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A Prospectivly Randomized Phase-II Trial of Axitinib versus Everolimus as Second-Line Therapy in Metastatic Renal
Viktor Grünwald1, Thomas Hilser2, Johannes Meiler3
1Interdisciplinary Genitourinary Oncology at the West-German Cancer Center, Clinic for Internal Medicine (Tumor Research) and Clinic for Urology, University Hospital Essen, Essen, Germany.
Introduction:
Inhibition of neo-angiogenesis is a cornerstone of medical treatment in metastatic renal cell carcinoma (mRCC). While 1st line therapies were previously dominated by inhibitors of the vascular endothelial growth factor axis, 2nd line options were less clearly defined. We investigated the role of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in 2nd line treatment of mRCC patients.
Methods:
Key inclusion criteria were measurable mRCC, ECOG 0-1, IMDC risk: good or intermediate and adequate organ function. Patients who progressed on or were intolerant to bevacizumab + interferon were subject for randomization between TKI and EVE treatment. Cross-over occurred at time of progression during 2nd line treatment. Improvement of 2nd line progression-free survival (PFS) rate (PFR) at 6 months from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, objective response rate (ORR), overall survival (OS), safety, and patient reported outcomes.
Results:
In 2012-2015, a total of 22 patients were included. The study was stopped for poor accrual. Ten patients (46%) were randomized to receive 2nd line treatment with EVE (n = 5) or axitinib (n = 4)/sunitinib (n = 1). ECOG 0 was recorded in 20% (EVE) and 60% (TKI). Severe adverse events occurred in approx. 60% in each arm. ORR was 1/5 (20%) for TKI and 0/5 (0%) for EVE. PFR at 6 months was 20% in each arm. Median PFS was 3.7 months (EVE) and 2.2 months (TKI) (hazard ratio [HR] 1.0 [95% confidence interval [CI]: 0.26-3.85]). The OS was comparable between arms HR 1.12 (95% CI: 0.27-4.61).
Conclusion:
The rapid change of the treatment landscape, the limited use of bevacizumab and interferon in 1st line and the duration of 1st line treatment jeopardized BERAT trial recruitment. The small number of patients is a major limitation of our trial. Our observation indicated the poor prognosis in progressive patients and the limited efficacy of TKI or mTOR inhibitors in 2nd line treatment.
Insights
This study investigated second-line treatments for metastatic renal cell carcinoma (mRCC) using everolimus (EVE) or tyrosine kinase inhibitors (TKIs). The trial faced recruitment challenges, suggesting limited efficacy for both EVE and TKIs in this setting.
Area of Science:
- Oncology
- Medical Treatment
- Renal Cell Carcinoma Research
Background:
- Inhibition of neo-angiogenesis is crucial for treating metastatic renal cell carcinoma (mRCC).
- While vascular endothelial growth factor (VEGF) inhibitors dominated first-line therapy, second-line treatment options for mRCC were less defined.
- This study evaluated everolimus (EVE) versus tyrosine kinase inhibitors (TKIs) as second-line treatments for mRCC.
Purpose of the Study:
- To assess the efficacy of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in the second-line treatment of metastatic renal cell carcinoma (mRCC).
- To determine if second-line TKI or EVE treatment could improve progression-free survival rates compared to existing standards.
Main Methods:
- A randomized trial comparing second-line everolimus (EVE) or tyrosine kinase inhibitors (TKIs) in mRCC patients who progressed on or were intolerant to bevacizumab plus interferon.
- The primary endpoint was the 6-month progression-free survival rate (PFR).
- Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.
Main Results:
- The BERAT trial accrued only 22 patients and was stopped early due to poor recruitment.
- Ten patients received second-line treatment with EVE (n=5) or a TKI (n=5).
- The 6-month PFR was 20% for both arms, with median PFS of 3.7 months for EVE and 2.2 months for TKI. Objective response rates were 0% for EVE and 20% for TKI.
Conclusions:
- Recruitment challenges were attributed to a rapidly evolving treatment landscape and limited first-line use of bevacizumab plus interferon.
- The small patient numbers limit definitive conclusions.
- The study suggests poor prognosis for progressive mRCC patients and limited efficacy of TKIs or mTOR inhibitors in the second-line setting.
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