Renal cell carcinoma (RCC), the most common form of kidney tumor, accounts for up to 92% of all cases of kidney cancer . In the United States alone, an estimated 64,770 new cases of renal tumors are expected to be diagnosed during 2012, which will ultimately attribute to 13,570 deaths . The incidence of kidney cancer in China is low, compared with the average global incidence rate (2.1 vs 4.0 per 100,000) . However, the incidence of and death rate from kidney cancer in China has risen during recent years .
Surgery forms the primary standard of care for most localized kidney cancers . However, one third of patients who undergo surgery for localized disease will experience recurrence and approximately a quarter of patients have locally invasive or metastatic RCC (mRCC) at the time of diagnosis . In such settings, targeted agents have been shown to afford significant clinical benefit with acceptable safety [5–11]. The vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib and sorafenib are approved in China for first-line treatment of patients with mRCC.
Sequential lines of therapy are typically required to maintain clinical benefit in patients with mRCC. Clinical practice guidelines in the United States and Europe recommend targeted agents or cytokines for first- and subsequent-line treatment of patients with mRCC [12–15]. VEGF-targeted agents are recommended as first-line therapy for the majority of patients (those who are at low or intermediate risk). Everolimus is recommended for patients who fail initial VEGFr-TKI therapy and axitinib for patients who fail previous systemic therapy. Although there are currently no approved therapies in China for the treatment of patients with mRCC refractory to VEGFr-TKIs, local clinical practice guidelines recommend everolimus for this patient population.
The PI3K/AKT/mTOR pathway is dysregulated in many cancers, including RCC . mTOR is a serine/threonine kinase that binds specifically to the FK506 binding protein 12 (FKBP12)-rapamycin complex . mTOR is activated by components of the PI3K pathway and tuberous sclerosis complex (TSC) and regulates protein synthesis required for cell growth and proliferation, metabolism, and angiogenesis . Overactivation of mTOR signaling occurs via a number of mechanisms, including overexpression or activation of growth factor receptors, activating mutations in PI3K/AKT, or decreased expression of TSC . Overproduction of VEGF and other growth factors in tumor cells leads to activation of mTOR signaling in neighboring endothelial cells, thereby increasing angiogenesis . Inhibition of mTOR signaling results in decreased cell growth and proliferation, cellular metabolism, and angiogenesis, ultimately leading to cell cycle block at the G1 phase . The mTOR inhibitor everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits the mTOR serine-threonine kinase .
Everolimus has been evaluated in patients with cancer in multiple clinical studies. Phase 1 PK/PD studies demonstrated that continuous daily dosing with everolimus 10 mg resulted in a more profound and sustained inhibition of mTOR than that achieved with a weekly dosage schedule [20, 21]. Anti-tumor activity of everolimus 10 mg daily was shown in a phase 2 trial of patients with mRCC [22, 23], and results of the phase 3 RECORD-1 study demonstrated a progression-free survival (PFS) benefit of everolimus 10 mg daily over placebo in patients with VEGFr-TKI–refractory mRCC (4.9 vs 1.9 months; HR 0.33; 95% CI, 0.25-0.43; P < .001) . In addition, pharmacodynamic modeling of tumor growth in patients enrolled in RECORD-1 demonstrated that everolimus 5 mg daily and 10 mg daily significantly slowed the growth of mRCC target lesions, non-target lesions, and new metastases compared with placebo (P < .001) [24, 25].
A phase 1 study in Chinese patients with advanced solid tumors (N = 24), including mRCC (n = 6), was conducted to specifically evaluate the efficacy and safety of everolimus in a Chinese population . Results demonstrated that everolimus doses of 5 mg and 10 mg daily were well tolerated, and 67% of patients experienced stable disease as their best overall tumor response . Median duration of everolimus exposure for patients with mRCC was 26.4 weeks (6.1 months). Herein, we report results of a larger study of everolimus in Chinese patients with mRCC.