Ivosidenib Promising Against Refractory Bile Duct Cancer

By Marilynn Larkin

May 26, 2020

NEW YORK (Reuters Health) - Ivosidenib improved progression-free survival in patients with previously treated isocitrate dehydrogenase 1 (IDH1)-mutant cholangiocarcinoma in a phase 3 placebo-controlled trial.

Ivosidenib is a small-molecule targeted inhibitor of IDH1 developed by the study funder, Agios Pharmaceuticals.

"There is a tremendous need for molecularly targeted treatment options for patients with advanced/metastatic disease that has progressed following standard chemotherapy," Dr. Andrew Zhu of Massachusetts General Hospital Cancer Center in Boston told Reuters Health by email. "The results of (this) study underscor(e) the need for molecular testing of cholangiocarcinoma and the potential of this oral, targeted therapy to provide meaningful clinical benefit."

Dr. Zhu and colleagues enrolled adult patients from 49 hospitals in six countries with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on up to two previous treatment regimens, with an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1.

As reported in The Lancet Oncology, 185 patients (median age, 62; about 63% women) were randomly assigned to 500 mg ivosidenib once daily in continuous 28-day cycles (124 patients) or placebo (61). The median follow-up for progression-free survival was 6.9 months.

Overall, progression-free survival was significantly improved with ivosidenib (median 2.7 months vs. 1.4 months; hazard ratio 0.37).

Progression-free survival for those receiving ivosidenib was 32% at six months and 22% at 12 months. By contrast, no patients in the placebo group were free from progression for six months or more.

The most common grade 3 or worse adverse event in both treatment groups was ascites (7% in each group). Serious adverse events occurred in 30% patients receiving ivosidenib versus 22% of those receiving placebo. There were no treatment-related deaths.

"This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma," the authors conclude.

Dr. Zhu said future studies "will explore novel agents or combination strategies to overcome the primary and acquired resistance to ivosidenib."

Dr. Igor Astsaturov, Associate Professor, Department of Hematology/Oncology, at Fox Chase Cancer Center in Philadelphia commented in an email to Reuters Health, "This is an amazingly interesting result which already has had a dramatic impact on lives of patients with cholangiocarcinoma."

"Besides the direct demonstration of clinical efficacy by showing marked increase in progression- free survival, the unintended outcome of the trial is that all patients with this tumor are now required to be tested for a variety of cancer gene mutations," said Dr. Astsaturov, who is not an author of the paper. "Even though IDH1 mutations are very uncommon and are confined to a potentially well-differentiated variant of this cancer type, other drug-amenable mutations will be found and matched with the relevant drugs or clinical trials."

"Since the mutation is confined exclusively to the cancer cells and this pathogenic enzyme is not present in the body cells, the side-effects profile is extremely favorable, as reflected in the study," he added. "Some of my patients who participated in the study are still on the drug and doing well!"

"I would also anticipate that the IDH2 gene mutated biliary cancers may benefit from the equally potent IDH2 inhibitor, enasidenib, or dual inhibitors of IDH1/2," he noted.

The study was funded by Agios Pharmaceuticals. Dr. Zhu and a number of the coauthors have received fees from the company. Six coauthors are employees.

SOURCE: https://bit.ly/36s3vHk The Lancet Oncology, online May 13, 2020.