In a trial of initial targeted therapies, patients with metastatic renal cell carcinoma (mRCC) treated with tivozanib (AVEO Pharmaceuticals) showed extended progression-free survival (PFS) compared with patients treated with sorafenib (Nexavar, Bayer HealthCare and Onyx Pharmaceuticals), but overall survival (OS) was not prolonged.
Sorafenib was the first tyrosine kinase inhibitor (TKI) approved for treatment of mRCC. As Phase II clinical trials of tivozanib, another TKI, have shown promise, investigators designed this Phase III study to compare the two treatments head to head. In the international, multicenter clinical trial, 517 patients with histologically confirmed mRCC, with a clear cell component, prior nephrectomy and no previous treatments with vascular endothelial growth factor (VEGF)–targeted therapies or inhibitors of mammalian target of rapamycin (mTOR) were enrolled in a two-arm study. Patients were randomly assigned to receive a daily 1.5-mg oral dose of tivozanib (n=260) for three weeks, followed by one week off, or a dose of two 200-mg tablets of sorafenib administered twice daily (n=257) for four weeks. The study allowed for one-way crossover: 156 of 257 (61%) patients in the sorafenib arm switched to tivozanib as disease progressed. The researchers were led by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center, New York City, and results were published in the Journal of Clinical Oncology (2013; 31:3791-3799, PMID: 24019545).
Median PFS, which was the primary end point, was 11.9 months for tivozanib and 9.1 months for sorafenib (hazard radio [HR], 0.797; 95% confidence interval [CI], 0.639-0.993; P=0.042). Median OS was slightly longer in the sorafenib arm (29.3 months) than in the tivozanib arm (28.8 months; HR, 1.245; 95% CI, 0.954-1.624; P=0.105).
Adverse events (AEs) varied between groups. In the tivozanib group, grade 3 or 4 AEs occurred most frequently as hypertension (n=70); in the sorafenib arm, grade 3 or 4 AEs occurred most frequently as hypertension (n=46), hand–foot syndrome (n=43) and diarrhea (n=17).
This comparison study did not establish a strong preference, although the researchers felt that “further study of tivozanib is warranted.”
Sumanta Kumar Pal, MD|
Assistant Professor, Genitourinary Malignancies
Co-Director, Kidney Cancer Program
City of Hope
Before 2005, few viable treatment options existed for mRCC. Immunotherapeutic agents such as interleukin-2 yielded benefit in only a small subset of patients, and drugs such as interferon-α were associated with poor clinical outcomes. Since 2005, however, the treatment landscape for mRCC has changed dramatically. Seven targeted agents have been approved and can be divided broadly into two categories: VEGF inhibitors and inhibitors of mTOR. In the former category are both VEGF-receptor TKIs (VEGF-TKIs), including sunitinib, sorafenib, axitinib and pazopanib, and VEGF-ligand inhibitors, including bevacizumab.
With four VEGF-TKIs currently available, one might question the need for additional agents with a similar mechanism of action. Despite this, a consistent paradigm in drug development for mRCC has been to refine the specificity and affinity of VEGF-TKIs for VEGF receptors (VEGFRs). Results from the recent TIVO-1 (Tivozanib versus Sorafenib in 1st line Advanced RCC) trial, may bring an end to this paradigm, however. TIVO-1, comparing tivozanib and sorafenib in patients with treatment-naive mRCC, was predicated on the fact that tivozanib appeared to generate more potent inhibition of VEGFR2 with fewer off-target effects. Ultimately, the failure of the study to show a meaningful improvement in PFS strongly challenged these assumptions. Much attention was also given to the fact that median OS appeared to be higher in the sorafenib arm. This could potentially be explained by the geography of the study—many patients were accrued in Eastern Europe, where treatment options are limited. Given that TIVO-1 permitted crossover, many patients in the experimental group may have been exposed to the sequence of tivozanib followed by sorafenib. In contrast, many control patients may have received sorafenib alone, without any post-study therapies. Several experts have thus suggested that the OS result from TIVO-1 simply reflects the benefit of two sequential therapies as compared with just one drug alone.
TIVO-1 is not the only failed attempt to bring a more potent and selective VEGF-TKI into the front-line setting. The AGILE study, comparing axitinib and sorafenib in treatment-naive patients, similarly failed to demonstrate a statistically significant improvement in PFS with axitinib. Flaws in study design may have marred the outcome of AGILE—specifically, the small sample size allowed for the detection of only large treatment effects. Regardless, both AGILE and TIVO-1 may slow the race to devise a superior VEGF-TKI.
If building a better VEGF-TKI does not represent the way forward in mRCC, what path should clinical investigations take? Currently, there is a resurgence of interest in immunotherapeutic approaches. Inhibitors of programmed death-1 (PD-1) and its ligand (PD-L1) have demonstrated exceptional activity in melanoma, and early data in mRCC appears to be promising. Vaccines (both autologous and multipeptide) are also under investigation in mRCC Phase III clinical trials. Finally, targets outside of the VEGF–mTOR signaling axis are being increasingly acknowledged. Mesenchymal-epithelial transition (MET) is one such moiety—early data for the dual VEGFR2 and MET inhibitor cabozantinib appears to be very encouraging. Thus, the future of mRCC therapy may lie in entirely new therapeutic avenues, rather than in next-generation inhibitors of existing targets.
Dr. Pal reported no relevant financial disclosures.