Efficacy and Safety of Ivosidenib in Patients with Previously Treated CCA with an IDH1 Mutation: The ClarIDHy Trial

The global, phase 3, multicenter, randomized, double-blind ClarIDHy study (ClinicalTrials.gov Identifier: NCT02989857) compared the first-in-class, oral, small-molecule inhibitor of mutant IDH1 ivosidenib with placebo in patients with previously treated unresectable or advanced cholangiocarcinoma (CCA) who harbor IDH1 mutations. Final results of the ClarIDHy study were presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Annual Meeting.

In the ClarIDHy study, eligibility criteria included unresectable or metastatic CCA, centrally confirmed IHD1 mutations by next-generation sequencing, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; measurable disease (RECIST version 1.1), and 1 or 2 prior therapies. Eligible patients were randomized in a 2:1 ratio to receive ivosidenib (500 mg once daily in continuous 28-day cycles) or placebo. Stratification was by number of prior systemic therapies (1 or 2). The study design allowed crossover from placebo to ivosidenib upon radiographic disease progression. The primary end point was progression-free survival (PFS) by blinded independent radiology center (IRC). Secondary end points included overall survival (OS), objective response rate, investigator-assessed PFS, safety, and health-related quality of life (HRQOL). Since crossover may confound estimates of survival, rank-preserving structural failure time (RPSFT) was applied to adjust for crossover in the trial. The data cutoff was May 31, 2020.

A total of 187 eligible patients were randomized to receive ivosidenib (n = 126) or placebo (n = 61). The median age of the study population was 62 years. The majority of the participants were female, had intrahepatic CCA (91%), and had metastatic disease (93%). Overall, 47% of the patients had received 2 prior therapies. The majority of patients receiving placebo (70.5%) crossed over to open-label ivosidenib upon radiographic disease progression and unblinding, as permitted by the study protocol. At data cutoff, 25 (15.1%) patients remained on ivosidenib for ≥1 years, including 6 crossover patients.

The primary end point was met with significant improvement in PFS by IRC with ivosidenib versus placebo (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.25-0.54; P <.0001), which extended across all prespecified subgroups tested, including sex, prior lines of therapy, extent of disease at screening, cancer type at initial diagnosis, and ECOG PS. The disease control rate was 53% with ivosidenib versus 28% with placebo.

OS analysis, following 79% OS events in the ivosidenib arm and 82% in the placebo arm, showed a favorable trend for improved OS with ivosidenib treatment versus placebo (median OS, 10.3 vs 7.5 months, respectively; HR, 0.79; 95% CI, 0.56-1.12; one-sided P = .093). After accounting for crossover, the RPSFT-adjusted median OS was 5.1 months with placebo (HR, 0.49; 95% CI, 0.34-0.70; P <.0001).

Common all-grade ivosidenib treatment-emergent adverse events (TEAEs) that occurred in ≥15% of the patients included nausea (41.5%), diarrhea (35.0%), fatigue (30.9%), cough (25.2%), abdominal pain (24.4%), decreased appetite (24.4%), ascites (22.8%), vomiting (22.8%), and anemia (17.9%). A higher proportion of patients in the ivosidenib cohort, compared with the placebo cohort, experienced grade ≥3 TEAEs (53.0% vs 37.3%, respectively). The most common grade ≥3 TEAEs associated with ivosidenib therapy included ascites (9.0%), anemia (7.2%), and increased blood bilirubin (5.4%). No treatment-related deaths were reported. Treatment discontinuation due to adverse events occurred more frequently in the placebo arm than in the ivosidenib arm (8.5% vs 6.6%, respectively).

Compared with those in the placebo group, ivosidenib-treated patients preserved HRQOL physical functioning subscale and pain subscales. Patients in the ivosidenib cohort experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2, day 1, compared with those in the placebo group (nominal P <.05).

The final results of the ClarIDHy trial demonstrated the clinical benefit of ivosidenib in patients with previously treated, unresectable or metastatic CCA who harbor an IDH1 mutation in terms of PFS, safety, and HRQOL, demonstrating a favorable OS trend despite a high rate of crossover.

These results were recently published, and on August 25, 2021, the US Food and Drug Administration (FDA) approved ivosidenib for adult patients with previously treated, locally advanced or metastatic CCA with an IDH1 mutation, as detected by an FDA-approved test.

Sources

Abou-Alfa GK, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl_15):4069-4069.

Zhu AX, Macarulla T, Javle MM, et al. Final overall results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 2021;7:1669-1677.