European Approval Sought for Ivosidenib in IDH1-Mutated AML and Cholangiocarcinoma

A marketing authorization application (MAA) has been submitted to the European Medicines Agency (EMA) for 2 indications of ivosidenib (Tibsovo): in combination with azacitidine in the frontline treatment of patients with IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy and in previously treated patients with locally advanced or metastatic IDH1-mutated cholangiocarcinoma.¹

Data from the phase 3 AGILE study (NCT03173248) showed that ivosidenib plus azacitidine (n = 72) significantly improved event-free survival (EFS) vs azacitidine alone (n = 74; HR, 0.33; 95% CI, 0.16-0.69; P = .0011) in patients with IDH1-mutated AML.² The addition of the IDH1 inhibitor to azacitidine also improved overall survival (OS) vs azacitidine alone, at a median of 24.0 months vs 7.9 months, respectively (HR, 0.44; 95% CI, 0.27-0.73; P = .0005).

Ivosidenib was also found to result in a statistically significant improvement in progression-free survival (PFS) vs placebo per independent review committee assessment (HR, 0.37; 95% CI, 0.25-0.54; P < .001), when evaluated in previously treated patients with IDH1-mutated, locally advanced or metastatic cholangiocarcinoma, according to findings from the phase 3 ClarIDHy trial (NCT02989857).³ The median PFS in the investigative (n = 126) and control (n = 61) arms were 2.7 months (95% CI, 1.6-4.2) and 1.4 months (95% CI, 1.4-1.6), respectively.

“This MAA submission is a further step toward the availability of [ivosidenib] in Europe, a targeted therapy for patients with previously untreated IDH1-mutated AML, and previously treated, locally advanced or metastatic IDH1-mutated cholangiocarcinoma – 2 rare cancers for which therapeutic options are limited,” Claude Bertrand, executive vice president of R&D of the Servier Group, stated in a press release. “We look forward to working with the EMA throughout the evaluation process of [ivosidenib], which is the first IDH1 mutation–specific targeted therapy to be submitted in Europe.”

Ivosidenib in IDH1-Mutated AML

AGILE enrolled those with untreated AML per the World Health Organization criteria. Patients had to have centrally confirmed IDH1 mutational status, an ECOG performance status of 0 to 2, and could not be eligible to receive induction chemotherapy.

Here, a total of 146 participants were randomized 1:1 to receive ivosidenib at a once-daily dose of 500 mg or placebo with azacitidine at a dose of 75 mg/m² for 7 days in 28-day cycles. Patients were stratified by region and whether they had de novo vs secondary AML.

The primary end point of the trial was EFS, and secondary end points included complete response (CR) rate, overall survival (OS), CR plus CR with partial hematological recovery (CRh) rate, and objective response rate (ORR).

The median age of patients in the investigative and control arms was 76.0 years (interquartile range [IQR], 70.5-79.5) and 75.5 years (IQR, 70.0-80.0), respectively. Moreover, in the ivosidenib arm, 75% of patients had de novo disease and 25.0% had secondary AML. Notably, 22.2% of those in the investigative arm had poor-risk genetics vs 27.0% of those on the control arm.

Data from the trial were presented during the 2021 ASH Annual Meeting. At the time of the presentation, a total of 27 of those on the investigative arm (n = 72) were still receiving treatment vs 12 patients on the control arm (n = 74).

The doublet produced an ORR of 62.5% (95% CI, 50.3%-73.6%) vs 18.9% (95% CI, 10.7%-29.7%) with azacitidine alone (P < .0001). The median time to CR in the ivosidenib/azacitidine and azacitidine-alone arms was 4.3 months and 3.8 months, respectively. In the investigative arm, the CR + CRh rate was 52.8% (95% CI, 40.7%-64.7%) vs 17.6% (95% CI, 9.7%-28.2%) in the control arm (P < .0001). The 24-week CR rates in the ivosidenib/azacitidine and azacitidine-alone arms were 37.5% and 10.8%, respectively.

Regarding safety, 93.0% of those who received ivosidenib/azacitidine experienced grade 3 or higher toxicities vs 94.5% of those who received azacitidine alone. The most common grade 3 or higher adverse effects (AEs) reported in the investigative and control arms, respectively, were febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%).

Ivosidenib in IDH1-Mutated Cholangiocarcinoma

ClarIDHy enrolled a total of 187 patients with IDH1-mutated cholangiocarcinoma who were at least 18 years of age and previously received 1 or 2 therapies that had to include a gemcitabine- or 5 fluorouracil–containing regimen. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and adequate hematologic, hepatic, and renal function.

Patients were randomized 2:1 to receive ivosidenib at a daily dose of 500 mg or placebo. Those receiving placebo were permitted to crossover to the IDH1 inhibitor after they experienced radiographic disease progression.

