Exploring the Reasons Why the CANTATA Trial Was Negative in RCC

Nizar M. Tannir, MD, FACP, discusses why telaglenastat in combination with cabozantinib did not improve efficacy in compared with cabozantinib alone in patients with metastatic renal cell carcinoma.

Nizar M. Tannir, MD, FACP, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, and Ransom Horne, Jr. Professorship for Cancer Research, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discusses why telaglenastat (CB-839) in combination with cabozantinib (Cabometyx) did not improve efficacy in compared with cabozantinib alone in patients with metastatic renal cell carcinoma (RCC).

The phase 2 CANTATA trial (NCT03428217), presented at the 2021 American Society of Clinical Oncology Annual Meeting, did not meet its primary end point of progression-free survival (PFS). Tannir believes there might be a few reasons why this study was negative while other studies testing telaglenastat have been positive.

Transcription:

0:08 | This was obviously an unselected patient population, not based on biomarker. I think the question is, why was the study negative? Why didn't the telaglenastat plus cabozantinib arm show superiority in terms of PFS compared to placebo plus cabozantinib? Was the partner, which is cabozantinib, not the right partner? I think [when] we go back to the hypothesis, which is tumor metabolism—is blocking the glutamine pathway, glutamine [synthetase] is the enzyme that converts glutaminate to glutamine. That depends. Is that relevant in oncology? I do believe yes, it is. There's a high expression of this enzyme in many tumor types. I think there are strong preclinical data in vitro and in vivo to suggest that this is relevant pathway in oncology and tumor metabolism. But could another partner, another agent combined with telaglenastat, would have would that have shown a different result? Would that have shown a positive result?

1:22 | If I may just mention the results of a study that was presented at ESMO [European Society for Medical Oncology Annual Meeting] 2019—which the manuscript is in preparation—where the MTOR inhibitor everolimus was combined with telaglenastat versus placebo plus everolimus. The smaller study of 69 patients had a similar design but 2:1 randomization in favor of the active agent telaglenastat plus everolimus. In that study, the PFS was also the primary end point, and it was double. The median PFS was double with telaglenastat plus everolimus was 3.8 months in very heavily pretreated patient population versus 1.9 months with placebo plus everolimus.

2:14 | So I do believe blocking glucose and glutamine, these 2 pathways are important in terms of metabolism. I do believe their hypothesis was right. However, maybe the study was negative maybe because cabozantinib may not have been the best partner for this. One could think maybe the pharmacokinetics or pharmacodynamics, or maybe one could, thinking forward, have a more selected patient population with patients that are more metabolically driven, than maybe just unselected clear cell RCC.

3:04 | I think here it's important to mention that there is a study combining telaglenastat plus chemotherapy in patients with nonsquamous [non–small] cell lung cancer that are driven by a mutation, and therefore maybe in that patient population that's biomarker selected, we will see maybe positive results. So there are some other ideas being now formulated to see if we can test the same combination in other rare tumors, of the kidney for example, renal medullary carcinoma, or hereditary RCC, or [other] tumors which are more metabolically driven, where we could see probably in those selected tumors, maybe the efficacy of blocking glutamines.