Ivosidenib, a potent and selective inhibitor of isocitrate dehydrogenase-1 (IDH1), is an antineoplastic agent.1
Newly Diagnosed Acute Myeloid Leukemia
Ivosidenib is used, as monotherapy or in combination with azacitidine, for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation in patients who are ≥75 years of age or who are not candidates for intensive induction chemotherapy.1 Susceptible IDH1 mutations are defined as those resulting in increased 2-hydroxyglutarate levels in the leukemic cells and where efficacy of ivosidenib is predicted by either clinically meaningful remissions at the recommended dosage of the drug and/or inhibition of IDH1 mutation activity at ivosidenib concentrations sustainable at the recommended dosage.1 Ivosidenib has been designated an orphan drug by FDA for the treatment of AML.4 Patients should be selected for treatment based on the presence of IDH1 mutations.1 Information on FDA-approved tests for the detection of IDH1 mutations is available at: [Web].1 Safety and efficacy of ivosidenib for this use are primarily supported by a randomized, placebo-controlled clinical trial evaluating ivosidenib in combination with azacitidine and an open-label, multicenter, noncomparative, phase 1 study evaluating ivosidenib monotherapy.1, 5, 19 Ivosidenib with or without azacitidine is generally recommended as one of several regimens that can be considered for treatment of newly diagnosed AML in older adults or adults with significant comorbidities.22, 23
Efficacy of ivosidenib monotherapy in the treatment of newly diagnosed AML with an IDH1 mutation is based on the results of an open-label, multicenter, noncomparative, phase 1, dose-escalation and dose-expansion study (AG120-C-001) in adults with advanced hematologic malignancies harboring IDH1 mutation (as detected by the Abbott RealTime® IDH1 mutation test).1 This cohort of patients included 28 adults with newly diagnosed AML who were ≥75 years of age or who were not candidates for intensive induction chemotherapy.1, 5 Patients were not candidates for intensive induction chemotherapy if they met at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, severe cardiac or pulmonary disease, hepatic impairment (bilirubin concentration exceeding 1.5 times the upper limit of normal [ULN]), or creatinine clearance <45 mL/minute.1
The median age of patients enrolled in the newly diagnosed AML cohort of this phase 1 study was 77 years (range: 64-87 years); 86% were white, 68% were ≥75 years of age, 54% were male, and 78% had an ECOG performance status of 0 or 1.1 In addition, 68% had adverse-risk cytogenetics, 32% had intermediate-risk cytogenetics, 61% were transfusion dependent at baseline, 68% had AML with myelodysplasia-related changes (AML-MRC), 21% had de novo AML, and 11% had therapy-related AML (t-AML; secondary AML).1 Approximately one-half (46%) of patients enrolled in the cohort had received prior therapy with a hypomethylating agent for an antecedent hematologic disorder.1 IDH1 mutations at codon R132C, R132G, R132H, R132L, or R132S were present in 86, 4, 7, 4, or 0%, respectively, of patients enrolled in the newly diagnosed AML cohort.1
Patients received an initial ivosidenib dosage of 500 mg orally once daily.1 Therapy was continued until disease progression or unacceptable toxicity occurred or stem cell transplantation was required.1 Following ivosidenib therapy, 7% of patients with newly diagnosed AML underwent stem cell transplantation.1 The median duration of ivosidenib therapy was 4.3 months.1
At a median follow-up of 8.1 months, complete remission (CR) or complete remission with partial hematologic recovery (CRh) was achieved in 42.9% of patients receiving ivosidenib for newly diagnosed AML; 28.6% of patients achieved CR.1 The median duration of best response (CR or CRh) had not been reached at the time of the analysis.1 The median time to best response was 2.8 months; the majority (92%) of these patients achieved an initial best response within 6 months of initiating ivosidenib therapy.1 Among patients who were transfusion dependent at baseline, 41.2% became transfusion independent during any 56-day period during the study.1 The majority (54.5%) of patients who were transfusion independent at baseline remained transfusion independent during any 56-day period during the study.1