The primary end point of the trial was PFS per blinded independent radiology central review, and secondary end points included OS, ORR, PFS per local review, safety and tolerability, pharmacokinetics, pharmacodynamics, and health-related quality of life.

The data cutoff date for the final OS analysis of the trial was May 31, 2020.4 The median age among the 187 patients was 62 years (range, 33-83). Among these patients, 0.5% were American Indian or Alaska Native, 12% were Asian, 1% were Black or African American, 0.5% were Native Hawaiian other Pacific Islander patients, 57% were White, and 0.5% were of another race.

Among the 126 patients who received the IDH1 inhibitor, the median age was 61 years (range, 33-80) and 65% of patients were female. Among the 61 patients who received placebo, the median age was 63 years (range, 40-83) and 61% were female. Of all 187 patients, 93% had metastatic disease, 47% received 2 prior lines of therapy, and 70% had IDH1 R132C.

At the time of the data cutoff, 70% of patients who were on the placebo arm crossed over to receive ivosidenib.

Data showed that the median OS with ivosidenib was 10.3 months (95% CI, 7.8-12.4) vs 7.5 months (95% CI, 4.8-11.1) with placebo (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .09). The rank-preserving structural failure time–adjusted median OS was 5.1 months (95% CI, 3.8-7.6) in the control arm (HR, 0.49; 95% CI, 0.34-0.70; 1-sided P < .001). The 12-month OS rates in the ivosidenib and placebo arms, respectively, were 43% (95% CI, 34%-51%) and 36% (95% CI, 24%-48%).

The most common grade 3 or higher treatment-emergent AE (TEAE) reported in the investigative and control arms, respectively, was ascites (9% vs 7%), followed by anemia (7% vs 0%), increased blood bilirubin level (6% vs 2%), and hyponatremia (6% vs 10%).

Five percent of patients on the investigative arm experienced a TEAE that resulted in death, although none of these effects were determined to be associated with treatment. Serious TEAEs were experienced by 34% of those who received the IDH1 inhibitor; 2% of these effects were considered to be linked with treatment. Twenty-four percent of patients who received placebo experienced serious TEAEs, although none were linked with treatment.

FDA Updates

In May 2019, the FDA approved ivosidenib for use in patients with IDH1-mutated acute myeloid leukemia (AML), specifically for those with newly diagnosed disease who were at least 75 years of age and who have comorbidities that preclude the use of intensive induction chemotherapy and for those with relapsed/refractory AML. The regulatory decision was based on data from a phase 1 trial where ivosidenib elicited a CR of 28.6% and a CR plus CR with partial hematologic recovery rate of 42.9%.⁵

In August 2021, the FDA approved ivosidenib for use in adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring an IDH1 mutation, as detected by an FDA-approved test.⁶ The decision was based on findings from ClariDHY.⁵

Most recently, in March 2022, the regulatory agency granted a priority review to a supplemental new drug application seeking the approval of the IDH1 inhibitor for use in combination with azacitidine in the treatment of patients with previously untreated IDH1-mutated AML.⁷ The application is supported by data from AGILE.

References

1. Servier submits a marketing authorization application to the European Medicines Agency (EMA) for TIBSOVO (ivosidenib tablets) for patients with IDH1-mutated acute myeloid leukemia (AML) and cholangiocarcinoma. News release. Servier; March 10, 2022. Accessed March 10, 2022. https://prn.to/3I61Qs1
2. Montesinos P, Recher C, Vives S, et al. AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. Blood. 2021;138(suppl 1):697. doi:10.1182/blood-2021-147805
3. Zhu AX, Macarulla R, Javle MM, et al. Final results from ClarIDHy, a global, phase III, 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 3):266. doi:10.1200/JCO.2021.39.3_suppl.266
4. 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. 2021;7(11):1669-1677. doi:10.1001/jamaoncol.2021.3836
5. Agios announces FDA approval of supplemental new drug application (sNDA) for TIBSOVO as monotherapy for newly diagnosed adult patients with IDH1 mutant acute myeloid leukemia (AML) not eligible for intensive chemotherapy. News release. Agios Pharmaceuticals Inc; May 2, 2019. Accessed March 10, 2022. https://bit.ly/2DNjOkV
6. Servier announces FDA approval of TIBSOVO (ivosidenib tablets) in IDH1-mutated cholangiocarcinoma. News release. Servier Pharmaceuticals; August 25, 2021. Accessed March 10, 2022. https://prn.to/3sZYQb7
7. Servier announces FDA filing acceptance and priority review for TIBSOVO (ivosidenib tablets) in combination with azacitidine for patients with previously untreated IDH1-mutated acute myeloid leukemia. News release. Servier Pharmaceuticals; March 7, 2022. Accessed March 10, 2022. https://prn.to/3CtMlJy