Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Patients receiving Ivosidenib had longer overall survival as compared to patients on placebo.

2. Quality of life measures favored Ivosidenib as compared to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Advanced cholangiocarcinoma is aggressive with a poor prognosis. Previous phase-1 trials investigating ivosidenib have shown increased overall survival (OS) in advanced cholangiocarcinoma with the IDH1 mutation. This current phase-3 randomized trial investigated the impact of treatment with ivosidenib on overall survival as compared to placebo amongst patients with IDH1-mutant chemotherapy-refractory cholangiocarcinoma. By comparing OS, quality of life (QOL), and safety/tolerability between a treatment arm (ivosidenib) and control arm (placebo), it was shown that these outcome measures were increased in patients receiving ivosidenib. Median OS was greater in the ivosidenib group than the placebo group, even after adjusting for treatment-arm crossover. Ivosidenib outperformed placebo on most measures of QOL, including physical functioning, pain, emotional and cognitive function, fatigue, anxiety, and dyspnea. QOL results for appetite and eating were similar between groups. Safety and tolerability outcomes were similar between treatment arms. Nausea of any severity was the most common adverse effect noted in both groups and the most common severe adverse effect was ascites. Adverse effects associated with treatment occurred in 4% of patients receiving ivosidenib and required a dose reduction, while no patients on placebo required treatment interruption. A major limitation to this study is that the OS outcome is likely confounded by permitting crossover from placebo to treatment arm. Seventy percent of the patients from placebo arm crossed over to the treatment arm as their disease had progressed. A second limitation is that the small sample sizes at the start of each treatment cycle affected the QOL analysis. In general, ivosidenib is a tolerable treatment for advanced cholangiocarcinoma with increased overall survival and QOL measures as compared to placebo.

Relevant Reading: Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study

In-Depth [randomized controlled trial]: This transnational, multi-center, phase 3 randomized trial of 187 eligible patients with IDH1-mutant advanced cholangiocarcinoma compared treatment outcomes with ivosidenib to placebo on overall survival (OS), quality of life (QOL), and safety/tolerability. Patients were randomized to either treatment arm or placebo by 2:1 ratio; 126 received ivosidenib and 61 received placebo. The eligibility requirements included adult patients with functional bone marrow, kidney, and hepatic function with IDH1 mutation cholangiocarcinoma and a 3-month expected survival who have had disease progression but had not received IDH1-specific treatment. Analysis showed median OS on ivosidenib was 10.3 months (95% confidence interval (CI), 7.8-12.4 months) and 7.5 months (95% CI, 4.8-11.1months) for patients receiving placebo (hazard ratio (HR) = 0.79; 95% CI,0.56-1.12). The results after adjusting for treatment-arm crossover using a rank-preserving structural failure time (RPSFT) model was a median OS of 5.1 months for placebo (HR = 0.49; 95% CI, 0.34-0.70; 1-sided P < 0.001). Five assessments were used to determine QOL (EORTC QLQ-C30, ORTC QLQBIL21, PGI-C, PGI-S, and EQ-5D-5L). The QOL measure of physical functioning was better in the treatment group compared to placebo where a higher score indicates better QOL for this measure. The least-squares mean (SE) difference from baseline in the treatment group compared to placebo in cycle 2 was 11.0 (P = 0.002). The pain scale results were similar, with ivosidenib showing better QOL outcomes. A lower score in this QOL measures is better. The SE difference from baseline for ivosidenib compared to placebo was -10.4 (2-sided P = 0.04). QOL measures of appetite loss and eating were similar between groups, while ivosidenib outperformed placebo on measures of emotional/cognitive function, fatigue, anxiety, and dyspnea. Nausea was the most common adverse effect in both groups; 42% of patients receiving ivosidenib and 29% of patients on placebo were affected. Ascites, the most common grade 3 adverse effect, was reported in 9% of treatment group patients and 7% of placebo patients. Treatment discontinuation secondary to adverse effects occurred for 7% of patients on ivosidenib and 8% of those on placebo.

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