Naiyer A. Rizvi, MD, Price Family ​Professor of ​Medicine, director, Thoracic Oncology, co-director, Cancer Immunotherapy, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, research director, Price Family Comprehensive Center for Chest Care, NewYork-Presbyterian Hospital, discusses the rationale to evaluate the investigational glutaminase inhibitor telaglenastat (CB-839) in patients with non–small cell lung cancer (NSCLC) who harbor 

-mutant tumors are thought to be highly proliferative and largely dependent on glutamine to complete anabolic metabolism, says Rizvi. Moreover, fast-growing tumors have significant anabolic metabolism requirements. These requirements can be dependent on glucose or glutamine, depending on the body’s anabolic state.

Glutamine is metabolized to glutamate for DNA protein synthesis, Rizvi explains. Additionally, glutamine is converted to glutathione, which can protect cancer cells from oxidative stress, says Rizvi. 

As such, preclinical models with telaglenastat in patients with 

-mutant NSCLC have shown that inhibiting glutamine metabolism with an agent such as telaglenastat can increase the oxidative stress within the cancer cells. Giving telaglenastat in combination with standard of care options, such as pembrolizumab (Keytruda), carboplatin, and pemetrexed, may elicit improved tumor destruction, concludes Rizvi.

Videos

Naiyer A. Rizvi, MD, discusses the rationale to evaluate the investigational glutaminase inhibitor telaglenastat in patients with non–small cell lung cancer who harbor KEAP1 or NRF2 mutations.  



Dr. Rizvi on the Rationale to Evaluate Telaglenastat in KEAP1/NRF2-Mutant NSCLC 

Telaglenastat (CB-839) has been evaluated in combinations with several novel agents to determine whether targeting a new mechanism of action would improve clinical responses in patients with renal cell carcinoma (RCC), according to Chung-Han Lee, MD, PhD, who added that other efforts are underway to examine this agent further in this disease.

Results from the phase 2 ENTRATA trial (NCT03163667) presented during the 

 showed that the addition of telaglenastat to everolimus extended progression-free survival (PFS) compared with everolimus monotherapy in patients with heavily pretreated advanced or metastatic RCC. Specifically, the median PFS with telaglenastat/everolimus was 3.8 months versus 1.9 months with single-agent everolimus (HR, 0.64; 95% CI, 0.34-1.20; one-sided 

 =.079). According to Lee, this trial provided proof of principle to examine the agent further.

“For the longest time, the majority of agents that we had for RCC were either angiogenesis inhibitors, mTOR inhibitors, or immune checkpoint inhibitors,” Lee said. “However, telaglenastat truly represents an entirely new class of medications that are now being studied. Due to its new mechanism of action, and the fact that it’s well tolerated, it is a very exciting addition to the paradigm.”

Telaglenastat is now under exploration in combination with cabozantinib (Cabometyx) compared with cabozantinib alone in patients with advanced or metastatic RCC with a clear cell component who had received more than 2 previous therapies, added Lee.

, Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the promise of telaglenastat in RCC and the research efforts examining the agent in different combinations.

: What is the mechanism of action of telaglenastat in RCC?

: Telaglenastat, also known as CB-389, is a glutaminase inhibitor that

inhibits the conversion of glutamine into glutamate. Generally, when we think about cancer, 2 main energy sources are critical: the glucose pathway and the glutamine pathway.

Part of the Warburg effect is the conversion and overreliance on glycolysis, or the utilization of glucose to generate energy. However, in order to still populate different aspects of the tricarboxylic acid (TCA) cycle, many different malignancies rely on glutamine as a source of carbon. Telaglenastat essentially blocks that utilization.

How does the agent affect tumor metabolism in this disease?

RCC has been studied extensively and is thought to be a metabolic malignancy, meaning that there are often many different metabolic alterations that are important to pathogenesis. Several preclinical studies have demonstrated that almost all the aspects or molecules within the TCA cycle rely on glutamine in order to produce those numbers. Also, the molecules from glutamine are important for fatty acid synthesis.

Telaglenastat blocks the ability for the cells to utilize glutamine. This is why it led to multiple clinical studies to see whether or not by altering that metabolism can be important for treatment, as a novel mechanism.

What is some of the research that has been done with telaglenastat?

Telaglenastat has been studied in RCC in multiple formats. The agent has been evaluated, not only in combination with an immune checkpoint inhibitor, but in the phase 2 ENTRATA study, it was studied in combination with everolimus, which is an mTOR-targeted agent.

