Advances in the treatment of advanced renal cell carcinoma and GIST

The drugs sunitinib and temsirolimus showed impressive results in treating advanced disease that had a traditionally poor prognosis.

Issue: December 1, 2006

At the 2006 ASCO Annual Meeting researchers showed that the multitargeted therapy sunitinib was superior to conventional interferon-alfa in the first-line treatment of metastatic renal cell carcinoma.

“This is the first demonstration of a benefit over cytokine treatment in a randomized phase-3 trial,” said lead researcher Robert John Motzer, MD, from Memorial Sloan-Kettering Cancer Center in New York, at an ASCO press briefing. “Sunitinib [Sutent, Pfizer] is the new reference standard for the first-line treatment of metastatic [renal cell carcinoma].”

Patient responses to conventional second-line therapy have been modest, at best. In a previous trial, 3% of 113 patients with renal cell carcinoma (RCC) responded to cytokine therapy. First-line trials have made substantial improvements in response, with objective rates of 11% with interferon-alfa and 14% with high-dose interleukin-2.

In their phase-3 trial, Motzer and colleagues used sunitinib as first-line therapy for 750 patients with clear cell histology and metastatic disease. Patients were randomized patients (375 per arm) to receive either sunitinib or interferon-alfa.

The differences in response between the conventional therapy and sunitinib groups were significant. Of the 327 patients treated with interferon-alfa, only 6% achieved an objective response. Thirty-one percent of the 335 evaluable patients in the sunitinib arm achieved an objective response. None of the patients in either arm achieved a complete response to treatment. More patients in the interferon-alfa arm experienced disease progression: 45% vs. 21% in the sunitinib arm (P<.001).

Sunitinib in GIST

At the 2006 Gastrointestinal Cancers Symposium in San Francisco, George D. Demetri, MD, director for the Center for Sarcoma and Bone Oncology at the Dana Farber Cancer Institute in Boston, showed that sunitinib was safe and effective therapy for patients who have failed imatinib (Gleevec, Novartis) as a front-line therapy for advanced gastrointestinal stromal tumors (GIST).

Interim data from Demetri’s double-blind, placebo-controlled phase-3 trial revealed a greater than 70% reduction in the relative risk of disease progression (P<.001). Time to progression was 6.3 months for patients in the sunitinib arm vs. 1.5 months for patients in the placebo arm. Following these results, all patients in the placebo arm crossed over to the sunitinib arm. There was also a significant survival benefit associated with sunitinib, Demetri said, as sunitinib decreased the relative risk of death by 51% (P<.006). The median overall survival had not yet been reached.

mTOR inhibitor temsirolimus

At ASCO, Hudes and colleagues showed that monotherapy with 25 mg of IV temsirolimus (CCI-779, Wyeth) each week significantly improved overall survival of patients with metastatic renal cell carcinoma and poor-risk features compared with interferon, according to second interim analysis results of the Global Trial for Advanced Renal Cell Carcinoma, or ARCC.

Hudes said these data build a strong case for 25 mg of weekly temsirolimus as a standard therapy for patients with renal cell carcinoma (RCC) and at least three poor-risk features, which include Karnofsky performance status 60 to 70, anemia, high serum lactate dehydrogenase, elevated serum calcium level, time from diagnosis within one year and two or more organ sites of metastatic disease.

The ARCC trial compared temsirolimus with interferon in 629 patients with poor risk, metastatic RCC. Researchers randomized patients to three treatment arms: 207 patients received up to 18 million units of subcutaneous interferon therapy, three times a week; 209 patients received 25 mg of weekly IV temsirolimus; and 210 patients received 15 mg of weekly IV temsirolimus plus 6 million units of subcutaneous interferon, three times a week. The primary endpoint was overall survival.

Compared with the interferon arm, temsirolimus therapy and the combination therapy led to median increases in survival of 49% (P=.0069) and 15% (P=.6912), respectively. Patients receiving single agent temsirolimus survived for a median of 3.6 months longer than patients receiving interferon, with overall survival durations of 10.9 and 7.3 months, respectively.

Editors’ notes: The results reported by Motzer and colleagues represent an important step forward in the development of improved therapies for patients with RCC. Sunitinib and related compounds appear to make a substantial impact on the outcome in RCC and this study provided strong support for that concept. While an impact of sunitinib on survival may be difficult to discern from Motzer’s study because of crossover, there is clear evidence of an important treatment effect. This is among the first studies to demonstrate a substantial effect of systemic therapy in advanced RCC.

The ASCO study of temsirolimus indicates important antitumor activity of another class of small molecules in advanced RCC. After decades of frustrating attempts to discover agents with activity in this disease, this is surely an exciting time. The precise mechanisms of action of agents such as this may be more complex than they may initially appear. However, when compared head to head with the “standard” therapy (interferon), an agent with which no one has been happy with for 20 years, the results are very encouraging. There is finally good news developing in the quest to develop effective therapy for patients with RCC. – Donald L. Trump, MD, FACP

What is so incredibly important about the work of Demetri and colleagues is that it shows that understanding mechanisms of resistance to a targeted cancer agent can rapidly lead to new drugs for patients with resistance. It is truly remarkable that less than four years after the approval of imatinib for GIST, a second drug is now available for patients who have relapsed during imatinib therapy. – Brian J. Druker, MD

For more information:

Demetri G, van Oosterom AT, Garrett C, et al. Improved survival and sustained clinical benefit with SU11248 (SU) in pts with GIST after failure of imatinib mesylate (IM) therapy in a phase III trial. Abstract 8. Presented at: 2006 Gastrointestinal Cancers Symposium; Jan. 26-28, 2006; San Francisco.

Hudes G, Carducci M, Tomczak P, et al. Interim results of a phase 3 study of temsirolimus (TEMRS) or interferon-alpha (INF) of the combination of TEMRS + INF in the treatment of poor-risk patients with advanced renal cell carcinoma. LBA4. Presented at: 2006 ASCO Annual Meeting; June 2-6, 2006; Atlanta.

Motzer RJ, Hutson TE, Tomczak P, et al. Phase 3 randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. LBA 3. Presented at: 2006 ASCO Annual Meeting; June 2-6, 2006; Atlanta.