Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, Dana-Farber Cancer Institute, and Jerome and Nancy Kohlberg Chair and professor of medicine, Harvard Medical School, discusses data with novel treatment strategies in genitourinary cancers presented at the 2019 ESMO Congress.
Several abstracts were presented at the 2019 ESMO Congress regarding novel combination approaches in the treatment of patients with renal cell carcinoma (RCC). For example, in the phase II ENTRATA trial, investigators evaluated the combination of the glutaminase inhibitor telaglenastat and everolimus versus everolimus alone in patients with heavily pretreated advanced RCC. Notably, the combination displayed a statistically significant improvement in progression-free survival (PFS) versus everolimus alone (HR, 0.64; 95% CI, 0.34-1.20; 1-sided P = .079), serving as proof-of-concept for telaglenastat and combined glutaminase inhibition in advanced disease, says Choueiri. Additionally, the ongoing phase II CANTATA trial is evaluating telaglenastat in combination with cabozantinib (Cabometyx) in advanced RCC.
In the phase Ib/II TiNivo trial, the combination of the PD-1 inhibitor nivolumab (Opdivo) and the VEGF TKI tivozanib (Fotivda) was evaluated in patients with advanced RCC. Although novel combinations of immunotherapy and VEGF TKIs are not new to the field, tivozanib is unique in that it is a highly selective inhibitor of VEGFR, explains Choueiri. Results showed that among 25 patients enrolled, there was a 56% objective response rate (ORR) and a median PFS of more than 1.5 years. The combination was also well tolerated, and as such, Choueiri expects that it will move forward in development. Notably, tivozanib has been evaluated as a single agent versus sorafenib (Nexavar) in the frontline and refractory settings; however, due to its lack of benefit over sorafenib, its future will likely lie in combination, says Choueiri.
In addition to new trials of novel combinations, biomarker analyses were also performed on existing combinations. For example, in the phase III JAVELIN 101 trial, Choueiri presented data that indicated that patients benefited from the combination of axitinib (Inlyta) and avelumab (Bavencio), regardless of whether they received nephrectomy or had partial sarcomatoid histology. Historically, patients with sarcomatoid histology have a poor prognosis, but given these data, Choueiri believes checkpoint inhibition should become a standard of care in this patient population.
HIF-2α, although historically difficult to target, is another potential strategy under evaluation, adds Choueiri. At the meeting, data from a phase I/II study (NCT02974738) demonstrated an ORR of 24% in patients with heavily pretreated advanced RCC. Although investigators reported anemia and hypoxia, the agent was otherwise well tolerated and could be an optimal combination partner, according to Choueiri.
Moreover, data from the phase III IMvigor130 trial demonstrated a 1.9-month improvement in median PFS with the frontline combination of atezolizumab (Tecentriq) and chemotherapy versus chemotherapy and placebo in patients with locally advanced or metastatic urothelial cancer. However, investigators failed to report a statistically significant improvement in OS between these arms. Notably, a comparison between atezolizumab monotherapy and chemotherapy alone revealed an improvement in OS with the PD-L1 inhibitor in patients with high PD-L1 expression. These data suggest that these regimens may not be appropriate for all comers, but may be beneficial in those with high PD-L1 expression, explains Choueiri.
Finally, there are antibody—drug conjugates, which could become staples of treatment in advanced bladder cancer, projects Choueiri. In a heavily pretreated patient population, sacituzumab govitecan showed an ORR of 29% in the phase II TROPHY-U-O1 trial. Additionally, over 70% of patients with cisplatin-ineligible locally advanced urothelial cancer responded to the combination of enfortumab vedotin plus pembrolizumab (Keytruda).