Efficacy of ivosidenib in combination with azacitidine in newly diagnosed AML is supported primarily by results of a randomized, multicenter, double-blind, placebo-controlled clinical trial (AG120-C-009) in 146 adult patients with an IDH1 mutation.1, 19 Patients were included who were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy.1 Patients were randomized to receive either ivosidenib 500 mg or placebo orally once daily on Days 1-28 in combination with azacitidine 75 mg/m2 per day either subcutaneously or IV on Days 1-7 or Days 1-5 and 8-9 of each 28-day treatment cycle beginning on Cycle 1 Day 1.1 Treatment was continued for a minimum of 6 cycles unless patients experienced disease progression, unacceptable toxicity, or were undergoing hematopoietic stem cell transplantation.1 Efficacy was established based on event-free survival (EFS) (defined as time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurred first), overall survival, and complete remission.1
At baseline, the median age of patients was 76 years; 16-17% were white, 21-26% were Asian, 51-58% were male, 44-54% had an ECOG performance status of 1, 59-67% had intermediate-risk cytogenetics, 63-69% had the R132C IDH1 mutation, and 72-75% had de novo AML.1
EFS was substantially improved with ivosidenib compared with placebo (event rates of 65% versus 84%).1, 19 Overall survival was substantially prolonged with ivosidenib compared with placebo (median overall survival of 24 versus 7.9 months).1 Ivosidenib also showed benefit in CR and CRh.1
Recommendations from the National Cancer Institute (NCI) on intensive treatment of newly diagnosed AML suggest a minimum of 2 agents as combination chemotherapy consisting of cytarabine and an anthracycline or mitoxantrone.22 Addition of midostaurin or gemtuzumab ozogamicin can be considered for certain patients.22 The American Society of Hematology (ASH) recommends chemotherapy over supportive care in newly diagnosed AML for older adults (≥55 years of age).23 Intensive chemotherapy is suggested over less intensive regimens for older adults; post-remission therapy is also recommended.23
According to NCI recommendations, less intensive chemotherapy is an option for older adults or adults with significant comorbidities.22 Less intensive treatments that can be considered include hypomethylating agents (azacitidine and decitabine) with or without venetoclax, low-dose cytarabine with or without venetoclax or glasdegib, ivosidenib with or without azacitidine, and enasidenib.22 According to the ASH guideline for older adults, less intensive treatments that are conditionally recommended include monotherapy with either low-dose cytarabine or a hypomethylating agent.23 The ASH guideline acknowledges that the preference of monotherapy over combination therapy may change based on current evidence demonstrating effectiveness of combination treatment with either hypomethylating agents or cytarabine and either glasdegib or venetoclax.23
Relapsed or Refractory Acute Myeloid Leukemia
Ivosidenib is used for the treatment of adults with relapsed or refractory AML with a susceptible IDH1 mutation.1 Susceptible IDH1 mutations are defined as those resulting in increased 2-hydroxyglutarate levels in the leukemic cells and where efficacy of ivosidenib is predicted by clinically meaningful remissions at the recommended dosage of the drug and/or inhibition of IDH1 mutation activity at ivosidenib concentrations sustainable at the recommended dosage.1 Ivosidenib has been designated an orphan drug by FDA for the treatment of AML.4 Patients should be selected for treatment based on the presence of IDH1 mutations.1 Information on FDA-approved tests for the detection of IDH1 mutations is available at: [Web].1 Safety and efficacy of ivosidenib for this use are primarily supported by results of an open-label, single-arm cohort of adults with relapsed or refractory AML with an IDH1 mutation.1, 2 The National Cancer Institute (NCI) states that there is no standard treatment regimen for relapsed or refractory AML; patients who are unable or unwilling to undergo intensive therapy may be candidates for reduced-intensity therapies, including ivosidenib.22
The indication for ivosidenib in the treatment of relapsed or refractory AML with IDH1 mutation is based principally on the results of an open-label, multicenter, noncomparative, phase 1, dose-escalation and dose-expansion study (AG120-C-001) in adults with advanced hematologic malignancies harboring IDH1 mutation (as detected by the Abbott RealTime® IDH1 mutation test).1, 2, 5 This cohort of patients included 174 adults with relapsed or refractory AML.1