During the 2019 ESMO Congress, we presented [data on] the combination of telaglenastat and everolimus versus everolimus alone. In the study, patients were randomized 2:1 to receive either the combination or everolimus monotherapy. We wanted to see whether using this novel agent and targeting a new mechanism of action would improve the clinical responses seen with metabolic inhibitors, such as everolimus.

Could you expand on some of the efficacy data that were reported?

[Results showed] an improvement in PFS in this small, proof-of-principle study. The numbers did not yet meet their statistical significance; however, they did meet its bar based on the power setting ratings that were established for the clinical trial design. We must think of this as a proof of principle, showing that there is activity by using this new mechanism of action.

What is currently known about the safety profile of this combination?

Telaglenastat, as a new mechanism of action, was very well tolerated. We didn't see many toxicities beyond what we would typically see with everolimus monotherapy. I believe that the combination of a novel mechanism of action and the fact that it’s extremely well tolerated, really lends credence to trying to develop this concept and compound further.

Within RCC, perhaps one of the most important studies with telaglenastat, right now, is a randomized phase [2] study of the combination of telaglenastat plus cabozantinib versus cabozantinib alone. I believe this is a very large study consisting of about 400 patients, that will demonstrate the efficacy of the compound. This will also give us more information regarding not only the safety and tolerability, but also the efficacy.

Motzer RJ, Lee C-H, Emamekhoo H, et al. ENTRATA: Randomized, double-blind, phase 2 study of telaglenastat (tela; CB-839) + everolimus (E) vs. placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). 

. 2019;50(suppl 5):889-890. doi:10.1093/annonc/mdz394.048

Articles

Chung-Han Lee, MD, PhD, discusses the promise of telaglenastat in renal cell carcinoma and the research efforts examining the agent in different combinations.

Novel Mechanism of Action and Tolerability Makes Telaglenastat a Promising Player in RCC

Chung-Han Lee, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the rationale for evaluating telaglenastat in renal cell carcinoma (RCC).

Research regarding the natural history of RCC has shown that the disease appears to be a metabolic malignancy, says Lee. This means that many different metabolic alterations affect disease pathogenesis in RCC. 

 Several preclinical studies ​have demonstrated that almost all of the molecules within the tricarboxylic acid cycle rely on glutamine​, which play​s an important role in the synthesis of fatty acid​s, Lee adds.

Notably, telaglenastat is able to block cells from utilizing glutamine​, explains Lee.

As such, this agent is being further evaluated in multiple clinical trials to determine if patients can derive benefit from an altered metabolism, Lee concludes

Chung-Han Lee, MD, PhD, discusses the rationale for evaluating telaglenastat in renal cell carcinoma. 

Dr. Lee on the Rationale for Evaluating Telaglenastat in RCC   

Benjamin P. Levy, MD, associate professor of oncology and clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, discusses the mechanism ​of action of telaglenastat in non–small cell lung cancer (NSCLC).

A growing body of evidence ​suggest​s that telaglenastat should be further evaluated in NSCLC, says Levy.

Patients with NSCLC whose tumors harbor 

 mutations could be suitable populations to receive telaglenastat, Levy says.

are associated with constitutive activation in

, ​explains Levy. Moreover, this pathway is highly reliant on glutamine metabolism.

To feed into the NRF2 pathway, glutamine must ​first be converted to glutamate by the mitochondrial enzyme phosphate-activated glutaminase​, says Levy.

pathways are highly reliant on phosphate-activated glutaminase​, which can be inhibited with telaglenastat, Levy concludes.

Benjamin P. Levy, MD, discusses the mechanism ​of action of telaglenastat in non–small cell lung cancer.

