TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in:...Adult patients with newly-diagnosed AML who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy...Adult patients with relapsed or refractory AML

IDH1 or IDH2 Treatment Induction, preferred regimen added: Ivosidenib once daily (500mg) PO and azacitidine 75 mg/m2 SC or IV...

In the AGILE study in patients (pts) with newly diagnosed IDH1-mutated acute myeloid leukemia, IVO plus azacitidine (AZA) significantly improved event-free survival (EFS)...Long-term follow-up data are presented….OS rates were 62.9% and 38.3% at 12 months and 53.1% and 17.4% at 24 months, with IVO+AZA and PBO+AZA, respectively.

To evaluate long-term data from AGILE on OS, transfusion independence, blood count recovery and safety in patients with newly diagnosed IDH1-mutated AML receiving IVO+AZA….OS rates were 62.9% and 38.3% at 12 months and 53.1% and 17.4% at 24 months, with IVO+AZA and PBO+AZA, respectively.

Servier...announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion and recommended granting a marketing authorization for Tibsovo® (ivosidenib tablets) - an inhibitor of the mutated isocitrate dehydrogenase-1 (IDH1) enzyme - for two indications:...in combination with azacitidine, for the treatment of adult patients with newly diagnosed IDH1-mutated Acute Myeloid Leukemia and not eligible for standard induction chemotherapy...The positive CHMP opinion is based on clinical data from the AGILE (AML) and ClarIDHy (CCA) studies.

In this phase 3 trial, we randomly assigned patients with newly diagnosed IDH1-mutated acute myeloid leukemia...At a median follow-up of 12.4 months, event-free survival was significantly longer in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group (hazard ratio for treatment failure, relapse from remission, or death, 0.33; 95% confidence interval [CI], 0.16 to 0.69; P = 0.002)...Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population.

Servier...today announced that the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for TIBSOVO® (ivosidenib tablets) as a potential treatment for patients with previously untreated IDH1-mutated acute myeloid leukemia (AML). The sNDA was granted Priority Review, which accelerates the review and shortens the review time goal from 10 months to 6 months....The sNDA acceptance is supported by results from the AGILE study, a global, Phase 3 trial in patients with previously untreated IDH1-mutated AML...

In this global, double-blind, randomized, placebo-controlled, phase 3 study, patients were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA)...Key eligibility: untreated AML (WHO criteria), centrally confirmed mIDH1 status...EFS was statistically significant (HR = 0.33 [95% CI 0.16, 0.69]; P = 0.0011) in favor of the IVO+AZA arm. Median OS with IVO+AZA was 24.0 months vs 7.9 months with PBO+AZA (HR = 0.44 [95% CI 0.27, 0.73]; P = 0.0005). CR rate with IVO+AZA was 47.2% (34/72 patients; 95% CI 35.3%, 59.3%) vs 14.9% (11/74 patients; 95% CI 7.7%, 25.0%) with PBO+AZA (P < 0.0001).

...Previously untreated AML (de novo or secondary) defined according to World Health Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL) [AML with t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation...

Complete response (CR) plus CR with incomplete count or incomplete platelet recovery (CRi/p) rates were 63.2% vs 49.5% for IVO+HMA vs VEN+HMA (p=0.025), with the difference based on the higher CR rate for IVO+HMA (42.9% vs 26.7%; p=0.007)….In a large, balanced cohort of nearly 300 patients with ND mIDH1 AML ineligible for IC, patients treated with IVO+HMA had higher rates of CR and CR+CRi/p, achieved CR faster, and had longer EFS compared to those treated with VEN+HMA.

We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated...Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%...Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

We analyzed all patients (pts) with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of >12 mo….A subset of pts with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders)...

We conducted a multi-center, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML...Two-year progression-free (PFS) was 81%, and two-year overall survival (OS) was 88%...Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase 1 study.

