observed in RCC and may correlate with a more aggressive tumor phenotype [54]. The therapeutic potential of inhibiting this pathway in RCC is now being explored. Although there are many mTOR inhibitors in development, temsirolimus and everolimus have advanced to phase 3 testing and are approved for advanced RCC.

Temsirolimus is an intravenous rapamycin derivative, and was approved by the FDA for treatment of patients with advanced RCC in May 2007. The pivotal phase III trial randomized 626 patients with poor-prognosis metastatic RCC (all histologic subsets) to receive temsirolimus (25 mg IV weekly), IFN-α (3–18 MU three times weekly) or a combination (temsirolimus 15 mg weekly + 6 MU IFN-α three times weekly) [40]. The primary study endpoint was overall survival. Patients receiving temsirolimus monotherapy demonstrated statistically longer survival than those treated with IFN-α (10.9 months for the temsirolimus group, 7.3 months in the IFN-α group; 0.73 hazard ratio; p = 0.0069) [40]. Comparison of the two groups receiving IFN-α ± temsirolimus did not demonstrated significant improvement in survival. The most common adverse effects reported were asthenia, rash, anemia, nausea, peripheral edema, hyperlipidemia and hyperglycemia. Retrospective radiologic review demonstrated temsirolimus related pneumonitis in 52/178 (29 %) evaluable patients receiving temsirolimus, and represents an important class-effect toxicity which the practicing oncologist should be aware of [55]. This study enrolled patients with metastatic RCC and at least 3 of 6 poor prognostic features (Karnofsky PS <80 %, time from diagnosis to randomization <12 months, serum LDH >1.5 ULN, Hemoglobin <LLN, corrected serum calcium >10 mg/dl and >1 metastatic site). Selection of these criteria was based on several prognostic factor analyses previously published [42, 56]. The rationale for this study in patients with multiple poor prognostic features was based on a retrospective analysis of phase II data suggesting efficacy in such a population [57]. Based on these results, temsirolimus is considered a first-line therapeutic option for patients with metastatic RCC who have poor risk prognostic features. Additionally, a retrospective analysis of histologic patient subsets suggests potential efficacy in the non-clear cell patients, although prospective validation is required [58]. An ongoing trial is randomizing non-clear cell RCC patients to either sunitinib or everolimus in the front-line setting.

Everolimus is an orally administered rapalogue, which was approved by the FDA in March 2009 for the treatment of advanced RCC patients who had failed previous therapy with either sorafenib, sunitinib or both. This was based on the clinical results from the RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily. A phase III, randomized, double-blind, placebo-controlled trial, accrued 416 advanced RCC patients with a component of clear cell histology, who had failed prior treatment with sorafenib, sunitinib, or both. Previous therapy with other agents such as cytokines or bevacizumab was also permitted. Patients were randomized in a 2:1 fashion to receive either everolimus 10 mg PO once daily (n = 277) or a placebo (n = 139). The primary endpoint was progression free survival, and the trial was stopped at the second interim analysis. By central review the median PFS for patients treated with everolimus was 4.9 months as compared with 1.9 months in the placebo group (HR 0.33, 95 % CI 0.25–0.43; p <0.001) [41, 59]. In the 124 patients previously receiving only sorafenib, the median PFS was 5.9 months for the everolimus group versus 2.8 months for the placebo group (HR 0.25; 95 % CI 0.16–0.42). In the 184 sunitinib patients, the median PFS was 3.9 versus 1.8 respectively (HR 0.34; CI 0.23–0.51). Response rates were low, with five everolimus (1.8 %) and no placebo patients having partial responses. Median overall survival was similar between the two groups (14.8 for everolimus arm versus 14.4 months for the placebo arm; HR 0.87; 95 % CI 0.65–1.15; p = .162). This endpoint was likely confounded by the crossover of patients with disease progression on placebo to open label everolimus. The most common adverse events reported were stomatitis (40 %), rash (25 %), fatigue (20 %), hypercholesterolemia (76 %), hypertriglyceridemias (71 %) and hyperglycemia (50 %). Pneumonitis was reported in 14 % compared with zero in the placebo group. Based on these data, everolimus is considered a therapeutic option for patients who have experienced disease progression on VEGF-targeted tyrosine kinase inhibitors. The precise timing of everolimus use (second-line versus later) is still under debate, as 79 % of patients in the phase III everolimus trial had received two or more prior systemic therapies. The role of these mTOR inhibitors in the treatment of renal cancer will continue to evolve. Both temsirolimus and everolimus are being studied or considered in multiple other clinical scenarios and therapeutic strategies including in combination regimens, sequential therapy with VEGF pathway inhibitors, the adjuvant setting, and in patients with non-clear cell histology.