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Targeting Glutamine Metabolism:

the CANTATA Trial for Patients With Metastatic
Renal Cell Carcinoma (mRCC)

 

      

Andrew W. Hahn, MD1 .          Nazir M. Tannie, MD, FACP1

 

1Department of Genitourinary Medical Oncology

Division of Cancer Medicine

MD Anderson Cancer Center

Houston, TX

 

 

Abstract

Despite the progress made in the management of advanced renal cell carcinoma with the regulatory approval of immune checkpoint inhibitor-based regimens, nivolumab plus ipilimumab, pembrolizumab plus axitinib, and avelumab plus axitinib as first-line therapies for the treatment of patients with metastatic renal cell carcinoma (mRCC), an unmet need still exits for the development of therapies with novel mechanism of action for patients with mRCC who do not respond or experience a relapse after an initial response to these first-line therapies. Altered cellular metabolism is a hallmark of cancer, and renal cell carcinoma (RCC) cells have been shown to depend on glutamine metabolism for energy demands. Telaglenastat (CB-839) is a selective glutaminase inhibitor that is being studied in combination with cabozantinib in the randomized CANTATA trial as second-line or third-line therapy in patients with mRCC who had progressive disease after prior therapy with dual immune checkpoint inhibitors or a VEGFR-TKI followed by immune checkpoint inhibitors, or the combination of an immune checkpoint inhibitor plus a VEGFR-TKI. Herein, we present a clinical vignette reflective of a patient enrolled on the CANTATA trial, review the preclinical and early phase clinical trial rationale for telaglenastat plus cabozantinib, and provide an in-depth discussion of the CANTATA trial.

 

Case Report

Mr. L is a 58 year-old male who initially presented with a palpable abdominal mass and was found to have a 10 x 8 centimeters (cm) right renal mass which was histologically confirmed to be clear-cell renal cell carcinoma (ccRCC). At that time, he had a right nephrectomy with radical lymph node dissection and was found to have 3 lymph nodes positive for ccRCC. Two months after his nephrectomy, a restaging CT chest, abdomen, and pelvis showed interval development of a 1.5 cm lesion in the liver and small pulmonary nodules suspected to be metastatic RCC (mRCC). He began first-line sunitinib for International Metastatic RCC Database Consortium (IMDC) intermediate-risk disease. After 8 months of stable disease, he experienced radiographic progression. He was then started on second-line nivolumab and continued this immunotherapy until radiographic progression 13 months later. Most recently, he was enrolled in a clinical trial of cabozantinib plus telaglenastat versus cabozantinib plus placebo as third-line treatment for IMDC intermediate-risk mRCC. He experienced a durable partial response on this clinical trial and remains on treatment 15 months later without any grade 3 or 4 adverse events.

In the above clinical vignette, Mr. L was enrolled on the CANTATA trial (NCT03428217), a randomized clinical study comparing telaglenastat (CB-839) plus cabozantinib versus cabozantinib plus placebo in patients with mRCC who had previously progressed on at least one line of systemic treatment. There is a growing need for novel salvage therapies for mRCC as combinations of VEGF targeted therapy and immune checkpoint inhibitors are now approved as first-line treatment. Telaglenastat is a selective glutaminase inhibitor that is designed to target one of the hallmarks of cancer, altered cellular metabolism (Figure).1 In cancer cells, the Warburg effect results in a deficit of essential metabolites for tumorigenesis. In RCC cells, HIF-1α and HIF-2α mediate a switch to use glutamate to fuel the tricarboxylic acid cycle (TCA) cycle.2,3 Glutamate is also used by cancer cells to synthesize amino acids and balance cellular oxidative stress. Thus, RCC cells are dependent on glutamine metabolism, and glutaminase plays a key role by converting glutamine into glutamate.4

 

Figure. Glucose and glutamine metabolism in renal cell carcinoma cells with the mechanism of action of telaglenastat.

 

There is preclinical rationale and phase 1 clinical trial data supporting the CANTATA trial. In a preclinical study of VHL-deficient human RCC cell lines, glutaminase inhibition compromised de novo pyrimidine synthesis, increased levels of reactive oxygen species by impairing glutathione biosynthesis, and impaired cell growth by selectively inducing DNA replication stress.5 In a separate preclinical study, telaglenastat plus cabozantinib had synergistic antiproliferative activity in vitro and enhanced anti-tumor activity in murine RCC xenografts.6 These preclinical studies led to a phase 1 clinical trial of telaglenastat plus cabozantinib in 13 patients with metastatic clear-cell or papillary RCC who had progressed on at least one prior VEGF-targeted therapy.7 Telaglenastat plus cabozantinib was well tolerated with similar toxicity to cabozantinib alone and had promising antitumor activity, with an objective response rate (ORR) of 42% (5 responders out of 12 evaluable patients). Among the 12 patients evaluable for response, 10 patients had ccRCC and 2 patients had papillary RCC; 5 of the 10 patients with ccRCC achieved a partial response. Finally, telaglenastat has also been studied in combination with everolimus in 69 patients with mRCC in the ENTRATA trial. In this randomized phase 2 clinical trial using 2:1 randomization between telaglenastat plus everolimus vs placebo plus everolimus as third-line or beyond treatment, the experimental arm of telaglenastat plus everolimus met its primary endpoint by improving progression-free survival (PFS) compared to placebo plus everolimus (HR=0.64, P=0.079; median PFS 3.8 vs. 1.9 months).8

