FAILURE OF RENAL ADJUVANT TRIALS

Neither sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals) nor sunitinib (Sutent, Pfizer Inc), when given in the adjuvant setting, prolong disease-free survival (DFS) in patients with completely resected, locally advanced renal cell carcinoma (RCC) who are at high risk for recurrence, a large phase 3 trial has found.

Both drugs are oral tyrosine kinase inhibitors (TKIs) that block vascular endothelial growth factor (VEGF), and both are effective in the treatment of metastatic RCC.

Results from the phase 3 trial, known as ASSURE, were highlighted at a press conference preceding Genitourinary Cancers Symposium (GUCS) 2015, in Orlando, Florida.

"No one is more disappointed than I am, except perhaps the patients who participated in this trial," Naomi Haas, MD, associate professor of medicine, University of Pennsylvania, in Philadelphia, told reporters.

"As we analyze smaller subsets of patients, hopefully we will learn more about who might benefit from these kinds of approaches and who they may be detrimental in, but overall, we certainly did not see any difference in the median disease-free survival in the larger group of patients," she said.

The trial involved 1943 patients with completely resected locally advanced RCC of either clear or non–clear cell histology who were stratified as intermediate to high or very high risk on the basis of University of California, Los Angeles, international staging criteria.

"Cancers were at least 4 cm in size with high-grade disease, but we also included patients who had larger cancers or who were node positive," Dr Haas observed.

Patients were assigned to either sunitinib daily for 4 of 6 weeks for nine cycles for 1 year; sorafenib, twice daily for nine cycles for 1 year; or placebo for 1 year.

Treatment groups were balanced according to the type of kidney cancer, the type of surgery patients had undergone, performance status, and the risk for recurrence, Dr Haas noted.

At 5 years, median DFS rates were not different between the three groups, at 5.6 years for sorafenib and sunitinib and 5.7 years for placebo.

	Sunitinib	Sorafenib	Placebo
Patients	647	649	647
DFS events	265	272	270
5-Year DFS	53.8%	52.8%	55.8%
97.5% Confidence interval	49% - 59.1%	48% - 58%	51% - 60.9%

Overall survival rates ranged between 77% and 81% in all treatment groups, "so again, essentially no difference on this initial assessment," Dr Haas commented.

As Dr Haas pointed out in a statement, the starting dose of both TKIs was reduced and then individually titrated to mitigate the effect of patient discontinuation from intolerance to treatment.

The redesign, done after accrual of 1322 patients, reduced the discontinuation rate from about 26% in both VEGF inhibitor arms to about 14% in patients starting at reduced doses.

Nevertheless, the most common adverse events of grade 3 and higher were hypertension, seen in 16% of both active treatment arms vs 4% for placebo; hand-foot reaction, seen in 15% of sunitinib patients and 33% of sorafenib patients vs 1% for placebo; and rash, seen in 2% of sunitinib patients vs 15% of their sorafenib counterparts, compared to <1 for="" p="" placebo.="">

In addition, fatigue was reported by 17% of sunitinib recipients and 7% of those on sorafenib compared with only 3% for patients on placebo.

"This is the first and largest trial reporting on efficacy with VEGF inhibitors as adjuvant therapy for patients with locally advanced kidney cancer who were at high risk for recurrence," Dr Haas concluded.

"And findings from this study suggest that patients with locally advanced kidney cancer completely resected should not be treated with either sorafenib or sunitinib."

Charles Ryan, MD, University of California, San Francisco, and ASCO expert, said that the fact that ASSURE was a negative study "in no way" diminishes from the importance of it.

"It's important to point out that the tyrosine kinase inhibitors are not chemotherapy, which can be expected to eradicate micrometastatic disease in the adjuvant setting of breast or colon cancer, for example," he said.

Indeed, both Dr Ryan and Dr Haas reminded reporters that little benefit has been seen when evaluating other antiangiogenic therapies in other solid tumor malignancies similarly used in an adjuvant setting.

"This study was designed to support or refute the use of sorafenib or sunitinib in the adjuvant setting [because] it was not intuitive that adjuvant use of these VEGF receptor TKIs would be beneficial in this setting," Dr Ryan said.

"So I was waiting for these data to decide whether I would use these drugs or not," he continued. "Based on the study's findings, I would not use these drugs in the adjuvant setting of RCC."

The study was funded by the National Institutes of Health. Dr Haas reported the following competing interests: consulting or advisory role with BMS, Merck, and GSK; expert testimony (immediate family member) for Lilly; and stock and other ownership interests (immediate family member) with TetraLogic Pharmaceuticals. Dr. Ryan has received honoraria from Astellas Pharma and Janssen Oncology, has served as a consultant or in an advisory role for Bayer and Millennium, and has obtained research funding from BIND, Karyopharm, and Novartis.

Genitourinary Cancers Symposium (GUCS) 2015. Abstract 403. To be presented February 28, 2015.