Ivosidenib Shows Modest OS Trend in IDH1+ Cholangiocarcinoma

Ivosidenib (Tibsovo) demonstrated a consistent trend toward improved overall survival (OS) compared with placebo in treatment-naïve patients with IDH1-positive cholangiocarcinoma, although the benefit was not determined to be statistically significant, according to final OS data from the phase 3 ClarIDHy trial (NCT02989857).¹

However, the OS end point can be impacted by crossover within the trial, according to Agios Pharmaceuticals, Inc, the drug developer. Thus, these data should be considered in the context of the 70% of participants in the placebo arm who crossed over to the investigational arm following radiographic disease progression. Further analyses that account for crossover could potentially support OS improvement with ivosidenib in this patient population.

Submission of a supplemental new drug application for ivosidenib in previously treated patients with IDH1-mutated cholangiocarcinoma is planned for the first quarter of 2021, according to Agios. The pharmaceutical company plans to work closely with regulators on the next step for the drug in the process. A full analysis of the data from CLarIDHy will be submitted for presentation at a future medical conference.

“Advanced cholangiocarcinoma is a rapidly progressing, aggressive disease with a grim prognosis for patients,” Chris Bowden, MD, chief medical officer at Agios, stated in a press release. “The data from the ClarIDHy phase 3 study show that treatment with [ivosidenib] has the potential to lengthen time to disease progression and have a clinically meaningful impact on life expectancy for patients with IDH1-mutant cholangiocarcinoma. We will collaborate closely with regulators to advance this potential new oral, targeted treatment option for patients.”

Previously reported data from ClarIDHy published inthe Lancet Oncology showed that ivosidenib resulted in a 63% reduction in the risk of disease progression or death compared with placebo in this patient population.²

A total of 185 patients with IDH1-mutated cholangiocarcinoma were randomized in a 2:1 fashion to receive oral ivosidenib at 500 mg daily (n = 124) or matched placebo (n = 61). Notably, crossover from the placebo arm to the ivosidenib arm was allowed following radiographic progression. The primary end point of the trial was PFS per blinded independent review. Secondary end points included OS, PFS per local review, safety, and response.

Before enrollment, patients had received 1 to prior therapies, including 1 gemcitabine-based or 5-flourouracil–containing regimen. The median age of participants was 62 years, and the majority, or 91%, had intrahepatic disease. Ninety-two percent of patients had metastatic disease. Moreover, 46% received 2 previous therapies, while the rest received just 1. All participants had tumors that harbored an IDH1 mutation and an ECOG performance status of 0-1. More patients in the placebo arm, 67.2%, had an ECOG performance status of 1 compared with 59.7% of those in the ivosidenib arm.

Additional results showed that the partial response rate with ivosidenib was 2.4% versus 0% with placebo. Moreover, more patients on the experimental arm achieved stable disease compared with those on the placebo arm, at 50.8% and 27.9%, respectively. The overall disease control rate for ivosidenib was 53% versus 28% with placebo.

At 6 months, 32% of patients who received ivosidenib remained alive and free of disease progression compared with no progression-free patients who received placebo. By month 12, the PFS rate was 22% with the IDH1 inhibitor.

The median OS was also longer with ivosidenib compared with placebo, at 10.8 months versus 9.7 months, respectively. At 6 months, a higher number of patients on the ivosidenib arm remained alive versus those on the placebo, at 67% versus 59%, respectively. By month 12, the OS rates were 48% versus 38% with ivosidenib and placebo, respectively.

When adjusting for the high crossover rate between the 2 cohorts, investigators conducted an analysis focused on rank-preserving structural failure time for placebo and found that the 6-month OS rate fell to 46% in the placebo cohort, with a median of 6 months. The 12-month OS rate had been unavailable because no participants remained on placebo at that time point. When utilizing these data, a 54% reduction in the risk of death was reported with the IDH1 inhibitor (HR, 0.46; 95% CI, 0.28-0.75; P <.001).

With regard to safety, the most commonly experienced treatment-emergent toxicities included nausea (35.5% with ivosidenib vs 25.4% with placebo), diarrhea (30.6% vs 15.3%, respectively), 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 (19.0% vs 18.6%), anemia (14.9% vs 5.1%), and vomiting (19.0% vs 16.9%). Treatment-emergent adverse effects (TEAEs) that led to drug discontinuation occurred in 8.5% of those on the placebo cohort versus 5.8% of those in the ivosidenib cohort.

Grade 3 or higher TEAEs were reported in more patients on the IDH1 inhibitor compared with placebo, at 46.2% versus 35.6%, respectively. The most common grade 3 or higher toxicities in these arms included ascites (7.7% vs 6.8%, respectively), bilirubin increase (5.8% vs 1.7%), anemia (5.1% vs 0%), and increased aspartate transaminase (5.1% vs 1.7%).

The IDH1 inhibitor is approved by the FDA for use in patients with acute myeloid leukemia (AML) with a susceptible IDH1 mutation. Specifically, ivosidenib is indicated for those with newly diagnosed disease who are 75 years of age or older or have comorbidities that preclude the use of intensive induction chemotherapy, and for those with relapsed or refractory disease.

References

1. Agios announces final overall survival data from phase 3 ClarIDHy study of TIBSOVO (ivosidenib tablets) in previously treated IDH1-mutant cholangiocarcinoma patients. News release. Agios Pharmaceuticals, Inc. September 21, 2020. Accessed September 22, 2020. https://bit.ly/3cjvA6I.
2. 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. Lancet Oncol. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1