Ivosidenib PFS Benefit in IDH1+ Cholangiocarcinoma Demonstrated in Newly Published Data

Ghassan K. Abou-Alfa, MD

Ivosidenib (Tibsovo) induced a 63% reduction in the risk of disease progression or death versus placebo in previously treated patients with IDH1-mutant advanced cholangiocarcinoma, according to findings from the phase 3 ClarIDHy study published in the Lancet Oncology.

“With no approved targeted therapies, and modest survival outcomes with chemotherapy in patients with unresectable or metastatic cholangiocarcinoma, there is an urgent need for new therapies. Although cholangiocarcinoma-associated genetic alterations are now better defined, there are still no approved targeted therapies in this disease,” wrote lead investigator Ghassan K. Abou-Alfa, MD, from the Memorial Sloan Kettering Cancer Center, and coauthors.

“This study of ivosidenib shows a benefit of targeting mutant IDH1 in patients with advanced, IDH1-mutant cholangiocarcinoma, and highlights the clinical relevance of tumor mutation profiling in the management of this rare cancer with poor outcomes,” added Abou-Alfa et al.

In the ClarIDHy study, 185 patients with IDH1-mutant cholangiocarcinoma were randomized in a 2:1 ratio to oral ivosidenib at 500 mg daily (n = 124) or matched placebo (n = 61). Crossover from the placebo arm to ivosidenib was permitted following signs of radiographic progression. The primary endpoint of the study was PFS by blinded independent review, with OS, PFS by local review, safety, and response as key secondary endpoints.

Prior to study entry, patients had received 1 to 2 prior therapies, including 1 gemcitabine- or 5-FU—containing regimen. The median age of patients was 62 years, 91% had intrahepatic disease, and 92% had metastatic disease. Nearly half of patients (46%) had received 2 prior therapies, and the remainder received 1. All patients had confirmed IDH1 mutations by next-generation sequencing and an ECOG performance score of 0 or 1. Slightly more patients in the placebo group had an ECOG score of 1 (67.2%) compared with the ivosidenib group (59.7%).

The partial response rate was 2.4% with the IDH1 inhibitor compared with 0% for placebo. Stable disease (SD) was experienced by 50.8% versus 27.9% of patients, for an overall disease control rate (PR plus SD) of 53% versus 28%, for ivosidenib and placebo, respectively.

At 6 months, 32% of patients in the ivosidenib arm remained alive and progression-free, compared with no progression-free patients in the placebo group. By month 12, the PFS rate was 22% in the investigational arm.

The median OS was 10.8 months with ivosidenib and 9.7 months for placebo. At 6 months, 67% of patients in the ivosidenib arm remained alive compared with 59% in the placebo group. By month 12, the OS rate was 48% with ivosidenib compared with 38% for placebo.

To adjust for the high rate of crossover between the arms, investigators performed an analysis looking at rank-preserving structural failure time (RPSFT) for placebo. In this analysis, the 6-month OS rate fell to 46% in the placebo group, and the median was 6 months. The 12-month OS rate was unavailable, as no more patients remained in the placebo arm at this point. When using the RPSFT data, there was a 54% reduction in the risk of death with ivosidenib, with medians of 6 versus 10.8 months, respectively (HR, 0.46; 95% CI, 0.28-0.75; P <.001).

The most common treatment-emergent adverse events (AEs) in the ivosidenib and placebo groups, respectively, were nausea (35.5% vs 25.4%), diarrhea (30.6% vs 15.3%), fatigue (26.4% vs 16.9%), cough (20.7% vs 8.5%), abdominal pain (21.5% vs 13.6%), ascites (20.7% vs 15.3%), decreased appetite (19% vs 18.6%), anemia (14.9% vs 5.1%), and vomiting (19% vs 16.9%). Treatment-emergent AEs led to discontinuation for 8.5% of those in the placebo arm compared with 5.8% of those in the ivosidenib group.

Grade ≥3 treatment-emergent AEs were experienced 46.2% of patents in the ivosidenib group compared with 35.6% for placebo. The most common grade ≥3 treatment-emergent AEs in the ivosidenib and placebo groups, respectively, were ascites (7.7% vs 6.8%), bilirubin increase (5.8% vs 1.7%), anemia (5.1% vs 0%), and AST increase (5.1% vs 1.7%).

Ivosidenib is currently approved by the FDA for the treatment of patients with acute myeloid leukemia (AML) with a susceptible IDH1 mutation. It is specifically approved for patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy; as well as for patients with relapsed or refractory AML.

Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study [published May 13, 2020]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(20)30157-1

The median progression-free survival was 2.7 versus 1.4 months, for ivosidenib and placebo, respectively (HR, 0.37; 95% CI, 0.25-0.54; P <.0001). In addition to the primary endpoint of PFS, the IDH1 inhibitor also showed a non-statistically significant improvement in overall survival (OS). Despite more than half of patients crossing over (57%), there was a 31% trend toward reduction in the risk of death with ivosidenib (HR, 0.69; 95% CI, 0.44-1.10; P = .06).