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Agios Pushing Ahead in IDH-Mutated Solid Tumors With Tibsovo, Vorasidenib


NEW YORK – In a paper published in the Journal of Clinical Oncology last month, researchers zoomed in on a cohort from a Phase I open-label dose escalation and expansion study of ivosidenib (Agios' Tibsovo) and reported that the drug may have activity in IDH1-mutated chondrosarcoma patients.

Agios already has a presence in hematologic malignancies, but this latest data is part of a broader focus at the company to advance precision oncology therapies for solid cancers. In addition to chondrosarcoma, the company has plans to expand ivosidenib into IDH-mutated cholangiocarcinoma and glioma and is exploring an investigational pan-IDH inhibitor vorasidenib in IDH-mutated glioma.

The study led by Jonathan Trent and William Tap from Memorial Sloan Kettering found that in the chondrosarcoma cohort, which had 21 patients, 52 percent experienced stable disease after treatment with ivosidenib. In addition, the drug had minimal toxicity.

Chondrosarcoma is a rare cancer that usually occurs in the bones. Many patients with chondrosarcoma are resistant to standard chemotherapy but have no alternative options. Around 65 percent of chondrosarcoma patients harbor an IDH mutation.  

Ivosidenib is already approved in the US for adults with IDH1-mutated relapsed or treatment-refractory acute myeloid leukemia and for newly diagnosed IDH1-mutated AML patients who are ineligible for intensive chemotherapy. The US Food and Drug Administration has also approved Abbott Laboratories' RealTime IDH1 assay to identify those with IDH1 mutations who are eligible for ivosidenib therapy. 

Ivosidenib is an inhibitor of the enzyme isocitrate dehydrogenase-1 (IDH1), which is normally present throughout human cells and is responsible for catalyzing the conversion of isocitrate to alpha-ketoglutarate. When the enzyme is mutated, whether it's the isoform IDH1 versus IDH2, alpha-ketoglutarate is converted into 2-hydroxyglutarate, which is thought to be an oncogenic metabolite that can rewire the cell's normal metabolism and cause epigenetic alterations that can lead to the development of cancer.

"When we think about cancer, we think of multiple hits to the genome that triggers the development of a tumor. But we think [mutated IDH] is a very early onset genetic aberration that leads to the development of cancer," said Susan Pandya, VP of clinical development at Agios. "We view it as it is a driver in the disease biology."

Because IDH is a gain-of-function mutation that results in the product 2-hydroxyglutarate (2-HG) that can be measured in the plasma of patients, investigators have been looking for reductions in 2-HG levels in patient biopsies as a metric to see if the drug has been acting on-target. The suppression of 2-HG after treatment has been observed in cholangiocarcinoma, AML, and glioma.

Since the first approvals of the drug in AML, Agios has been exploring ivosidenib in a variety of hematologic indications. For example, in one Phase III trial, the firm is exploring ivosidenib in newly diagnosed, IDH1-mutated AML patients in combination with induction therapy and consolidation therapy, followed by maintenance therapy. 

In AML, intensive chemotherapy combinations are usually delivered in an inpatient setting to get a patient to the stage where they can receive a bone marrow transplant, which is a potentially curative option in this disease.

There is also the Phase III AGILE trial, in which researchers are studying ivosidenib in combination with hypomethylating drug azacitidine versus azacytidine alone in previously untreated IDH1-mutated AML patients. Enrollment for the trial is expected to wrap up by the end of this year. Pandya said that the company is interested running future trials of ivosidenib in the frontline setting for AML.

Given the company's success in hematological malignancies with ivosidenib, she said the next step in the program was to address IDH-mutated solid tumors. The Phase I trial data that led to the JCO paper represents Agios' foray outside of hematologic cancers.

Agios' Phase I studies for ivosidenib are open to any type of IDH1-mutated tumors, but the majority of enrolled patients fell into one of three categories: cholangiocarcinoma, glioma, and chondrosarcoma. These three cancers happen to have the highest frequency of IDH mutations.

The company is supporting investigator-sponsored trials (ISTs) in chondrosarcoma and a Phase II chondrosarcoma trial by MSK is active and recruiting patients. 

However, Agios' most advanced IDH1-mutated solid tumor program for ivosidenib is in cholangiocarcinoma, a cohort that broke off of the original Phase I solid tumor trial. After showing promising improvements in progression-free survival, the monotherapy advanced into the Phase III ClarIDHy trial. Researchers presented updates from this trial at the European Society for Medical Oncology meeting last year.

In that study, the drug met its primary endpoint of progression-free survival. Additionally, primary analysis showed that ivosidenib was able to reduce the risk of disease progression or death by 63 percent. Pandya said the company expects a more mature overall survival readout in cholangiocarcinoma by mid-2020 and hopes to use the results to support a supplemental new drug application by year-end.

There are no approved targeted therapies for cholangiocarcinoma. The standard of care is combination chemotherapy in the frontline setting and no definitive second-line option.

Shortly after Agios completed Phase I studies of ivosidenib in IDH-mutated gliomas, the company started a second wave of Phase I studies with vorasidenib, an investigational brain-penetrant pan-IDH inhibitor that captures both the IDH1 and IDH2 isoforms, in glioma patients.

In a Phase I study involving IDH-mutated glioma patients who were undergoing surgery, investigators further evaluated vorasidenib or ivosidenib. In those who received the vorasidenib before undergoing brain tumor surgery, researchers found a greater than 90 percent suppression of 2-HG, a metabolite that's often elevated in IDH-mutated glioma patients, compared to controls. This indicated the drug was acting as intended. There was similar activity seen with ivosidenib.

"What we also saw from this … dataset that was compelling was a response rate of up to 33 percent among those patients who continue to receive vorasidenib in the post-operative setting," said Pandya. When tumors are excised, oftentimes there's residual disease left behind that can be monitored with imaging to further study the effects of treatment. Patients who continued to receive vorasidenib post-operatively also saw shrinkage in their tumors.

"We saw that the median treatment duration from our earlier Phase I dataset with vorasidenib was extending out to 22 months, which was very encouraging," Pandya said, adding that based on this data Agios is now starting a Phase III trial, called Indigo, in this setting. The randomized trial will enroll up to 366 patients, and the company has activated some US study sites. 

"What we're trying to do with our IDH inhibitor vorasidenib is position it in the context of patients who've had surgery but have residual disease and are not ready for more aggressive therapy," said Pandya. "This is a really exciting opportunity to intervene on a mutant protein that's very likely driving the biology of the tumor, but also prevent patients from having to experience all the nasty side effects that are associated with more intensive therapy."