The median age of patients enrolled in the relapsed or refractory AML cohort of this phase 1 study was 67 years (range: 18-87 years); 62% were white, 64% were ≥65 years of age, 51% were male, 77% had an ECOG performance status of 0 or 1, 37% had previously untreated relapsed AML, 26% had refractory AML, 37% had primary refractory AML, 60% had intermediate-risk cytogenetics, 27% had poor-risk cytogenetics, 63% were transfusion dependent at baseline, and 23% had previously undergone stem cell transplantation.1 Patients enrolled in the cohort had received a median of 2 prior therapies.1 IDH1 mutations at codon R132C, R132H, R132G, R132S, or R132L were present in 59, 25, 7, 6, or 4%, respectively, of patients enrolled in the relapsed or refractory AML cohort.1 Patients received an initial ivosidenib dosage of 500 mg orally once daily.1, 2 Therapy was continued until disease progression or unacceptable toxicity occurred or stem cell transplantation was required.1 Following ivosidenib therapy, 12% of patients underwent stem cell transplantation.1 The median duration of ivosidenib therapy was 4.1 months.1
At a median follow-up of 8.3 months, CR or CRh was achieved in 32.8% of patients receiving ivosidenib for relapsed or refractory AML with a median response duration of 8.2 months; 24.7% of patients achieved CR.1 The median time to best response (CR or CRh) was 2 months; all of these patients achieved an initial best response within 6 months of initiating ivosidenib therapy.1 Approximately one-third (37.3%) of patients who were transfusion dependent at baseline became transfusion independent during any 56-day period during the study.1 The majority (59.4%) of patients who were transfusion independent at baseline remained transfusion independent during any 56-day period during the study.1
The NCI states that there is no standard treatment regimen for patients with refractory or recurrent AML.22 Treatment options may include chemotherapy (intensive salvage chemotherapy and reduced-intensity therapy, including targeted therapy) and allogeneic hematopoietic cell transplantation (HCT).22
Intensive salvage chemotherapy may utilize a number of regimens, including fludarabine, cytarabine, and filgrastim (FLAG); mitoxantrone, etoposide, and cytarabine (MEC); standard or high-dose cytarabine and mitoxantrone; high-dose etoposide and cyclophosphamide; idarubicin and cytarabine; and other intensive regimens.22 Patients who are unable or unwilling to undergo intensive therapy may be candidates for reduced-intensity therapies such as gilteritinib, enasidenib, or ivosidenib, depending on the presence of specific mutations; hypomethylating agents, gemtuzumab ozogamicin, and clofarabine with or without cytarabine are also options.22 Allogeneic HCT may be an option in patients who have not experienced remission with intensive chemotherapy.22
Relapsed or Refractory Myelodysplastic Syndromes
Ivosidenib is used for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible IDH1 mutation.1 Patients should be selected for treatment based on the presence of IDH1 mutations.1 Information on FDA-approved tests for the detection of IDH1 mutations is available at: [Web].1 Ivosidenib has been designated an orphan drug by FDA for the treatment of MDS.4 Efficacy of ivosidenib for this use is principally supported by the results of an open-label, single-arm, multicenter study in adults with relapsed or refractory MDS harboring an IDH1 mutation.1
The indication for ivosidenib in the treatment of MDS is based principally on the results of an open-label, single-arm, multicenter study in 18 adults with relapsed or refractory MDS harboring an IDH1 mutation (as detected by the Abbott RealTime® IDH1 mutation test).1 The median age of patients enrolled in the study was 74 years (range, 61-82 years).1 The study population was 78% male, 78% white, 6% Black or African American, and the majority (56%) had an ECOG performance status of 1.1 Ivosidenib was administered at a starting dose of 500 mg orally daily for 28-day cycles.1 Therapy was continued until disease progression or unacceptable toxicity occurred or stem cell transplantation was required.1 Following ivosidenib therapy, 1 patient underwent stem cell transplantation.1 The median duration of exposure to ivosidenib was 8.3 months.1