Dr. Levy on the Mechanism of Action of Telaglenastat in NSCLC

Telaglenastat (CB-839), a novel drug that targets a key metabolic pathway, has shown encouraging antitumor activity in several cancer types. Now, investigators have launched the phase 2 KEAPSAKE trial to evaluate the agent in combination with standard-of-care chemoimmunotherapy as a first-line treatment for patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) with 

Patients whose tumors harbor these mutations do not respond well to treatment, even with the best standard of care, said Naiyer A. Rizvi, MD, the principal investigator on the KEAPSAKE study. Rizvi is the Price Family Professor of Medicine, director of thoracic oncology, and codirector of cancer immunotherapy at Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York. 

 mutations occur in more than 20% of patients but no drugs that specifically target these alterations have been approved, according to a presentation by Rizvi at the 2020 American Society of Clinical Oncology Virtual Scientific Program.

 mutations are the third most common tumor mutation in lung adenocarcinoma [after 

], so they are very common,” he said. “

 mutations are seen in both squamous and nonsquamous histology.” Dysregulated activity of the KEAP1/NRF2 pathway promotes tumor growth and survival, investigators have found. “These 

 mutations are highly dependent on glutamine metabolism. Glutamine is metabolized to glutamate for DNA protein synthesis but it also converts to glutathione, which protects the cancer cells from oxidative stress,” said Rizvi, who is the research director of the Price Family Comprehensive Center for Chest Care at NewYork-Presbyterian Hospital. “Preclinical models show that if you block glutamine metabolism with telaglenastat, you can increase the oxidative stress within the tumors 

and allow for potentially better tumor destruction when you give this with standard-of-care treatments.”

In the KEAPSAKE trial (NCT04265534), participants will be randomized to receive telaglenastat in combination with pembrolizumab (Keytruda), a PD-1 inhibitor, plus carboplatin and pemetrexed (Alimta) versus placebo with pembrolizumab and the chemotherapy combination (Figure).

 Telaglenastat will be administered orally with food at 800 mg twice daily in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks. Patients will be assessed every 3 months for up to 3 years.

The primary end points are progression-free survival (PFS) per RECIST 1.1 criteria and safety and tolerability of telaglenastat. Secondary end points include objective response rate, duration of response, and overall survival.

; alterations in these genes have been associated with lack of response to standard therapy with pembrolizumab. Additionally, 

KEAPSAKE, which recently opened for recruitment, is expected to enroll 120 patients in 57 study locations in the United States. Eligible patients must have stage IV nonsquamous NSCLC that has not been previously treated in the metastatic setting and no 

, or other actionable mutation for which there is already an approved therapy.

 mutation status will be determined by next-generation sequencing using the Guardant360 CDx assay, which analyzes genetic alterations in circulating cell-free DNA extracted from the plasma of peripheral whole blood.

 In August 2020, the FDA approved Guardant360 CDx as a companion diagnostic for osimertinib (Tagrisso) to identify 

 exon 19 deletions, L858R substitutions, and the T790M resistance mutation in patients with NSCLC. The test also is approved as a tumor profiling assay for NSCLC.

“The testing is an advantage for the patients, even if they don’t have a 

 mutation. They get this commercial assay that looks for not just 

mutations but other mutations within the panel as well. There is information to be gained no matter what your mutational status is or whether you go on the trial or not,” Rizvi said in an interview.

Figure. Telaglenastat Plus Chemoimmunotherapy in 

Early Efficacy Findings for Telaglenastat

Preclinical testing has shown that loss of 

 and promotes lung adenocarcinoma. In one study, it was shown that 

-mutated cancers are likely to respond to glutaminase inhibition.

In an ongoing phase 1/2 study (CX-839004; NCT02771626), telaglenastat was evaluated in combination with the PD-1 inhibitor nivolumab (Opdivo) in patients with advanced NSCLC who progressed on prior PD-1/PD-L1 inhibitor therapy. Patients with 

 mutations had a higher clinical benefit rate (CBR) and longer median PFS than those without these mutations.

mutations, the CBR was 75% in those with the alteration (3 of 4 patients) versus 15% in those without it (2 of 13 patients), with CBR defined as a combination of complete and partial responses and stable disease. The median PFS was 6.4 months for patients with the 

 mutation compared with 3.7 months for those with wild-type 

, with responses evaluated using modified RECIST 1.1 criteria for immune-based therapies.

Additionally, telaglenastat has demonstrated antitumor activity in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (RCC) in the phase 2 ENTRATA trial (NCT03163667). Patients in the double-blind study were randomized 2:1 to telaglenastat in combination with everolimus (Afinitor), an mTOR inhibitor (n = 46), or placebo plus everolimus (n = 23).

The telaglenastat combination doubled the median PFS to 3.8 months versus 1.9 months with the everolimus combination (HR, 0.64; 95% CI, 0.34-1.20; 1-sided 

 = .079). The most frequently reported grade 3 or higher adverse effects in the treatment arm versus the control group, respectively, were anemia (17.4% vs 17.4%), pneumonia (6.5% vs 4.3%), abdominal pain (6.5% vs 0%), thrombocytopenia (6.5% vs 0%), and fatigue (4.3% vs 8.7%).