Enasidenib significantly improved the response rates in patients with mIDH-2 AML....Ivosedanib significantly improved the response rates and survival rates in patients with mIDH-1 AML. Olutasidenib was also effective in patients with R/R mIDH-1 AML. More randomized double-blind multicenter clinical trials are needed to confirm these results.

146 patients were randomized to IVO+AZA (n=72) and PBO+AZA (n=74). Median age was 76.0 and 75.5 years, respectively. EFS was signifi cantly in favor of IVO+AZA (HR=0.33; 1-sided P=0.0011). Median OS was 24.0 vs 7.9 months for IVO+AZA vs PBO+AZA, respectively (HR=0.44; 1-sided P=0.0005). Complete response rates were 47.2% and 14.9% for IVO+AZA vs PBO+AZA, respectively (P<0.0001). : In patients with ICineligible, newly diagnosed mIDH1 AML, IVO+AZA signifi cantly improved EFS, OS, and clinical response compared with PBO+AZA.

...the clinical data from the bridging registrational study of ivosidenib in Chinese pts with mIDH1 R/R AML....The CR+CRh rate was 30.0% (9/30; 95% CI: 14.7–49.4%), with all 9 pts achieving CR....Objective response rate was 36.7% (11/30; 95% CI: 19.9–56.1%)....Ivosidenib was well tolerated and induced durable remissions with clinical benefits in Chinese pts with mIDH1 R/R AML...

To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts...There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population.

This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy...Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.

...this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML...In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance...

...Baseline characteristics, clinical response (including CR, CRi/CRp, MLFS), and overall survival (OS) for the subgroup of pts with mIDH1 R/R AML who received IVO 500 mg QD, responded to treatment and then underwent HCT are reported….mIDH1 was undetectable in 1/18 (6%) pts; 4/18 (22%) pts had reduction below 1% VAF in ≥1 at the last assessment prior to HCT....IVO monotherapy is a putative treatment option to induce remissions prior to HCT for mIDH1 R/R AML pts who are not considered candidates for intensive salvage therapy.

Six of these 7 acquired mIDH2 at relapse within the same clone as the original mIDH1, whereas mIDH2 was identified in a separate clone to mIDH1 in 1 patient. In the 2 of 9 cases in which mIDH2 was detected at baseline, mIDH2 was present in a separate clone to mIDH1....In a subset of patients with mIDH2 detectable at relapse, mIDH2 was mostly not detectable at baseline but emerged within the same clone as mIDH1, highlighting 2-HG restoration as an important mechanism of resistance to IVO.

In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. 

From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML)...With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7)...Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML.

In the first human clinical trial of an IDH1-mutant inhibitor, 17 patients with relapsed or refractory AML and IDH1 mutations were enrolled in one of four groups that received AG-120 (Agios Pharmaceuticals; Cambridge, MA) in escalating doses. The trial began in March 2014, and as of October 17, seven patients were responding to treatment, including four who experienced complete remissions; three had not yet been evaluated....Considering that some patients in the study experienced complete remission of their cancers, AG-120 may have potential to transform treatment for IDH1 mutant–positive AML…

...studies were undertaken to explore the IVO + AZA combination in a mIDH1 AML patient-derived xenograft (PDX) model in vivo....The IVO + AZA combination led to a > 99% reduction in hCD45+ cells within the bone marrow and undetectable disease in the peripheral blood of 7/10 mice by Week 10....Similar results were observed with IVO + VEN treated animal bone marrow (99% reduction in hCD45+ cells) and undetectable disease was observed in 8/10 mice by week 10.

In pts who achieved a best response of CR or CRh, the IDH1-MC rate in BMMCs was 64.3% (9/14), and 72.7% (8/11) in both PBMCs and neutrophils, by sensitive digital PCR...IDH1-MC was significantly associated with a best response of CR or CRh (p < 0.001...Overall survival at 12 mo was 88.9% (95% CI 43.3, 98.4) for pts with IDH1-MC in BMMCs (n = 9), as compared with 38.5% (95% CI 17.7, 59.0) for pts who did not achieve IDH1-MC (n = 21).