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SAN FRANCISCO -- Patients with refractory renal cell carcinoma (RCC) had statistically significant improvement in progression-free survival (PFS) with the multi-tyrosine kinase inhibitor tivozanib (Fotivda) compared with sorafenib (Nexavar), a randomized trial showed.

Patients treated with tivozanib had a median PFS of 5.6 months versus 3.9 months with sorafenib. The difference represented a 27% reduction in the hazard for progression or death (95% CI 0. 56-0.94, P=0.0165). Analyses of PFS at 1 and 2 years showed substantial advantages for tivozanib treatment (28% vs 11% and 18% vs 5%).

Patients with prior exposure to immuno-oncology agents derived greater benefit from tivozanib, including median PFS (7.3 vs 5.1 months, HR 0.55, P=0.028), 1-year PFS (35% vs 4%) and 2-year PFS (25% vs 0%), Brian Rini, MD, of the Cleveland Clinic, reported here at the Genitourinary Cancers Symposium.

However, an interim analysis of overall survival (OS) showed no benefit with tivozanib (median 16.4 months vs 19.7 months). Rini said a planned definitive analysis of OS will occur in August.

The findings meant that tivozanib will remain in regulatory limbo in the U.S at least into the third quarter of this year. That status that began almost 6 years ago when the FDA rejected Aveo Oncology's New Drug Application (NDA) for tivozanib, citing a lack of survival benefit from the TIVO-1 randomized trial involving more than 500 patients with advanced RCC.

Rini reported the , which included 351 patients with previously treated RCC. Aveo officials announced the company accepted an FDA recommendation not to submit an NDA on the basis of the TIVO-3 results, acknowledging that the preliminary survival data "do not allay [FDA] concerns about the potential detriment in OS" raised in a complete response letter the agency sent Aveo in 2013 after rejecting the initial NDA.

Encouraging Response Data in Uncommon RCC Subtypes

A third of patients with non-clear cell (ncc) RCC or clear cell with sarcomatoid differentiation (sccRCC) had objective responses to the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin).

Overall, 19 of 56 (34%) evaluable patients had objective responses, including more than half of the sccRCC subgroup (9/17, 53%) and a fourth of the sccRCC subgroup (10/39, 26%). Responses were observed in patients with and without sarcomatoid differentiation (44%, 26%, respectively) and with and without prior treatment (31%, 40%), , of the University of California San Diego.

An additional 13 patients attained stable disease during treatment, resulting in a clinical benefit rate of 57%. Responses had a median duration of 24 weeks. The entire study population had a median PFS of 8.4 months and median OS of 21.2 months.

The nccRCC subtype accounts for about 20% of all RCC, and sarcomatoid differentiation can coexist in any RCC subtype. The two disease categories comprise a heterogeneous group of RCC associated with differing tumor biology and molecular characterization. Patients with nccRCC or sccRCC have been underrepresented in clinical trials, and both disease subtypes are associated with inferior survival, said McKay. Retrospective analyses showed modest response rates to immune checkpoint inhibitors, providing a rationale for the combination of atezolizumab and bevacizumab.

Investigational Combination Active in Metastatic RCC

The tyrosine kinase inhibitor cabozantinib (Cabometriq, Cabometyx) plus the investigational glutaminase inhibitor telaglenastat (CB-839) achieved partial response or stable disease in 100% of a small group of patients with metastatic (m)RCC.

Five of 12 (42%) evaluable patients with clear cell (cc) and papillary RCC had partial responses, and the remaining seven had stable disease. Additionally, five of 10 patients with ccRCC responded, and the rest had stable disease. All 12 patients had some degree of tumor shrinkage, , of the MD Anderson Cancer Center in Houston.

The patients had a median treatment history of three prior regimens. All had exposure to one or more inhibitors of vascular endothelial growth factor, and seven of 12 had been treated with a checkpoint inhibitor. The most common adverse events (all grades) were diarrhea (eight patients); decreased appetite and increased liver enzymes (five each); and nausea and rash (four each). Grade ≥3 adverse events consisted of one case each of diarrhea, hypertension, decreased platelet count, and hallucination.

Cabozantinib has FDA approval for RCC. The rationale for the combination came from recognition that glutaminase regulates glutamine utilization, which is upregulated in RCC and a key contributor to tumor proliferation and survival. Results of the phase I study reported by Meric-Bernstam provided the basis for a phase II registration trial, which has begun patient enrollment.