As reported in JAMA Oncology by Andrew X. Zhu, MD, PhD, and colleagues, the final overall survival analysis of the pivotal phase III ClarIDHy trial showed prolonged overall survival with ivosidenib vs placebo in previously treated patients with unresectable or metastatic cholangiocarcinoma and an IDH1 mutation, with the difference being statistically significant after adjustment for substantial crossover from placebo to ivosidenib during the trial.1
The trial supported the August 2021 approval of ivosidenib in this setting, showing that ivosidenib significantly prolonged progression-free survival, the primary endpoint of the trial.
Andrew X. Zhu, MD, PhD
In the double-blind trial, 187 patients from sites in France, Italy, South Korea, Spain, the United Kingdom, and the United States who had experienced disease progression on prior therapy were randomly assigned 2:1 between February 2017 and May 2020 to receive ivosidenib at 500 mg once daily (n = 126) or placebo (n = 61) until disease progression or unacceptable toxicity. Crossover from placebo to ivosidenib was permitted for patients with disease progression as determined by radiographic findings.
As of the data cutoff date (May 2020) for the final analysis, 43 patients (70%) from the placebo group had crossed over to receive open-label ivosidenib.
Maximum treatment durations were 34.4 months (range = 0.1–34.4 months) with ivosidenib and 6.9 months (range = 0–6.9 months) with placebo. Median treatment durations were 2.8 months (range = 0.1–34.4 months) and 1.6 months (range = 0–6.9 months), respectively.
In the intention-to-treat analysis, median overall survival was 10.3 months (95% confidence interval [CI] = 7.8–12.4 months) in the ivosidenib group vs 7.5 months (95% CI = 4.8–11.1 months) in the placebo group (hazard ratio = 0.79, 95% CI = 0.56–1.12, P = .09). A prespecified rank-preserving structural failure time (RPSFT) model was used to adjust for crossover. The RPSFT-adjusted median overall survival with placebo was 5.1 months (95% CI = 3.8–7.6 months), yielding a hazard ratio for ivosidenib vs placebo of 0.49 (95% CI = 0.34–0.70, P < .001).
Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo. No treatment-related deaths were reported.
The investigators concluded: “This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable overall survival benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with [an] IDH1 mutation.”
Disclosure: This study was supported by Agios Pharmaceuticals. Dr. Zhu has served as a consultant or advisor for AstraZeneca, Bayer, Eisai, Exelixis, Gilead, Lilly, Merck, Roche/Genentech, and Sanofi-Aventis; and has received research funding from Bayer, Bristol Myers Squibb, Lilly, Merck, and Novartis
1. Zhu AX, Macarulla T, Javle MM, et al: Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: The phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 7:1669-1677, 2021.