CANTATA is an international, randomized, double-blind clinical trial that is actively enrolling 416 patients to telaglenastat plus cabozantinib or placebo plus cabozantinib.9 Randomization is stratified by prior PD-1 or PD-L1 antibody treatment and IMDC risk group. The primary endpoint is PFS per RECIST version 1.1 by blinded independent review committee. Secondary endpoints include overall survival, investigator-assessed PFS, ORR, duration of response, disease control rate, safety, pharmacokinetics, biomarker analyses, and quality of life assessment. The trial is designed to have 85% power and a hazard ratio of 0.69 and two-sided alpha of 0.05. Key inclusion criteria include: documented histological diagnosis of clear-cell RCC, Karnofsky performance status ≥ 70%, measurable disease per RECIST version 1.1, and 1-2 prior lines of systemic treatment including at least one VEGF targeted therapy or the combination of nivolumab plus ipilimumab. Key exclusion criteria include: prior treatment with telaglenastat or cabozantinib (or other MET inhibitor), active central nervous system disease, major surgery within 6 weeks or significant bleeding event within 3 months of first dose, inability to receive oral medications, or inability to discontinue proton pump inhibitors prior to randomization. The CANTATA trial is actively recruiting patients and the estimated date of primary analysis is September 30, 2020.

 

Conclusion

In conclusion, RCC is dependent upon glutamine metabolism, making glutaminase inhibition a novel and rational therapeutic target for patients with mRCC. CANTATA is an ongoing, randomized clinical trial evaluating telaglenastat, a selective glutamine inhibitor, plus cabozantinib versus cabozantinib plus placebo in 416 patients who had previously progressed on one or two prior lines of systemic therapy. The results of this trial have the potential to improve the outcomes of patients with metastatic clear-cell RCC by expanding the therapeutic options for these patients and incorporating in our armamentarium a first-in-class agent with a novel mechanism of action.

 

References

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.

2. Mullen AR, Wheaton WW, Jin ES, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011; 481:385-8.

3. Wise DR, Ward PS, Shay JE, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011;108: 19611-6.

4. Gameiro PA, Yang J, Metelo AM, et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell metabolism. 2013;17:372-85.

5. Okazaki A, Gameiro PA, Christodoulou D, et al. Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. J Clin Invest. 2017;127:1631-45.

6. Emberley E, Bennett M, Chen J, et al. CB-839, a selective glutaminase inhibitor, has anti-tumor activity in renal cell carcinoma and synergizes with cabozantinib and everolimus.  Keystone Symposia, Tumor Metabolism: Mechanisms and Targets; 2017; Whistler, Canada.

7. Meric-Bernstam F, Lee RJ, Carthon BC, et al. CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study. J Clin Oncol. 2019;37:549-.

8. Calithera Biosciences I. Calithera achieves positive topline results in randomized phase 2 ENTRATA study of telaglenastat with everolimus in renal cell carcinoma. http://ir.calithera.com/news-releases/news-release-details/calithera-achieves-positive-topline-results-randomized-phase-2?field_nir_news_date_value[min]=2019.

9. Tannir NM, Agarwal N, Dawson NA, et al. CANTATA: Randomized, international, double-blind study of CB-839 plus cabozantinib versus cabozantinib plus placebo in patients with metastatic renal cell carcinoma. J Clin Oncol.  2019;37:TPS682-TPS.  KCJ

 

Copyright © 2019

 

Vol 17, No 3    2019

The Official Journal of the Kidney Cancer Association

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There is preclinical rationale and phase 1 clinical trial data supporting the CANTATA trial. In a preclinical study of VHL-deficient human RCC cell lines, glutaminase inhibition compromised de novo pyrimidine synthesis, increased levels of reactive oxygen species by impairing glutathione biosynthesis, and impaired cell growth by selectively inducing DNA replication stress.5 In a separate preclinical study, telaglenastat plus cabozantinib had synergistic antiproliferative activity in vitro and enhanced anti-tumor activity in murine RCC xenografts.6 These preclinical studies led to a phase 1 clinical trial of telaglenastat plus cabozantinib in 13 patients with metastatic clear-cell or papillary RCC who had progressed on at least one prior VEGF-targeted therapy.7 Telaglenastat plus cabozantinib was well tolerated with similar toxicity to cabozantinib alone and had promising antitumor activity, with an objective response rate (ORR) of 42% (5 responders out of 12 evaluable patients). Among the 12 patients evaluable for response, 10 patients had ccRCC and 2 patients had papillary RCC; 5 of the 10 patients with ccRCC achieved a partial response. Finally, telaglenastat has also been studied in combination with everolimus in 69 patients with mRCC in the ENTRATA trial. In this randomized phase 2 clinical trial using 2:1 randomization between telaglenastat plus everolimus vs placebo plus everolimus as third-line or beyond treatment, the experimental arm of telaglenastat plus everolimus met its primary endpoint by improving progression-free survival (PFS) compared to placebo plus everolimus (HR=0.64, P=0.079; median PFS 3.8 vs. 1.9 months).8