Barcelona, Spain (UroToday.com) Professor Ignacio Durán provided a discussion of the recently presented ENTRATA and TROPHY-U-01 trials at the 2019 European Society for Medical Oncology annual meeting (ESMO) proffered paper session.
ENTRATA was a randomized phase II study of telaglenastat + everolimus vs. placebo + everolimus in heavily pre-treated metastatic renal cell carcinoma (mRCC) patients, reporting a median progression free survival (PFS) of 3.8 months for telaglenastat + everolimus compared to 1.9 months for placebo + everolimus (HR 0.64, 95% CI 0.34-1.20, 1-sided p = 0.079).
Dr. Duran notes that cancer cells go through a major reprogramming of cellular energy metabolism to support continuous cell growth and proliferation. Furthermore, he notes that HIF in clear cell RCC increases glucose transporters and also shifts the TCA cycle from predominant glucose utilization to a predominantly glutamine fueled system. As such, glutaminase inhibitors (ie. BPTES, CB-839, and 968) have shown an anti-proliferative activity in a wide range of cancers, including RCC. Because all forms of RCC are susceptible to extensive metabolic reprogramming, he questions why ENTRATA limited inclusion to clear cell RCC only. Looking closer at the results, Dr. Duran wonders if the control arm is performing much worse than expected (1.9 months PFS, 0% partial response)? A previous IMDC study utilizing everolimus in the fourth-line setting demonstrated that these patients had a median PFS of 3.6 months, 2/68 had a partial response, and 27/68 had stable disease.1 Additionally, he questions whether the experimental arm is performing better than historical phase I trials (PFS 3.8 months, 2.2% partial response, 57% stable disease)? Not particularly, as he notes that the phase I trial of telaglenastat + everolimus showed a PFS of 5.8 months. Dr. Duran stated that future steps based on this data is to assess combination therapy in this setting, including nivolumab + cabozantinib, which is ongoing.
The TROPHY-U-01 trial was a phase II study assessing antitumor activity of Sacituzumab govitecan in patients with heavily pretreated metastatic urothelial carcinoma with measurable disease. At a median follow-up of 4.1 months, the objective response rate (ORR) was 29% with two confirmed complete responses, five confirmed partial responses, and three unconfirmed partial responses.
Dr. Duran notes that there are four crucial components to effective antibody drug conjugates: a tumor antigen, a targeting antibody, a cytotoxic payload, and a conjugation strategy. TROP-2 is a trophoblast cell surface antigen that is linked to cell migration and anchorage-independent growth, with high expression in human epithelial cancers. It is also known to express in normal urothelium and in 83% of urothelial carcinomas with higher expression in invasive urothelial carcinoma. In TROPHY-U-01, Dr. Duran highlighted that this is a pretty standard population: median 3 prior anticancer regimens, 23% with liver metastases, and >80% with 0-1 Bellmunt risk factors. Furthermore, the adverse event profile is consistent with previous trials assessing Sacituzumab govitecan.
Generally, the results of TROPHY-U-01 compare favorably to other phase I/II studies in this disease space, as Dr. Duran beautifully summarized in the following table:
Future steps based on this data will include the completion of similar randomized controll trials (RCT)s, and exploring combination therapy.
Presented by: Ignacio Durán, MD, Ph.D., Chief of Oncology, Coordinator of the Genitourinary Oncology Program at the Medical Oncology Department in Hospital Universitario Virgen del Rocio, Seville, Spain, Associate professor at the Faculty of Medicine (University of Seville), co-investigator at the Institute of Biomedicine of Seville (IBIS)
- Stukalin I, Wells JC, Fraccon A, et al. Fourth-line Therapy in Metastatic Renal Cell Carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC). Kidney Cancer 2018;2(1):31-36.
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain