Current Therapeutic Approaches to Renal Cell Carcinoma

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.