At a median follow-up of 27.1 months, CR was achieved in 38.9% of patients receiving ivosidenib for relapsed or refractory MDS, with a median duration of CR that was not estimable.1 The median time to CR was 1.9 months.1 Of the 9 patients who were red blood cell and/or platelet transfusion dependent at baseline, 6 (67%) patients became transfusion independent during any 56-day period during the study.1 The majority (78%) of the 9 patients who were transfusion independent at baseline remained transfusion independent during any 56-day period during the study.1
Locally Advanced or Metastatic Cholangiocarcinoma
Ivosidenib is used for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation.1, 20, 21 Patients should be selected for treatment based on the presence of IDH1 mutations.1 Information on FDA-approved tests for the detection of IDH1 mutations is available at: [Web].1 Ivosidenib has been designated an orphan drug by FDA for the treatment of cholangiocarcinoma.4 Safety and efficacy of ivosidenib for this use are principally supported by a placebo-controlled trial in adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation and disease progression following 1-2 prior regimens, including at least 1 gemcitabine- or 5-fluorouracil (5-FU)-containing regimen.1
Safety and efficacy of ivosidenib in locally advanced or metastatic cholangiocarcinoma are based principally on the results of a randomized, multicenter, double-blind, placebo-controlled trial (AG120-C-005).1, 20, 21 The study included a total of 185 patients who had locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation whose disease had progressed following 1-2 prior regimens, including at least 1 gemcitabine- or 5-FU-containing regimen.1 Patients were randomized to receive either ivosidenib 500 mg orally once daily or placebo until disease progression or unacceptable toxicity occurred.1 Patients who were randomized to placebo were allowed to cross over to ivosidenib treatment after radiographic disease progression.1 The primary efficacy end point was progression-free survival (PFS) as determined by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.1
At baseline, the median age of patients was 62 years (range 33-83 years); 63% were female and 57% were white.1 Patients had an ECOG performance status of 0 (37%) or 1 (62%).1 All patients had received at least 1 prior line of systemic therapy; 47% had received 2 prior lines.1 Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease.1 Among all patients, 70% had an R132C mutation, 15% had an R132L mutation, 12% had an R132G mutation, 1.1% had an R132H mutation, and 1.6% had an R132S mutation.1
After a median follow-up of 6.9 months, PFS was significantly improved with ivosidenib compared with placebo (61% of patients in the ivosidenib group had a PFS event by IRC assessment compared wtih 82% of patients in the placebo group).1, 20 Although median overall survival was longer in patients receiving ivosidenib compared with placebo (10.3 months versus 7.5 months without adjusting for crossover), the difference was not significant.1, 20 In the analysis of overall survival, 70% of patients had crossed over from placebo to active drug.21
The most common malignant primary brain tumors in adults are gliomas.100 The classification of these tumors has evolved with the identification of various molecular features including IDH mutations.100 In gliomas, IDH mutations are highly prevalent and confer significant improved survival as compared to IDH wild-type glioma.100 The standard of care for IDH mutant gliomas generally involves maximal resection (when feasible) followed by a combination of radiation and chemotherapy.100 However, this approach does not significantly enhance survival and can result in long-term negative outcomes (e.g., cognitive decline) impacting quality of life.100 Of note, transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on MRI.102 Ivosidenib, a small molecule inhibitor that targets the IDH1 enzyme, has been evaluated as a potential treatment option in patients with non-enhancing, IDH-mutated glioma† in early phase trials, a retrospective study, and a case series.101, 102, 103, 104
