A Novel Combination Therapy

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A Novel Combination Therapy Takes an Innovative Approach by Targeting a Key Metabolic Pathway to Block RCC Growth

In this interview, a representative from the clinical development team of Calithera Biosciences discusses the potential impact of a novel drug combination undergoing study in a pivotal global randomized Phase 2 trial in renal cell carcinoma. Sam Whiting, MD, PhD, is Senior Vice President of Clinical Development. The new drug in development is teleglenastat (CB-839). One of the goals in the study is to demonstrate how targeting tumor metabolism pathways may take advantage of cancer-specific nutrient dependencies to block cancer growth. The interview was conducted by Robert A. Figlin, MD, Editor-in-Chief of the Kidney Cancer Journal.

Dr Figlin: Let’s begin by examining some topics related to tumor metabolism and biology and how various factors could play a role in promoting cell growth and proliferation. Please describe the importance of metabolic pathways in kidney cancer and how your work relates to such mechanisms.

Dr Whiting:  Metabolism is altered in cancer cells and a lot of oncologists know this from their training, that glucose metabolism in cancer typically is shunted toward production of lactic acid which is secreted from cells and shunted away from entry into the tricarboxylic acid (TCA) cycle, or Kreb’s cycle. Called the Warburg Effect, this metabolic phenomenon has been known for almost a century. The problem has been how best to target the abnormal metabolism in tumor cells.

The unique thing about inhibition of glutaminase as targeted by teleglenastat (CB-839) is that alterations in glucose metabolism in tumor cells are linked to alterations in glutamine metabolism. And, in particular, as cells use less glucose to drive the TCA cycle and other biosynthetic pathways, they use more glutamine. What Calithera did was to develop an inhibitor of glutamine metabolism that would specifically block the conversion of glutamine to glutamate in the cancer cell and “starve” cancer cells of this necessary amino acid. This process is fundamentally important to cancer cells because of their altered metabolism.

So glutamine biology is important to cancer cells because of their inherent difference from healthy cells and that allows telaglenastat to have more of a metabolic impact on tumor cells compared to healthy cells, which is an important characteristic of the drug.

 Dr Figlin: Help us understand some of the preclinical and Phase 1 results that have led to the CANTATA trial, which is looking at a combination with a tyrosine kinase inhibitor.

 Dr Whiting: The first preclinical work that we performed with telaglenastat was biochemical studies in the laboratory to show that the drug hit its target in cancer cells, which is an enzyme called glutaminase, and hitting that target in cancer cells did what was expected, that is, shutting down glutamine metabolism in the cancer cell. We demonstrated in a large number of cancer cell lines, representing many different types of cancer, that telaglenastat shut down glutamine metabolism in the cancer cell. We also were able to track the repercussions of that blockade in a cancer cell, showing that downstream products of glutamine metabolism that cancer cells were relying upon were decreased or blocked as well. Those included molecules used for DNA synthesis, fatty acid synthesis, and to protect cancer cells from oxidative stress. All of these, we were able to show in the lab, were inhibited by telaglenastat but, importantly, it didn’t have the same effect in normal tissues.

 Dr Figlin: Can you differentiate aspects of tumor and normal cell metabolism that need to be considered? What effect does the drug have in these settings?

Dr Whiting: The reason for the drug not having the same effect on normal cells is that cancer cells, to put it a crude way, can be addicted to glutamine to feed pathways for which healthy cells predominantly use glucose. We had this metabolic inhibitory effect in cancer cells and we showed that the effect was not nearly as strong in healthy cells.

Then we went into tumor models in animals and showed that we can inhibit the growth of tumors in animals just as we could kill cancer cells in the lab. And again, looking in the animal, the impact of telaglenastat was predominantly seen in the cancer and not in healthy tissues. This took a few years of diligent work and, ultimately, led to the initial Phase 1 program where telaglenastat was tested in patients with cancer. That was a very thorough clinical program that looked at the drug in a significant number of patients with a variety of cancer types.

Dr Figlin: What led you to focus more specifically on RCC?

Figure. Panel A: Best response of target lesions per RECIST 1.1 including RCC subtype (papillary or clear cell) and prior lines of therapy. Panel B: Change in target lesions by serial tumor assessments over time per RECIST 1.1, including RCC subtype.

Dr Whiting: Kidney cancer was always the “poster child” – it was the principal focus of our development because kidney cancer is so classically altered from the standpoint of metabolism. Essentially, it is a great target for telaglenastat. The most common kidney cancer—clear cell renal cell carcinoma – is driven by a mutation in the VHL pathway. And 80% or more of clear cell RCC patients have a loss of this tumor suppressor pathway. As a result of that, it is known that they become more dependent on glutamine biology to support cancer cell growth and proliferation.

Consequently, from the beginning, kidney cancer was a very logical target, and in the Phase 1 program we tested telaglenastat in patients with kidney cancer. We actually saw activity in a few different subtypes of kidney cancer but found that maybe the most exciting was the clear cell type as expected. Very rapidly, actually, we looked at whether telaglenastat could be combined with other drugs that are standardly used to treat kidney cancer and if that combination could provide a synergistic or multiplicative benefit in patients.

We looked at two partner drugs early on—one was everolimus, an approved drug used in patients who are often in the third line or later of treatment. After that we looked at combining telaglenastat with cabozantinib, which is a newer approval in kidney cancer in 2016. And both of these combinations came out of the lab in the sense that we were able to show in cell lines that the two drugs together were able to hit both glucose and glutamine metabolism in a way that was synergistically damaging to cancer cells.

Dr Figlin: How encouraged were you by the response rates you observed?

Dr Whiting: That hypothesis was pursued in patients and we found that with both combinations, the everolimus combination and the cabozantinib combination, that there was encouraging activity in patients with advanced kidney cancer. The cabozantinib combination was particularly exciting to us because there was a response rate in which tumors shrank by a significant extent in 50% of patients with clear cell RCC.  This was a small number of patients and needs to be confirmed in a larger trial that is now enrolling, but we knew that cabozantinib by itself had shown in published results a response rate of about 17%, and so 50% looked encouraging in that setting. We also had patients who were treated for a long period of time, so it looked like that benefit was durable.

We also had a toxicity profile for the two drugs together that looked to us and our investigators favorable because the combinations of telaglenastat with everolimus or cabozantinib looked similar to the standard drug alone – the tolerability was similar to everolimus or cabozantinib even when we added telaglenastat.

So that encouraging data led to a large, very rigorously designed clinical trial to formally test whether telaglenastat with cabozantinib, when used to treat patients with 2nd line or 3rd line clear cell RCC, was clearly a better treatment for patients than cabozantinib alone, which is a standard of care approach for these patients.

This is a trial that is randomized, so patients will get telaglenastat or placebo with the standard of care cabozantinib. It is blinded, so investigators and patients and the radiologists assessing outcomes do not know the treatment arm. It has a rigorous design in terms of assessing benefit and the company is hopeful that this will clearly show that this combination is active and helping patients with advanced RCC, leading to an approval for telaglenastat and making it available to patients with RCC.

Dr Figlin: Thank you for this discussion and sharing your insights. We look forward to further results from the clinical trial as they become available. KCJ