Sequencing VEGFR-Targeted and mTOR-Targeted Therapy in Advanced Renal Cell Carcinoma

By Daniel C. Cho, MD
Published: Monday, Feb 02, 2015
Source: Friends of Cancer ResearchWith 8 therapies approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma (RCC), practitioners are faced with the challenge of selecting the most appropriate therapies for their patients within this crowded therapeutic landscape.

When selecting a treatment plan for a previously untreated patient with advanced RCC, practitioners must frequently think beyond the first line of therapy and approach the patient with a possible sequence of therapies already in mind. Sequential therapy with various single agents is a practical reality for most patients with advanced RCC for numerous reasons, including: (1) the availability of multiple molecularly targeted agents with distinct toxicities or mechanisms of action; (2) the fact that responses to molecularly targeted agents in RCC are typically neither complete nor durable; therefore treatment with these agents must be thought of as noncurative except in rare circumstances; and (3) the fact that combination regimens of available therapies have not demonstrated substantially improved efficacy. Therefore, the goal for the practitioner treating patients with advanced RCC must be to administer these agents sequentially so as to maximize duration of disease control and quality of life for individual patients.

Selection of First-Line Agents

Clear Cell RCC

Perhaps the first question a practitioner should address when faced with an untreated patient with advanced clear cell RCC is whether or not the patient is a candidate for immune therapy. Although the idea of sequential therapy is based upon the assumption that advanced RCC is incurable, it should be remembered that a subset of patients can experience durable remissions from immune therapy. In the current era, immune therapy with high-dose (HD) interleukin-2 (IL-2) is still frequently given to patients with RCC at specialized centers. While IL-2 has historically been felt to benefit only a small subset of patients, recent studies suggest that in the modern era response to HD IL-2 exceeds 25%, with approximately 8% to 10% of patients exhibiting complete responses that last for more than 2 years, although efforts to identify predictive biomarkers have not yet been successful.1 These improved results are most likely the result of limiting consideration of HD IL-2 to patients with certain characteristics, such as younger age, good performance status, few medical comorbidities, clear cell tumor histology, and disease that is not rapidly growing.

With respect to sequence, several clinical trials have shown that molecularly targeted therapies, both those targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), have substantial activity in cytokine-refractory patients.2-5 At the same time, a small retrospective study has suggested that the efficacy of HD IL-2 following VEGF–targeted therapies may be limited.6 While the latter point must be proven prospectively, these data support the premise that HD IL-2 should be considered a primary therapy for appropriately selected patients with advanced RCC.

While first-line treatment with immune therapy outside of a clinical trial is currently limited to HD IL-2, the early clinical activity reported with PD-1 and PD-L1 antibodies suggests that this might change in the near future.7-10 These novel immunotherapies have shown activity in multiple clinical scenarios, however, so their eventual place in sequential therapy regimens remains unclear at present. Moreover, the durability of responses to these novel agents has yet to be fully characterized. Nonetheless, the fact that treatment with VEGF- or mTOR-targeted agents so infrequently results in durable or complete remissions supports the approach that a regimen containing an immune therapy should at least be considered first line in all patients with clear cell RCC.

Once it is determined that a patient is not a candidate for immune therapy, the practitioner must select from several different FDA-approved agents characterized by 2 broad classes: (1) VEGF-targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab [plus interferon-alfa (IFN)]); and (2) mTOR inhibitors (temsirolimus) (Figure 1). Two other agents, the VEGF-targeted tyrosine kinase inhibitor (TKI) axitinib and the mTOR inhibitor everolimus, are approved only following failure of at least 1 prior therapy. The practitioner’s next decision point is affected by the assessment of the patient’s prognosis. Currently, the National Comprehensive Cancer Network (NCCN) gives a category 1 recommendation to sunitinib, pazopanib, and bevacizumab/interferon, along with a category 2A recommendation to sorafenib, for the first-line treatment of patients with predominantly clear cell advanced RCC.11

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