A phase 1, open-label, multicenter, dose-escalation, and dose-expansion study assessed ivosidenib therapy in 66 adult patients (41 males/25 females) with mutant IDH1 advanced solid tumors.101 Twelve (18.2%) patients had a glioblastoma diagnosis and the remaining patients had a low-grade glioma (e.g., oligodendroglioma, astrocytoma, oligoastrocytoma).101 Of the 66 patients, 20 were enrolled in the dose escalation phase and 46 in the dose expansion phase.101 The escalation phase provided oral doses of ivosidenib of 100 mg twice daily or 300-, 500-, 600-, and 900 mg once daily.101 All patients in the dose expansion phase were administered ivosidenib 500 mg once daily.101 For the dose expansion phase, patients were separated into 2 cohorts based on presence or absence of tumor contrast enhancement at enrollment.101 All enrolled patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an expected survival of at least 3 months.101 The median age was 41 years, and the median number of prior therapies was 2.101 The primary objective of the study was to evaluate the safety and tolerability of ivosidenib and determine the maximum tolerated dose or recommended phase 2 dose.101 Secondary objectives included evaluation of dose-limiting toxicities and preliminary clinical response.101
The maximum tolerated dose of ivosidenib was not reached during the study and no dose-limiting toxicities were noted.101 Most patients (95.5%) experienced at least 1 adverse event of any grade or causality.101 The most common adverse events (≥10%) were headache, nausea, fatigue, vomiting, seizure, diarrhea, hyperglycemia, aphasia, reduced neutrophil count, depression, hypophosphatemia, and paresthesia.101 Grade ≥3 adverse events were observed in 13 (19.7%) patients and included headache, hypophosphatemia, and seizure.101 The most common treatment-related adverse events were fatigue, reduced neutrophil count, and diarrhea.101 Discontinuation of ivosidenib therapy due to an adverse event did not occur; however, 8 patients experienced a dose interruption due to an event.101
Local investigators assessed clinical response to therapy.101 The best overall response was a partial response in 1 patient; 44 patients (66.7%) experienced stable disease, and 21 patients (31.8%) had progressive disease.101 As of the data cutoff of January 16, 2019, patients with nonenhancing tumors had an improved median treatment duration as compared to those with enhancing tumors (18.4 vs 1.9 months).101 In addition, 66.7% of patients with nonenhancing tumors at baseline experienced a reduction in tumor measurements as compared to 33.3% of patients with enhancing tumors, and 30 (85.7%) of the 35 patients with nonenhancing tumors had a best response of stable disease compared to 14 (45.2%) of the 31 patients with enhancing tumors.101 Median progression-free survival was 13.6 months in the nonenhancing group and 1.4 months in the enhancing group.101
A phase 1, randomized, controlled, open-label, multicenter perioperative study compared ivosidenib to vorasidenib in adult patients with recurrent, mutant IDH1-R132H, non-enhancing oligodendroglioma or astrocytoma.102 In Cohort 1, patients were randomized 2:2:1 to receive ivosidenib 500 mg orally daily for 4 weeks, vorasidenib 50 mg orally daily for 4 weeks, or a control of no treatment prior to surgery.102 After documenting mutant IDH1 enzyme inhibition in tumors, cohort 2 was opened to test alternative dose regimens, with patients randomized 1:1 to ivosidenib 250 mg orally twice daily or vorasidenib 10 mg orally once daily.102 Treated patients received 28 (+7) days of medication up to and including the day of surgery.102 All patients had the option to receive postoperative treatment until disease progression or unacceptable toxicity.102 Postoperatively, control patients were randomized 1:1 to ivosidenib 500 mg (n=3) or vorasidenib 50 mg (n=2).102 The median age of patients was 37 years in the ivosidenib group and 49 years in the vorasidenib group.102 The majority of patients (87.8%) in the study had grade 2 tumors.102 The primary endpoint was the concentration of D-2-hydroxyglutarate (2-HG; a metabolic product of mutant IDH enzymes) in surgically resected tumors.102 Secondary endpoints included safety and preliminary clinical activity; pharmacokinetics were also assessed.102
As of April 29, 2020 (analysis cutoff date), 49 patients were randomized before surgery.102 All patients proceeded to surgery without unplanned delays.102 Overall, 24 patients received at least one dose of vorasidenib, and 25 patients received at least one dose of ivosidenib.102 At the time of the analysis cutoff date, 17 (70.8%) patients remained on vorasidenib treatment.102 Five (20.8%) patients discontinued therapy due to disease progression and 2 (8.3%) discontinued per clinician decision.102 Fifteen (60.0%) patients remained on ivosidenib treatment, 3 (12.0%) did not continue ivosidenib postoperatively, 6 (24.0%) discontinued therapy due to disease progression, and 1 (4.0%) discontinued due to an adverse event.102
