Ivosidenib Wins European Approval for IDH1-mutated AML and Cholangiocarcinoma

The European Commission (EC) has approved ivosidenib tablets (Tibsovo) in combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an IDH1 R132 mutation who are not eligible to receive standard induction chemotherapy, and as monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who received at least 1 prior line of systemic therapy.¹

The AML approval was supported by data from the phase 3 AGILE trial (NCT03173248), which showed that ivosidenib plus azacitidine elicited a statistically significant improvement in event-free survival (EFS; HR, 0.33; 95% CI, 0.16-0.69; P = .002) and overall survival (OS; HR, 0.44; 95% CI, 0.27-0.73; P = .001) vs azacitidine plus placebo. Patients treated with ivosidenib plus azacitidine (n = 72) experienced a median OS of 24.0 months (95% CI, 11.3-34.1) vs 7.9 months (95% CI, 4.1-11.3) for those treated with azacitidine plus placebo (n = 74).²

The regulatory decision for ivosidenib monotherapy for the treatment of patients with IDH1 R132–mutated cholangiocarcinoma was based on findings from the phase 3 ClarIDHy trial (NCT02989857). Data demonstrated that ivosidenib produced a statistically significant improvement in progression-free survival (PFS) per independent review committee (IRC) assessment vs placebo (HR, 0.37; 95% CI, 0.25-0.54; P < .001).¹

“The prognosis for patients diagnosed with AML or cholangiocarcinoma has historically been poor with very limited treatment options. With today’s approval by the European Commission, [ivosidenib] is now the first targeted IDH1 inhibitor approved in Europe,” Arnaud Lallouette, MD, executive vice president of Global Medical & Patient Affairs at Servier, stated in a news release.

“This further affirms our unparalleled scientific leadership in harnessing the IDH mutation and commitment to finding new therapeutic solutions for patients with difficult and hard-to-treat cancers.”

In May 2022, the FDA approved ivosidenib in combination with azacitidine for the treatment of patients with newly diagnosed IDH1-mutated AML who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.³

The regulatory agency approved ivosidenib for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by an FDA-approved test, in August 2021.⁴

The global, multicenter, double-blind, randomized, placebo-controlled AGILE trial enrolled patients with newly diagnosed IDH1-mutated AML who were ineligible for intensive induction chemotherapy. Patients were randomly assigned to receive 500 mg of oral ivosidenib or matching placebo once daily with subcutaneous or intravenous azacitidine at 75 mg/m2 for 7 days during each 28-day cycle.

The primary end point of AGILE was EFS. Secondary end points included complete remission (CR) rate, OS, CR with partial hematologic recovery rate, and objective response rate (ORR).¹

Regarding safety, grade 3 or higher adverse effects (AEs) included febrile neutropenia (28% and 34% for the ivosidenib and placebo arms, respectively) and neutropenia (27% and 16%). Additionally, any-grade bleeding events occurred in 41% of patients in the ivosidenib arm vs 29% in the placebo arm. Any-grade infection was reported in 28% of patients treated with ivosidenib and 49% of patients given placebo. Differentiation syndrome of any grade was observed in 14% of patients in the ivosidenib group and 8% of patients in the placebo group.²

The global, randomized ClarIDHy trial enrolled previously treated patients with IDH1-mutant cholangiocarcinoma who had documented disease progression following 1 or 2 systemic therapies in the advanced setting.¹

Patients were randomly assigned 2:1 to receive 500 mg of oral ivosidenib or placebo once daily. Crossover to the ivosidenib arm was permitted at the time of documented radiographic progression per RECIST v1.1 criteria.

PFS per IRC assessment served as the primary end point. Secondary end points consisted of investigator-evaluated PFS, safety and tolerability, ORR, OS, duration of response, pharmacokinetics, pharmacodynamics, and quality-of-life assessments.

The most common AEs reported in patients treated with ivosidenib during the ClarIDHy study included fatigue, nausea, abdominal pain, diarrhea, decreased appetite, ascites, vomiting, anemia, and rash.

References

1. Servier receives European Commission approval of Tibsovo® (ivosidenib tablets) in IDH1-mutated acute myeloid leukemia and IDH1-mutated cholangiocarcinoma. News release. Servier. May 10, 2023. Accessed May 10, 2023. https://www.prnewswire.com/news-releases/servier-receives-european-commission-approval-of-tibsovo
2. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344
3. FDA approves ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. News release. FDA. May 25, 2022. Accessed May 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-combination
4. FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. News release. FDA. August 25, 2021. Accessed May 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma