medwireNews: The combination of telaglenastat and cabozantinib offers no extra benefit over cabozantinib alone in the second- or third-line treatment of advanced clear cell renal cell carcinoma (RCC), suggest phase 2 trial results.
Presenting the findings at the 2021 ASCO Annual Meeting, researcher Nizar Tannir (The University of Texas MD Anderson Cancer Center, Houston, USA) explained that telaglenastat (previously known as CB-839) is a first-in-class, selective glutaminase inhibitor that has demonstrated “promising” antitumor activity in combination with the multikinase inhibitor cabozantinib in both preclinical and phase 1 studies.
The CANTATA trial, however, did not demonstrate a significant improvement in the primary endpoint of independently assessed progression-free survival (PFS) with the addition of oral telaglenastat 800 mg twice daily versus placebo to cabozantinib 60 mg/day.
Among 444 patients who had received one or two prior lines of therapy (including at least one antiangiogenic agent or nivolumab–ipilimumab), the median PFS was 9.2 months with telaglenastat plus cabozantinib and a comparable 9.3 months with placebo plus cabozantinib.
The overall response rate was also similar between the telaglenastat and placebo groups, at 31.2% and 27.8%, respectively, and two patients in each group had a complete response.
Overall survival data were not mature at the time of analysis, but the median survival durations were a comparable 22.2 and 24.8 months for telaglenastat- and placebo-treated participants at this timepoint.
Tannir highlighted an analysis of PFS in the subgroup of patients who had received prior immune checkpoint inhibitor therapy (62% of total population), among whom there was “a modest numerical difference” between telaglenastat and placebo treatment, at a median of 11.1 and 9.2 months (nonsignificant hazard ratio=0.77).
This “hypothesis-generating observation […] could inform the future development of telaglenastat,” said the presenter.
He reported that the combination was “well tolerated, with adverse event profiles consistent with the known risks of each of the two agents.”
Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 71% of telaglenastat-treated patients and 79% of those given placebo, with hypertension (17 vs 18%) and diarrhea (15 vs 13%) the most common events of this severity in both groups. The corresponding rates of grade 5 TEAEs were 3% and 1%.
Ten percent of patients in the telaglenastat group and 15% of those in the placebo group discontinued cabozantinib due to TEAEs, while a respective 12% and 13% discontinued telaglenastat or placebo.
Discussing future perspectives, Tannir said that “while the addition of telaglenastat did not improve outcomes with cabozantinib in this unselected population of patients with clear cell [RCC], future studies are warranted to determine the impact of glutaminase inhibition in biomarker-selected patient populations with high dependence on glutamine and glutaminase, and in combination with other therapeutic partners.”
He added that the development of telaglenastat in such patient populations is continuing and highlighted the ongoing KEAPSAKE trial investigating the combination of telaglenastat and pembrolizumab plus chemotherapy in treatment-naïve patients with KEAP1/NRF2-mutated nonsquamous metastatic non-small-cell lung cancer.
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2021 ASCO Annual Meeting; 4–8 June