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The integration of novel biologic agents in the treatment of renal cell carcinoma (RCC) is proceeding at a fast pace, based on the improvements in response rates and progression-free survival observed with two novel agents, sorafenib (Nexavar) and sunitinib (Sutent), said Robert J. Motzer, MD, from Memorial Sloan-Kettering Cancer Center in New York. “We can’t yet tell if one of these agents is a winner over the other, as it is hard to compare trials, but there clearly is progress over cytokine treatment in RCC,” Dr. Motzer reported.
Sorafenib and sunitinib have demonstrated strong clinical
benefit in patients with cytokine-resistant RCC. In the first-line setting,
suitable patients should still be offered the option of high-dose interleukin-2
(IL-2, aldesleukin [Proleukin]), but treatment with these biologics is now an
acceptable option and may, in fact, become preferred for most patients with
metastatic disease, Dr. Motzer suggested.
Nearly 40,000 persons are diagnosed with RCC each year in the United States. Up to one-half develop metastases, for which there is no effective treatment. The poor long-term survival has made drug discovery for this neoplasm “the highest priority,” he said.
In 1992, high-dose IL-2 was approved by the US Food and Drug Administration (FDA) for treatment of RCC. This approval was based on complete response rates of 7%–9%, including a durable complete response in 4%–5% of patients. However, IL-2 has not improved survival, must be administered by experienced clinicians in specialized centers, and requires intensive supportive care. “With 20 years of experience, high-dose IL-2 continues to be given to only a minority of patients with metastatic RCC,” Dr. Motzer said.
By combining IL-2 with interferon alfa, it has been possible to increase clinical response rates, although median survival is not significantly improved, and toxicities have worsened with the combination.
Four targeted agents are in various stages of clinical trials. The anti-VEGF (vascular -endothelial growth factor) agent bevacizumab (Avastin) is being combined with interferon alfa in patients with metastatic RCC in the CALGB 90206 study (n = 700) and in the BO17705 trial (n = 638). The mTOR inhibitor temsirolimus (CCI-779) is being evaluated as first-line treatment in high-risk patients with advanced RCC (n = 600). Clinical trials are furthest along for the orally administered tyrosine kinase inhibitors sorafenib and sunitinib.
In the Sorafenib Randomized Discontinuation Trial (RDT), patients who responded to sorafenib at 12 weeks (³ 25% tumor shrinkage) continued to receive this drug; those with stable disease were randomized to receive continued treatment or placebo. A significant improvement in progression-free survival after randomization was achieved with sorafenib—a median of 24 weeks versus 6 weeks with placebo (P = 0.0087; Ratain MJ et al. J Clin Oncol 23[suppl]:389s, 2005. Abstract 4544).
The RDT led to the pivotal study of sorafenib, the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs), which randomized 905 patients with advanced RCC to receive 400 mg bid of sorafenib or placebo (Escudier B et al. European Cancer Conference, October 30–November 3, 2005; Paris, France. Abstract 794).
Effect of sorafenib on progression-free survival, based on investigator assessment, in TARGETs. Adapted from Escudier B et al. European Cancer Conference, 2005. Abstract 794.
In TARGETs, progression-free survival was 5.5 months with sorafenib vs 2.8 months with placebo, for a nearly 50% reduction in risk. In a planned interim analysis conducted after 220 events, the overall survival was 14.7 months with placebo but had not been reached for sorafenib, a 28% reduction in risk with sorafenib (P = 0.018), which was considered a strong trend.
Based on these encouraging findings, sorafenib is being integrated into multiple experimental approaches for metastatic RCC: adjuvant/neoadjuvant settings, monotherapy for untreated patients, standard cytokine regimens, targeted therapies, and chemotherapeutic regimens.
Sunitinib has been evaluated in two independent, single-arm, multicenter phase II trials. In trial 014 (n = 63) and trial 1006 (n = 106), patients with advanced disease for whom prior cytokine therapy failed received sunitinib (4 weeks on, 2 weeks off) until disease progression or intolerability.
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| Dr. Motzer |
In the pooled analysis of the trials (by independent review), partial responses were observed in 42% of patients and disease stabilization in 24%, outcomes that Dr. Motzer called “unprecedented in this disease.” For the combined -trials, median progression-free survival was 8.2 months, compared with 2.5 months for historic controls.
With both sorafenib and sunitinib, tumor shrinkage occurs early, and responses may last more than 12 months. Both agents are generally well tolerated. Hand-foot syndrome is the primary adverse effect, occurring in approximately 30% of patients, although grade 3/4 events are uncommon. Events are usually manageable with dose reductions or delays. Although fatigue is common with these agents and a higher proportion (38%) of grade 2 or 3 fatigue is observed in patients with sunitinib, patients recover during periods off the drugs. A small proportion of patients (7%–11%) receiving sunitinib experience slight declines in left ventricular ejection fraction.
The interim analysis of a phase III trial of sunitinib versus interferon alfa as first-line treatment of metastatic RCC in 690 patients is expected to be reported at ASCO 2006.
Additional trials will evaluate sunitinib together with bevacizumab, gefitinib (Iressa), or interferon alfa.
Both sorafenib and sunitinib substantially prolong progression-free survival, Dr. Motzer concluded. At this point, clinicians will probably select one over the other based on their familiarity with the agents.