Current Therapeutic Approaches to Renal Cell Carcinoma

Case Continued

Based on the MSKCC prognostic factor model, the patient is deemed to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

• What is the appropriate first-line therapy in managing this patient’s metastatic disease?

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology [57,58]. In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus [59]. Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option [21].

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features [60]. Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response [61]. A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient [62].

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients [63].

Biologics

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology [64]. Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients [65].

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study [66,67]. However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

VEGF Monoclonal Antibodies

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo [68]. In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SQ] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001) [47,48]. Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

Tyrosine Kinase Inhibitors

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib. Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues [52,53] compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SQ 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy [69–71].

Pazopanib. Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4% [72]. This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy [50]. In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib. Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy [73]. A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029) [51]. Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib. Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving one prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted [74]. In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2) [46]. The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

Cabozantinib

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a randomized, open label, phase 3 trial of cabozantinib versus everolimus in advanced RCC, Choueiri and colleagues [75] compared the efficacy of cabozantinib with everolimus in patients with metastatic RCC who had progressed on previous VEGFR-targeted therapies. In this study, 658 patients were randomly assigned to receive cabozantinib (60 mg orally daily) or everolimus (10 mg orally daily). Results of the study found that PFS was longer with cabozantinib in patients who had previously been treated with other TKIs (median PFS of 7.4 months versus 3.8 months; HR 0.58), corresponding to a 42% reduction in the rate of disease progression or death. The most common grade 3 and 4 toxicities seen with cabozantinib were similar to its class effect and consisted of hypertension, diarrhea, and fatigue. In the final analysis of the data, the median overall survival was 21.4 months (95% CI 18.7–not estimable) with cabozantinib and 16.5 months (95% CI 14.7 to 18.8) with everolimus (HR 0.66; 95% CI 0.53 to 0.83; P = 0.00026). The median follow-up for overall survival and safety was 18.7 months. These results highlight the importance of cabozantinib as a first line option in treatment of previously treated patients with advanced RCC [76].

mTOR Inhibitors

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis [77]. Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model) [54]. The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SQ 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SQ 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hypercholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.