FDA批准Ivosidenib治疗IDH1+胆管癌的新药申请

Data from the Phase 3 ClarIDHy clinical trial support the NDA for ivosidenib. The latest results from the trial were presented at the American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO-GU). In the ClarIDHy trial, ivosidenib reduced the risk of death by 21% compared with placebo in patients with IDH1-mutant cholangiocarcinoma, meeting the trial's primary endpoint of improved progression-free survival [PFS].

In this trial, use of ivosidenib also showed an improvement in overall survival (OS). Median OS was 10.3 months for patients who received ivosidenib versus 7.5 months for those who received placebo (HR, 0.79; 95% CI, 0.56-1.12; one-sided P=0.093). At 6 months, the OS rate was 69% in the ivosidenib group and 57% in the placebo group. At 1 year, the OS rates were 43% and 36%, respectively.

The placebo group was allowed to switch to ivosidenib at the time of radiographic progression. Based on prespecified analyses, patients in the placebo group who adjusted their medication to ivosidenib had a median OS of 5.1 months (HR, 0.49; 95% CI 0.34-0.70, one-sided P<0.0001).

Safety data from the trial have been previously published. Data show that in the ivosidenib group and placebo group, the most common treatment-related adverse reactions (TEAEs) were nausea (38.0% vs 28.8%), diarrhea (33.1% vs 16.9%), fatigue (28.9% vs 16.9%), and abdominal pain (22.3% vs 15.3%), cough (21.7% vs 8.5%), decreased appetite (21.7% vs 18.6%), ascites (19.9% vs 15.3%), vomiting (19.9% vs 18.6%) and anemia (18.1% vs 5.1%).

Grade 3 adverse events occurred in 53% of patients in the trial. The most common grade ≥3 adverse events in the ivosidenib and placebo groups were ascites (9.0% and 6.8%, respectively), increased blood bilirubin (5.4% and 1.7%, respectively), and anemia (7.2% and 0%, respectively).

The ClarIDHy trial was an international, randomized trial of 187 patients with previously treated IDH1-mutant cholangiocarcinoma. The selected patients were randomly divided into two groups in a 2:1 ratio, receiving daily oral ivosidenib 500 mg (n=126) or placebo (n=61). Patients were eligible if they were 18 years of age or older, had IDH1-mutant cholangiocarcinoma, and had received 1 or 2 prior treatments, including 1 regimen containing gemcitabine or 5-fluorouracil.

In addition to the primary endpoint, the trial explored key secondary endpoints including overall survival, objective response rate, PFS, safety and tolerability, pharmacokinetics, pharmacodynamics and health-related quality of life.

Baseline screening revealed that the median age of enrolled patients was 62 years. 92.4% of patients had intrahepatic lesions, and 92.3% had liver metastases. Most patients (46.7%) had received 2 treatments, and the remaining patients had received 1 treatment. Next-generation sequencing confirmed that 71.05% of patients had IDH1 mutations in R132C. The remaining patients showed R132L/G/S/H IDH1 mutations. At baseline examination, 35.4% of patients had an ECOG performance status of 0 and 1.63% had an ECOG performance status of 1.

The ClarIDHy trial is the first phase 3 randomized trial in previously treated IDH1-mutant cholangiocarcinoma. Ivosidenib is an oral, first-class oral small molecule IDH1 inhibitor that has previously shown promise in acute myeloid leukemia and is approved by the FDA for use in patients over 75 years old with newly diagnosed disease or with comorbidities that preclude intensive induction chemotherapy; as well as in patients with relapsed or refractory AML.

If ivosidenib is approved by the FDA for the treatment of IDH1-mutated cholangiocarcinoma, the drug would be the first FDA-approved systemic therapy for this disease.

References:

https://www.targetedonc.com/view/fda-receives-new-drug-application-for-ivosidenib-in-idh1-cholangiocarcinoma