Telaglenastat is currently being evaluated in the phase 2 CANTATA trial (NCT03428217), in which telaglenastat in combination with cabozantinib (Cabometyx) is being compared with placebo plus cabozantinib in patients with previously treated advanced or metastatic RCC. The primary end point is PFS.

Findings from the study, which has completed enrollment of 444 patients, are expected late in 2020 or early in the first quarter of 2021, according to Calithera Biosciences, the company developing telaglenastat.

Telaglenastat is also being studied in combination with azacitidine (Vidaza) in a single-arm phase 1/2 study (NCT03047993) in patients with intermediate- and high-risk myelodysplastic syndromes. Findings from an interim analysis involving 19 patients were presented at the 2019 American Society of Hematology Annual Meeting. The regimen demonstrated an overall response rate of 65%, including complete responses of 11%, a 1-year overall survival rate of 50%, and 1-year event-free survival rate of 33%.

Skoulidis F, Neal JW, Akerley WL, et al. A phase II randomized study of telaglenastat, a glutaminase (GLS) inhibitor versus placebo, in combination with pembrolizumab (pembro) and chemotherapy as first-line treatment for KEAP1/NRF2-mutated non-squamous metastatic non- small cell lung cancer (mNSCLC). 

. 2020;38(suppl 15):TPS9627. doi:10.1200/JCO.2020.38.15_suppl. TPS9627

Best SA, Sutherland KD. “Keaping” a lid on lung cancer: the Keap1-Nrf2 pathway. 

. 2018;17(14):1696-1707. doi:10.1080/15384101.2018.1496756

KEAPSAKE: a study of telaglenastat (CB-839) with standard-of-care chemoimmunotherapy in 1L KEAP1/NRF2-mutated, nonsquamous NSCLC (KEAPSAKE). ClinicalTrials.gov. Updated September 21, 2020. Accessed September 29, 2020. https://clinicaltrials.gov/ct2/show/NCT04265534 

Skoulidis F, Arbour KC, Hellman MD, et al. Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer. 

. 2019;37(suppl 15):102. doi:10.1200/ JCO.2019.37.15_suppl.102 

Calithera Biosciences initiates KEAPSAKE randomized phase 2 trial of telaglenastat in combination with chemoimmunotherapy to treat aggressive form of lung cancer. News release. Calithera Biosciences Inc. September 24, 2020. Accessed October 4, 2020. https://bit.ly/3lhejhx 

Summary of safety and effectiveness data (SEED). Guardant360 CDx. FDA. August 7, 2020. Accessed October 4, 2020. https://www.accessdata.fda.gov/cdrh_docs/ pdf20/P200010B.pdf 

Romero R, Sayin VI, Davidson SM, et al. Keap1 loss promotes Kras-driven lung cancer and results in a dependence on glutaminolysis. 

. 2017;23(11):1362-1368. doi:10.1038/nm.4407 

Data from randomized phase 2 ENTRATA study demonstrate telaglenastat with everolimus improves progression-free survival in renal cell carcinoma. News release. Calithera Biosciences Inc. September 29, 2019. Accessed September 28, 2020. https://bit.ly/2HXvruD 

Calithera Biosciences reports second quarter 2020 financial results and recent highlights. News release. Calithera Biosciences. August 10, 2020. Accessed September 29, 2020. https://bit.ly/3itozl9

Guerra VA, Burger JA, Borthakur GM, et al. Interim analysis of a phase II study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in advanced myelodysplastic syndrome (MDS). 

. 2019;134(suppl 1):567. doi:10.1182/blood-2019-125970

Features

Telaglenastat, a novel drug that targets a key metabolic pathway, has shown encouraging antitumor activity in several cancer types.

Utilizing Tumor Metabolism in Solid Malignancies | Supplements and Featured Publications

Dr. Rizvi on the Rationale to Evaluate Telaglenastat in KEAP1/NRF2-Mutant NSCLC

Novel Mechanism of Action and Tolerability Makes Telaglenastat a Promising Player in RCC

Dr. Lee on the Rationale for Evaluating Telaglenastat in RCC

Dr. Levy on the Mechanism of Action of Telaglenastat in NSCLC

Investigators Tackle New NSCLC Target With Glutaminase Inhibitor