All patients experienced at least one adverse event in the study.102 The most common adverse events (≥20%) in the ivosidenib group were headache, anemia, diarrhea, seizure, hypocalcemia, cough, nasal congestion, hypokalemia, nausea, hyperglycemia, and insomnia.102 The most common adverse events (≥20%) in the vorasidenib group were nausea, headache, diarrhea, fatigue, increased alanine aminotransferase, constipation, and insomnia.102
Tumor samples from 40 of 49 patients were included in the tissue analyses.102 The mean reduction of 2-HG concentration in tumors relative to the control group was 91.1% for ivosidenib 500 mg once daily and 92.6% for vorasidenib 50 mg once daily.102 The preliminary objective response rate for ivosidenib 500 mg once daily was 35.7%, with 3 subjects achieving partial responses and 2 subjects achieving a minor response, and 12.5% for ivosidenib 250 mg twice daily, with a single partial response.102 The preliminary objective response rate for vorasidenib 50 mg once daily was 42.9% including 2 partial responses and 4 minor responses, and 10.0% for vorasidenib 10 mg once daily, with a single minor response.102
Based on the study results, vorasidenib 50 mg daily demonstrated the most consistent inhibition of mutant IDH and the greatest preliminary antitumor activity and was therefore the agent selected for further evaluation in a phase 3 study.102 Ivosidenib was found to possess considerably lower CNS penetration than vorasidenib, but reached adequate tumor concentrations to inhibit the mutant IDH in patients due to its high plasma exposure.102
A retrospective study from Johns Hopkins Hospital (2018-2022) evaluated the use of ivosidenib 500 mg once daily in adults with radiation/chemotherapy-naïve, IDH1 mutant, nonenhancing, radiographically active, grade 2/3 gliomas.103 Twelve patients (median age: 46 years; 10 males/2 females) who had undergone 116 MRI scans (71 pretreatment and 45 on-treatment) were included in the study.103 FLAIR-based tumor volumes, growth rates, and progression-free survival were analyzed.103 The median on-drug follow-up was 13.2 months.103
Results revealed that 50% of patients experienced ≥20% tumor volume reduction on-treatment and there was a reduced absolute growth rate during ivosidenib therapy as compared to before therapy.103 The median time to best response was 11.2 months, and 16.8 months in patients on ivosidenib for ≥1 year.103 Overall, responses required 5 months to be volumetrically detectable with responses becoming most evident after almost a year of treatment.103 Progression-free survival at 6, 9, and 12 months was 83%, 75%, and 70%, respectively.103 Median progression-free survival was not reached; however, mean progression-free survival was 26.4 months.103 One patient reported the occurrence of fluctuating diarrhea.
The use of ivosidenib for the treatment of IDH mutant gliomas was described in a retrospective case series, occurring from August 2018 to December 2022, at the MD Anderson Cancer Center.104 This series included 9 patients with IDH-mutant glioma (median age: 37 years; 8 males/1 female) administered ivosidenib 500 mg daily.104 As of January 11, 2023, all patients administered ivosidenib were still alive, with 78% experiencing stable disease.104 Median progression-free survival was 3.81 months after a median follow-up of 17.8 months.104 Patients with nonenhancing disease (n=4) had nonsignificant improvement in progression-free survival as compared to those with enhancing disease (8.28 vs. 3.81 months, respectively).104 Adverse events were noted in 2 patients; a single patient experienced grade 1 lethargy and another patient experienced a grade 3 surgical wound infection (unrelated to study drug).104
Based on current evidence, ivosidenib for the treatment of IDH mutant glioma has Level 3 (low strength/quality) evidence supporting its use.101, 102, 103, 104 Currently available data include phase 1 and retrospective studies and case series.101, 102, 103, 104 However, based on these data, ivosidenib may have a potential role in patients with nonenhancing, IDH-mutated glioma as an alternative regimen in select patients.101, 102, 103, 104
Ivosidenib is administered orally at approximately the same time each day without regard to meals; however, administration with a high-fat meal should be avoided because of increased systemic exposure of the drug.1 The tablets should be swallowed whole; they should not be chewed, crushed, or split.1
