Targeted Therapy: A Treatment Advance in Renal Cell Carcinoma
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42nd Annual Meeting of the American Society of Clinical Oncology
Atlanta, Georgia / June 2-6, 2006
An updated analysis of the TARGETs (Treatment Approaches in Renal Cancer Global Evaluation Trial) presented here during the scientific sessions confirmed an overall survival advantage for the tyrosine kinase inhibitor (TKI) and serine/threonine kinase inhibitor sorafenib compared with placebo in patients with advanced renal cell carcinoma. TARGETs is a randomized, double-blind, placebo-controlled trial that included 903 patients with advanced renal cell carcinoma and clear cell histology who failed one prior systemic therapy within the past 8 months.
The first planned survival analysis showed a 39% survival benefit for sorafenib compared with placebo. Median overall survival was 14.7 months with placebo but had not yet been reached for sorafenib at the time of the first planned analysis. Progression-free survival was twice as long in the treatment cohort at 24 weeks compared with 12 weeks for placebo (P<0.000001). The trial was unblinded due to the positive results and placebo patients were offered the option of crossing over to sorafenib. Response rate was 2%, which suggested that tumour shrinkage by classical criteria may not be correlated with slowing disease progression.
According to Dr. Walter Stadler, Director, Genitourinary Oncology Program, University of Chicago, Illinois, although the degree of tumour shrinkage is often modest with sorafenib, 74% of patients in the active-treatment arm of TARGETs showed some degree of tumour shrinkage and the agent was well tolerated in the study. Major grade 3 and 4 toxicities were hand-foot syndrome (6%) and hypertension (4%). Other toxicities, mainly mild to moderate, included fatigue, rash and diarrhea. “Hypertension is underestimated in phase III trials of vascular endothelial growth factor (VEGF) inhibitors; up to 70% of patients treated with these agents have hypertension,” Dr. Stadler confirmed. He added that hypertension is an acceptable side effect in patients with metastatic disease, but probably not in the adjuvant setting. “In earlier-stage patients, we can treat the hypertension,” he told delegates.
Other study results discussed here showed that blood pressure (BP) elevation is a biomarker for agents that inhibit the VEGF signalling pathway. Dr. Michael L. Maitland, Section of Hematology/Oncology, University of Chicago, who reported these results, said that the known variability in total sorafenib plasma concentrations at steady state did not account for the observed variability in BP response seen in this study of 30 patients with advanced renal cell carcinoma treated with sorafenib 400 mg b.i.d.
TARGETs: Updated Survival Data
As reported by Dr. Tim Eisen, medical oncologist, Lung Unit, Royal Marsden Hospital, London, UK, overall survival was maintained from the time of the first planned analysis, with overall survival of 19.3 months for sorafenib vs. 15.9 months for placebo (P=0.015, hazard ratio [HR] 0.77) at six months’ post-crossover, despite the potential confounding of crossovers in the trial. Almost 50% of the original placebo patients (n=216/452 patients) crossed over to active treatment after April 2005, when the trial was unblinded. After censoring the placebo patients, overall survival was 19.3 months for the active-treatment cohort vs. 14.3 months for placebo (P=0.010, HR 0.74).
These data show a favourable trend toward survival with sorafenib in advanced renal cell carcinoma. “Consider these data preliminary, although they are highly encouraging,” Dr. Eisen suggested, adding that these results were consistent with the first planned analysis. “Patients treated with sorafenib lived longer than those taking placebo, even though almost 50% of placebo patients crossed over to sorafenib. These preliminary data are encouraging and we await the final analysis.” The final analysis of overall survival is planned when 540 events occur.
Remarked Dr. David I. Quinn, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, “TARGETs is an important trial. Sorafenib has a survival advantage over placebo. Survival is survival, even though results so far do not quite meet the criteria for statistical significance. The study suggests that timing of initiation of sorafenib may not be critical, since crossover patients also enjoyed a benefit.” He also pointed out that sorafenib “plays well with other drugs” and is a good building block for combination regimens. “Studies of angiogenesis inhibitors combined with the best immunotherapy should be a priority,” he stated.
Findings from Other Studies
The mTOR inhibitor temsirolimus showed improved overall survival and progression-free survival compared with standard interferon alpha (IFNa) as first-line therapy in 626 poor-risk patients with metastatic renal cell carcinoma, according to a second planned interim analysis of a phase III trial presented here by Dr. Gary Hudes, Fox Chase Cancer Center, Philadelphia, Pennsylvania. It improved median overall survival by 3.6 months (49% improvement over standard therapy) and median progression-free survival by 1.8 months (95% improvement over standard therapy). The compound also appeared to be better tolerated than IFNa, with a 16% reduction in the proportion of grade 3 and 4 adverse events.
Another phase III trial reported here at ASCO showed that the multitargeted TKI sunitinib was more efficacious than standard therapy with IFNa. Results presented by Dr. Robert Motzer, Memorial Sloan-Kettering Cancer Center, New York, showed longer median progression-free survival at 11 months vs. 5 months (P<0.00001, HR 0.42) in previously untreated metastatic renal cell carcinoma patients with good performance status and favourable risk factors. An interim survival analysis using data from 15% of participants favoured sunitinib vs. IFNa (P=0.02, HR 0.65), although median survival has not been reached for either group and longer follow-up is needed. The most frequent grade 3 and 4 toxicities with sunitinib were lymphopenia (12%), neutropenia (11%), thrombocytopenia (8%), fatigue (7%) and hypertension (5%); 8% of sunitinib-treated patients discontinued therapy.
Targeted therapy should now be considered standard therapy and a reference agent against which new therapies should be compared in treatment of advanced renal cell carcinoma. The two oral agents currently in use for this indication, sorafenib and sunitinib, have demonstrated improved progression-free survival in previously-treated and previously untreated patients. A survival advantage has been demonstrated for sorafenib, at both the pre-crossover and post-crossover analyses, and also in an early analysis for sunitinib, although longer follow-up will be needed to confirm this interim finding. The mTOR inhibitor temsirolimus has been shown to improve overall survival in patients with advanced renal cell carcinoma and poor-risk features.
Future studies are needed to determine the optimal use of these new targeted therapies in combination with cytokines, with each other and with other targeted therapies. Even though further research is needed, clinicians may now offer improved treatment choices for patients with advanced kidney cancer. As summarized by Dr. Michael V. Atkins, Deputy Director, Cutaneous Oncology and Biologic Therapy Programs and Clinical Research, Beth Israel Deaconess Medical Center, and Professor, Department of Medicine, Harvard Medical School, Boston, Massachusetts, “This is a banner day for patients with advanced renal cell carcinoma.”