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Sunitinib and Sorafenib Ineffective as Adjuvant Therapies for Kidney Cancer

, by NCI Staff

Anatomy of the male urinary system (left panel) and female urinary system (right panel).

Results from a recent clinical trial show that adjuvant therapy with sunitinib (Sutent) or sorafenib (Nexavar) does not improve progression-free survival for patients with renal cell (kidney) cancer and may cause serious side effects.

Findings from the randomized, double-blind, placebo-controlled trial were published March 8 in The Lancet.

Answering an Open Question

Both sunitinib and sorafenib target proteins on cancer cells that promote tumor angiogenesis—the formation of new blood vessels that are needed to fuel tumor growth beyond a certain size.

“These agents have been very useful and have helped control disease in patients with metastatic renal cell carcinoma. But we didn’t know if there was a benefit to using them in the adjuvant setting,” for localized disease, said lead author Naomi Haas, M.D., of the University of Pennsylvania Abramson Cancer Center.

To answer this question, the trial investigators randomly assigned 1,943 patients from 226 treatment centers across the United States and Canada to receive 54 weeks of sunitinb, sorafenib, or a placebo. All patients had renal cell cancer that was amenable to surgery but were at high risk of recurrence. The main endpoint of the trial was disease-free survival, defined as the time from randomization to cancer recurrence, development of a second primary cancer, or death from any cause.

During the first 3 years of the trial, side effects in the sunitinib and sorafenib arms, including hand-foot syndrome and high blood pressure, occurred more often than expected, leading almost half of patients in those groups to discontinue treatment early.

In response, the researchers changed the trial protocol, lowering the dose of both drugs at the start of therapy and then increasing to a full dose if no or only low-grade side effects occurred for the first few treatment cycles. The change in dosing reduced the rates of discontinuation for both the sunitinib and sorafenib arms to 34 percent and 30 percent, respectively.

After a median follow-up period of 5.8 years, disease-free survival was similar in all three groups: 70 months in the sunitinib group, 73.4 months in the sorafenib group, and 79.6 months in the placebo group. Overall survival also did not differ between the groups.

No Target, No Benefit?

“The results of this study argue strongly against the use of anti-angiogenic therapy in the adjuvant setting of patients with primary resected renal cell carcinoma,” the authors wrote.

Sunitinib and sorafenib were approved in the mid-2000s to treat patients with metastatic renal cell cancer. Since that time, many doctors have also been using them in the adjuvant setting, explained Dr. Haas, with the hope that it will help prevent disease recurrence.

“I think that [these results are] going to put a stop to what has been going on in the clinic,” she added.

The lack of effect in the adjuvant setting suggests that small cancer deposits—called micrometastases—may not rely on angiogenesis to survive, unlike larger metastatic tumors, the authors explained.

If correct, this idea may help explain the high rate of side effects seen in the trial, said Dr. Haas. “These drugs actually might be more toxic in the adjuvant setting because there are no angiogenic targets for [them] to hit,” leading to more off-target interactions and, therefore, more side effects, she said.

This concept has led her team to propose a new trial design for adjuvant use of targeted drugs in patients with operable renal cell cancer. With the new trial design, doctors would administer the drugs prior to surgery (often called neoadjuvant  therapy), when tumor tissue with the selected target remains in the body. A trial of nivolumab (Opdivo), an immune checkpoint inhibitor, for renal cell cancer using this design is in the planning process.

“The current study has clearly demonstrated that the adjuvant use of sorafenib or sunitinib provides no survival advantage for these patients,” said Marston Linehan, M.D., chief of the Urologic Oncology Branch in NCI’s Center for Cancer Research. “These findings provide clarity for patients and their families, as well as for their physicians, and reinforce our efforts to develop more effective forms of therapy for patients with advanced kidney cancer.”

Although the trial did not show the hoped for results, the findings are no less important for informing patient care, agreed the study authors.

“Even though [the trial] did not establish a role for sorafenib or sunitinib in the adjuvant setting, its placebo-controlled design has provided a definitive answer that will help to prevent costs and toxic effects associated with inappropriate use of these agents,” they concluded.

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