The Silver Lining of Failure in Cancer Drug Development

CUREKidney Cancer Special Issue 2022

One expert explains how the road to cancer drug development isn’t a smooth one, but progress can be made nonetheless.

The news often highlights positive clinical trials, in which the outcomes that researchers were hoping for occur, potentially leading to Food and Drug Administration (FDA) approvals. But what happens with trials that miss the mark?

One expert said those “misses” should not be considered a loss altogether, but rather, something that is to be expected and does not mean the end of the road for a particular therapy.

“We have to accept that reality,” Dr. Nizar M. Tannir, professor in the department of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “Most trials are going to fail, but a silver lining is ... there will be lessons learned from a trial that failed. What went wrong? Was the drug not potent enough? ... Maybe we can repurpose a drug or use a drug in a different patient population.”

Tannir and colleagues are facing exactly that after the CANTATA clinical trial. Results from the trial were presented at a major oncology conference earlier this year and published in JAMA Oncology in September.

In the trial, 444 patients with metastatic clear cell renal cell carcinoma (RCC) were randomly assigned to Cabometyx (cabozantinib) with the glutaminase inhibitor telaglenastat or placebo. No significant difference was seen between the two groups for progression-free survival (the time during and after treatment that a patient lives with the disease without worsening), despite the treatment being well tolerated.

“That was disappointing for me and many of the investigators in the field who participated in the trial and for many people who were hopeful that maybe we will have a new class of agents, a new target for RCC, which is the glutamine pathway and tumor metabolism,” Tannir said. “But as we know, many, many trials fail — many trials with promising, encouraging data in earlier-phase trials.”

Tannir explained the reasoning behind inhibiting the enzyme glutaminase to treat patients with metastatic RCC.

“Many solid tumors including RCC had increased glutaminase expression when we tested tumor tissues,” he said. “The rationale behind that is the tumor cell relies on (certain) pathways for producing energy. A normal cell will produce energy for its survival via glucose (sugar), whereas a cancer cell has a faulty glucose utilization or metabolism, so tumor cells rely more and more on other pathways for survival. One of those pathways is (the amino acid) glutamine.”

Because the rationale is there, further research may continue in this area.

“(Results from CANTATA don’t) mean that the idea of targeting tumor metabolism or glutamine should be dead,” Tannir said. “When you give a treatment, everybody with kidney cancer, even if they all had clear cell (RCC), all of these RCCs are driven differently. You need to see if your drug is going to work. It might work for 10% of the patients, 15% or 20%. We need to identify who are (the) patients who (will benefit most).”

Tannir gave an example of another target with negative trials before it was approved by the FDA — anti-CTLA-4 therapies, which are immune checkpoint inhibitors. The first trial assessing an anti-CTLA-4 therapy was conducted more than 15 years ago in patients with RCC. In this phase 2 trial, patients were treated with a 3-milligram-per-kilogram dose of Yervoy (ipilimumab) and had a 13% objective response rate (a measurable response) to the therapy.

However, the dose was deemed too toxic for patients, leading to other studies with other doses. Yervoy was ultimately approved in combination with Opdivo (nivolumab) for RCC, among other indications.

It is important for patients to know how participation in clinical trials is valuable to further the space along.

“Patients need to participate in trials, we need to design and conduct trials, we need to develop new drugs, we need to test new drugs, and I hope patients will see the benefit of this,” Tannir said. “We appreciate the trust of patients and families to support (this). It’s not easy to participate in clinical trials. There is demand on patients and their caregivers — time, effort, transportation, finances, all this to enroll on a clinical trial.”

Tannir added that persistence is also necessary to further the field and develop additional treatment options.

“Do not despair, do not give up and do not be discouraged that the trial was negative,” Tannir said. “There will be other (trials) that will be positive. We just have to keep pushing the envelope; I am confident that in the near future we will make cancer history.”

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