Sorafenib, Sunitinib Fail in Phase III Adjuvant RCC Trial

Author(s):

Neither sorafenib nor sunitinib improved outcomes when administered after surgery to patients with locally advanced renal cell carcinoma (RCC), according to results from the phase III ASSURE trial, which were presented at a presscast held ahead of the 2015 Genitourinary Cancers Symposium.

Naomi B. Haas, MD

Median disease-free survival (DFS) was 5.6 years in both the sorafenib and sunitinib arms and 5.7 years in the placebo arm.

“The use of multitargeted VEGF tyrosine kinase inhibitors (TKIs), including sunitinib and sorafenib, in advanced disease, has provided benefit by way of disease control in thousands of patients,” Naomi B. Haas, MD, associate professor, Abramson Cancer Center of the University of Pennsylvania, said.

“The current standard of care, however, for patients with resected non-metastatic disease is close observation, with scans performed at regular intervals.”

The question then, Haas said, was whether either of these VEGF inhibitors could provide benefit for patients with resected primary disease in the adjuvant setting.

In this analysis, the 5-year DFS rate was 52.8% in the sorafenib arm (HR = 0.98; 97.5% CI, 0.81-1.19), 53.8% in the sunitinib arm (HR = 1.01; 97.5% CI, 0.83-1.23), and 55.8% in the placebo arm. In total, there were 272, 265, and 270 DFS events observed in the sorafenib, sunitinib, and placebo arms, respectively.

Following complete resection, 1943 patients (pT1b high grade to pT4 any grade disease, any node involvement) were classified based on risk (intermediate-high or very high), clear or non-clear histology, ECOG performance status, and surgery approach. Patients were then randomized 1:1:1 to receive one of the two VEGF inhibitors or placebo for one year. Sorafenib was administered daily and sunitinib was administered daily for 4 weeks of a 6-week cycle.

The trial’s primary endpoint was DFS and was designed to find an improvement from 5.8 to 7.7 years (HR = 0.25). Secondary endpoints focused on overall survival (OS) and side effects of prolonged administration.

At an interim analysis, the Data Safety Monitoring Committee recommended release of the results, though no efficacy or futility boundaries were crossed. Patients in the sorafenib and sunitinib arms received a median of 8 cycles of therapy (range 1-9), while patients in the placebo arm received a median of 9 cycles (range 1-9).

Patients on all three arms did better than what was expected, Haas noted.

OS rates were similar between all three arms. Five-year OS rates were 80.7% in the sorafenib arm (HR = 0.93; 97.5% CI, 0.69-1.23), 76.9% in the sunitinib arm (HR = 1.10; 97.5% CI, 0.83-1.45), and 78.7% in the placebo arm.

The most common grade ≥3 adverse events observed on the trial were hypertension (16%, 16%, 4%), hand-foot reaction (33%, 15%, 1%), rash (15%, 2%, 1%), and fatigue (7%, 17%, 3%), for sorafenib, sunitinib, and placebo, respectively.

“It’s important to point out that TKIs are not chemotherapy,” Ryan said. “They act in a different manner and therefore they may not be as effective against micrometastatic disease as chemotherapy is in other solid tumors.”

While no benefit was seen between the entire arms in this trial, Haas said, further analyses could reveal differences among smaller subsets of patients.

Beyond that, other trials (such as ATLAS looking at axitinib and SORCE looking at sorafenib) are focused on questions concerning duration of treatment.

Ryan said even a negative study such as ASSURE, which was the first and largest of its kind, can answer important questions.

“The fact that it is a negative study, I think, in no way diminishes from the importance of it,” Ryan said.

Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 403

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