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by Charles Bankhead Charles Bankhead, Staff Writer, MedPage Today February 18, 2013
This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Patients with metastatic renal cell carcinoma had improved progression-free survival when treated initially with axitinib instead of sorafenib, although the results did not meet a randomized trial's parameters for statistical significance.
Note that adverse events were more frequent with axitinib (all grades and grade 3+), including diarrhea, hypertension, weight loss, fatigue, decreased appetite, dysphonia, asthenia, and hypothyroidism. Hand-foot syndrome was more common with sorafenib.
Axitinib delayed disease progression for a median duration of 10.1 months, more than a 50% improvement compared with sorafenib (Nexavar), which is a slightly older tyrosine kinase inhibitor. However, the hazard ratio (HR) of 0.77 fell short of investigators ' ambitious goal of a 44% reduction in the hazard, reported Thomas Hutson, DO, of Baylor University Medical Center in Dallas, and colleagues.
Subgroup analysis revealed a consistent trend toward better PFS with axitinib, although confidence intervals overlapped the point of unity, Hutson said here at the Genitourinary Cancers Symposium.
"The study did not achieve its primary endpoint, statistically. We set the bar high," he explained. "First-line therapy with axitinib demonstrated a numerically longer PFS, a significantly higher objective response rate, and an acceptable safety profile."
Follow-up will continue until data have matured sufficiently for a survival analysis, he added.
An inhibitor of vascular endothelial growth factor receptor (VEGFR), axitinib has FDA approval as second-line therapy or beyond for advanced RCC. In a previous clinical trial, treatment with axitinib led to a median PFS of 13.7 months in patients with cytokine-refractory metastatic RCC.
In contrast, two trials of sorafenib showed a median PFS of 5.5 months in cytokine-refractory metastatic RCC and 5.7 months in patients with untreated metastatic RCC, Hutson said.
At the same time, axitinib and sorafenib were being compared in a randomized trial of second-line therapy for metastatic RCC. In light of the new first-line data, investigators amended the protocol to include a population of patients with previously untreated metastatic RCC.
The randomized comparison of first-line therapies had an ambitious clinical objective, Hutson acknowledged. The trial was statistically powered to detect a 78% improvement in median PFS, from 5.5 months with sorafenib to 9.8 months with axitinib. The goal for improvement translated into an HR of 0.56 and a statistical significance threshold of P=0.025.
Investigators randomized 188 patients 2:1 to axitinib or sorafenib. About 90% of the patient population came from outside the U.S. In addition to the primary endpoint of PFS, secondary endpoints included overall survival (OS), objective response rate (ORR), safety, response duration, symptoms, and health-related quality of life.
Patients with or without nephrectomy were eligible, but blood pressure had to be <140/90 mm Hg (antihypertensive medication was allowed).
The study population had a median age of 58, and men accounted for 70% to 75% of patients. Additionally, 85% to 90% of patients had undergone nephrectomy, 70% had lung metastases, 50% to 55% had positive lymph nodes, and about 95% of patients were classified as favorable or intermediate risk.
The results showed a median PFS of 10.1 months with axitinib versus 6.5 months with sorafenib (HR 0.77, 95% CI 0.56 to 1.05, P=0.038). A trend toward improved PFS was observed across performance-status categories, nephrectomy status, all racial/ethnic groups, men and women, all ages, and all risk categories.
Tumor response was assessed at baseline and weeks eight, 16, and 24, then every 12 weeks thereafter.
By independent review, 32.3% of target lesions exhibited partial responses to axitinib, 23.4% had stable disease of at least 20 weeks, and 19.8% had stable disease at less than 20 weeks. The same rates in the sorafenib arm were 14.6%, 27.1%, and 26%, respectively.
Axitinib-treated patients were more than twice as likely to obtain some degree of lesion response (ORR 2.21, P=0.0006).
Overall, dose interruptions occurred in 72% of the axitinib group and 78.1% of the sorafenib group. Discontinuation rates for adverse events were 49.7% and 45.8%, respectively. A fourth of patients in the axitinib arm required dose reductions compared with 42.7% of sorafenib-treated patients. Median relative dose intensity was 124.7% with axitinib and 98% with sorafenib.
Adverse events were more frequent with axitinib (all grades and grade 3+), including diarrhea, hypertension, weight loss, fatigue, decreased appetite, dysphonia, asthenia, and hypothyroidism. Hand-foot syndrome was more common with sorafenib.
Laboratory abnormalities occurred more often in the sorafenib arm, including neutropenia, anemia, thrombocytopenia, lymphopenia, hypophosphatemia, hypocalcemia, and lipase elevation. Axitinib-treated patients had higher rates of elevated hemoglobin and hypercalcemia.
The results with first-line axitinib differ from those reported last year and updated at the Genitourinary Cancers Symposium, said invited discussant Sandy Srinivas, MD, of Stanford University in Stanford, Calif. That phase II trial demonstrated a median PFS of 14.5 months for axitinib-treated patients.
In the trial reported by Hutson, both treatment groups did less well than expected, Srinivas said, noting PFS rates as high as 9.9 months in contemporary studies of sorafenib, as well as the higher PFS previously reported with axitinib. Additionally, the earlier trial of axitinib showed an ORR of 54% compared with the 32% reported by Hutson.
Differences in patient populations cannot explain the disparate results between the two axitinib trials, Srinivas continued. Instead, she pointed to recent trials in RCC and gastrointestinal stromal tumors wherein PFS and survival were significantly associated with achieved levels of sunitinib, not relative dose intensity as reported by Hutson.
"We know that area under the curve is important, as we have demonstrated with sunitinib," Srinivas said. "Perhaps we should monitor drug levels, as is the routine with antibiotics and antipsychotics, and which we do in our own practice for patients with adrenal cancer. I wonder if it is time for us to think about monitoring axitinib levels to get the most out of this drug."