Two phase III international randomized trials of sunitinib (Sutent) and of the investigational mTOR kinase inhibitor temsirolimus indicate targeted therapy may provide both clinical and survival benefits to patients with advanced renal cell carcinoma (RCC). Sunitinib is an oral multi-targeted receptor tyrosine kinase inhibitor of the VEGF and PDGF receptors.
ASCOTwo phase III international randomized trials of sunitinib (Sutent) and of the investigational mTOR kinase inhibitor temsirolimus indicate targeted therapy may provide both clinical and survival benefits to patients with advanced renal cell carcinoma (RCC). Sunitinib is an oral multi-targeted receptor tyrosine kinase inhibitor of the VEGF and PDGF receptors. Both drugs combat increased tumor angiogenesis, a hallmark of RCC. The studies were reported as late-breaking presentations at the 42nd Annual Meeting of the American Society of Clinical Oncology.
Sunitinib Phase III Protocol
In a planned interim analysis of the 750-patient study of sunitinib as first-line treatment of metastatic RCC, the agent yielded strong clinical responses, compared with interferon-alfa (INF-α) (abstract LBA3), said lead author Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University. Patients were randomized 1:1 to receive sunitinib in 6-week cycles, 50 mg orally once daily on a 4-weeks-on/2-weeks-off schedule, or IFN-α subcutaneously three times weekly in 6-week cycles, with the dose escalating from 3 to 9 MU over 3 weeks.
Median progression-free survival (PFS) as assessed by independent central review was 11 months for sunitinib vs 5 months for IFN-α (HR 0.415, P < .000001), and "nearly identical values" were noted by the investigators (11 months vs 4 months), Dr. Motzer reported. The objective response rate by RECIST was 31% for sunitinib vs 6% for IFN-α by third-party independent review of imaging studies, and 37% vs 9% by investigator assessment (P < .000001 for both assessments). Treatment benefits with sunitinib were realized across both high- and low-risk patient subgroups, Dr. Motzer emphasized. Median overall survival data are not yet mature, with only 114 survival events (HR 0.65 in favor of sunitinib, P = .0219).
Sunitinib was associated with more grade 3 neutropenia and thrombocytopenia, but only two patients were hospitalized for febrile neutropenia, Dr. Motzer said. Both agents were associated with fatigue, with a higher incidence of grade 3-4 fatigue seen with IFN-α. The incidence of hypertension, diarrhea, and hand-foot syndrome was higher with sunitinib, but the overall incidence of grade 3-4 adverse events was lower, and patients experienced a better quality of life on study with sunitinib vs IFN-α.
In conclusion, Dr. Motzer said, "sunitinib is the new reference standard for the first-line treatment of metastatic renal cell cancer... [and it] provides new hope for patients with metastatic RCC."
Global ARCC Trial
A planned interim analysis of the 626-patient phase III open-label Global ARCC (Advanced Renal Cell Carcinoma) trial showed a survival advantage with first-line temsirolimus in patients with advanced, poor-prognosis RCC, compared with IFN-α alone (abstract LBA4), reported Gary R. Hudes, director, Genitourinary Malignancy Program, Fox Chase Cancer Center. Patients with stage IV or recurrent RCC and at least three of six poor-risk features were randomized to three arms: IFN-α 3 MU escalating up to 18 MU, subcutaneously three times a week ; temsirolimus 25 mg IV once a week; or a combination of temsirolimus 15 mg once a week plus IFN-α 6 MU three times a week. The study was designed to compare the overall survival of patients in each of the temsirolimus-containing arms with those in the IFN-α alone arm.
As of March 15, 2006, there were 442 deaths. Median overall survival was 7.3 months for IFN-α, 10.9 months for temsirolimus, and 8.4 months for the combination; this translated to an increase in median survival of 49% for temsirolimus alone vs IFN-α (HR 0.73, P = .0069) and 15% for the combination vs IFN-α (HR 0.95, P = .6912). "This study demonstrates the first significant survival advantage for a new agent in metastatic renal cell carcinoma," Dr. Hudes said. Median PFS was 1.9 months for IFN-α, 3.7 months for temsirolimus alone, and 3.7 months for the combination, for a 95% improvement in median PFS with temsirolimus (P = .0001 for temsirolimus vs IFN-α and P = .0019 for the combination vs IFN-α).
Asthenia, the most common severe adverse event, was seen more often with IFN-α Dr. Hudes reported. Mild-to-moderate rash, peripheral edema, and stomatitis were more common with temsirolimus. Anemia, neutropenia, and thrombocytopenia were more common with the combination.
"Hyperglycemia and hyperlipidemia were greater in the temsirolimus-alone and combination arms, probably reflecting inhibition of mTOR-regulated glucose and lipid metabolism," Dr. Hudes said. He pointed out that significantly fewer patients in the temsirolimus-alone arm had any grade 3-4 adverse event69% vs 85% of IFN-α patients and 87% of combination patients.
Dr. Hudes noted that in this study, responses were seen in a population "whose cancer was so advanced that they would not qualify for most other clinical trials." Given that the current trial has shown mTOR to be "an important therapeutic target in renal cell carcinoma," he said, future trials "may further benefit patients with metastatic RCC by using temsirolimus in combination with agents that target VEGF and its receptor."