Ivosidenib extends overall survival in patients with previously treated, advanced cholangiocarcinoma whose disease harbors IDH1 mutations. Median overall survival was 10.3 months in patients who received the drug, versus 7.5 months in the placebo group. The difference was even larger—5.1 months—when researchers accounted for patient crossover into the treatment group.

Ivosidenib (Tibsovo; Servier Pharmaceuticals) extends overall survival (OS) in patients with advanced or metastatic cholangiocarcinoma who carry IDH1 mutations. That's according to the latest results from the clinical trial that led to the drug's approval (JAMA Oncol 2021 Sep 23 [Epub ahead of print]).

Chemotherapy has long been the standard treatment for cholangiocarcinomas that cannot be surgically removed, but targeted therapies for subgroups of patients are starting to receive FDA approval. Patients with FGFR2 fusions, which occur in about 10% to 15% of cholangiocarcinomas that originate inside the liver, now have two options: Pemigatinib (Pemazyre; Incyte) received the green light in 2020, and infigratinib (Truseltiq; QED Therapeutics) was approved in May (Cancer Discov 2021;11:OF5).

Another subgroup of patients carries mutations in IDH1. These alterations occur in about 13% of patients with tumors starting in the liver and in about 1% of patients with tumors originating in the bile ducts outside the organ. The phase III ClarIDHy trial tested ivosidenib—an IDH1 inhibitor approved to treat acute myeloid leukemia—in 187 patients with chemotherapy-refractory disease who were randomly assigned 2:1 to receive ivosidenib or placebo.

In 2020, researchers reported that ivosidenib met the trial's primary endpoint, increasing median progression-free survival (PFS) from 1.4 months to 2.7 months (Lancet Oncol 2020;21:796–807). The results also showed a 51% rate of stable disease. The FDA granted ivosidenib priority review based on these data and approved the drug for the treatment of cholangiocarcinoma at the end of August.

Now, a final efficacy analysis shows that ivosidenib also improves median OS, which was 10.3 months in the treated patients and 7.5 months in the placebo group. Patients in the latter group whose disease progressed were permitted to switch to the treatment arm, and when the investigators accounted for these crossovers, the median OS in the placebo group was even shorter, only 5.1 months.

Ivosidenib was well tolerated, with nausea and abdominal fluid buildup being the most common side effects.

“The results from our trial have validated IDH1 as a therapeutic target in cholangiocarcinoma, and we now have a new treatment option for patients with advanced cholangiocarcinoma harboring IDH1 mutations,” says lead author Andrew Zhu, MD, PhD, now at Jiahui International Cancer Center in Shanghai, China.

Despite positive PFS results reported from ClarIDHy, the objective response rate with ivosidenib was only 2%, says Gregory Gores, MD, of the Mayo Clinic in Rochester, MN, who wasn't connected to the trial. “So, you didn't feel comfortable with only PFS.” The new findings are important because they show that “ivosidenib does have an effect on overall survival,” he says.

Joseph Franses, MD, PhD, of Harvard Medical School in Boston, MA, who also wasn't connected to the trial, notes that “the drug does not seem to result in significant tumor shrinkage, but it does seem to stabilize the cancer in some patients.” The drug's limited side effects are an advantage, he adds. “It's easier on patients than chemotherapy.”

Now that ivosidenib has been approved, the next questions for researchers to answer are what combinations will improve its effectiveness, how resistance arises, and whether it works as a first-line therapy. –Mitch Leslie