If a dose of ivosidenib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.1 If a dose of ivosidenib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose.1 Return to the normal schedule the following day.1 Do not administer 2 doses within 12 hours.1
Store ivosidenib tablets at 20-25°C (excursions permitted between 15-30°C).1
Newly Diagnosed Acute Myeloid Leukemia (Monotherapy Regimen)
For the treatment of newly diagnosed AML with IDH1 mutation in patients who are ≥75 years of age or who are not candidates for intensive induction chemotherapy, the recommended adult dosage of ivosidenib as monotherapy is 500 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 For patients without disease progression or unacceptable toxicity, continue ivosidenib for a minimum of 6 months to allow time for clinical response.1
Newly Diagnosed Acute Myeloid Leukemia (Combination Regimen)
For the treatment of newly diagnosed AML with IDH1 mutation in patients who are ≥75 years of age or who are not candidates for intensive induction chemotherapy, the recommended adult dosage of ivosidenib as combination therapy is 500 mg once daily in combination with azacitidine.1 Ivosidenib therapy should be continued until disease progression or unacceptable toxicity occurs.1 For patients without disease progression or unacceptable toxicity, continue ivosidenib in combination with azacitidine for a minimum of 6 months to allow time for clinical response.1
Start ivosidenib administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m2 subcutaneously or IV once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle.1 Refer to the Prescribing Information for azacitidine for additional dosing information.1
Relapsed or Refractory Acute Myeloid Leukemia
For the treatment of relapsed or refractory AML with IDH1 mutation, the recommended adult dosage of ivosidenib is 500 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 In the principal efficacy study (AG120-C-001), most patients with relapsed or refractory AML achieved best response within 6 months of initiating ivosidenib; therefore, the manufacturer states that therapy should be continued for at least 6 months to allow time for response.1
Relapsed or Refractory Myelodysplastic Syndromes
For the treatment of relapsed or refractory myelodysplastic syndromes, the recommended adult dosage of ivosidenib is 500 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity.1 For patients without disease progression or unacceptable toxicity, continue ivosidenib for a minimum of 6 months to allow time for clinical response.1
Locally Advanced or Metastatic Cholangiocarcinoma
For the treatment of locally advanced or metastatic cholangiocarcinoma, the recommended adult dosage of ivosidenib is 500 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of IDH mutant glioma in adults†, the usual dosage of ivosidenib administered in clinical studies and case reports is 500 mg orally once daily.101, 102, 103, 104
Dosage Modification for Toxicity
If severe signs or symptoms of differentiation syndrome (e.g., pyrexia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, hypotension, peripheral edema, rapid weight gain, hepatic or renal impairment, multiorgan dysfunction) persist for more than 48 hours despite systemic corticosteroid therapy, withhold ivosidenib therapy until the toxicity improves to grade 2 or less.1
If noninfectious leukocytosis (white blood cell [WBC] count>25,000/mm3 or an absolute increase in total WBC of >15,000/mm3 from baseline) persists despite initiation of hydroxyurea therapy, withhold ivosidenib therapy.1 Upon resolution of leukocytosis, resume ivosidenib at a dosage of 500 mg daily.1
For corrected QT (QTc) interval of 480-500 msec, withhold ivosidenib therapy.1 When the QTc interval improves to ≤480 msec, resume ivosidenib at a dosage of 500 mg daily.1 Monitor ECG at least weekly for 2 weeks following resolution of QTc prolongation.1
If the QTc interval exceeds 500 msec, withhold ivosidenib therapy.1 When the QTc interval improves to ≤480 msec or no more than 30 msec from baseline, resume ivosidenib at a reduced dosage of 250 mg daily.1 If an alternate etiology for QTc interval prolongation is confirmed, re-escalate the dosage of ivosidenib to 500 mg daily.1
If symptomatic QTc interval prolongation (e.g., life-threatening arrhythmias) occurs, permanently discontinue ivosidenib therapy.1
If Guillain-Barré syndrome occurs, permanently discontinue ivosidenib therapy.1
If a grade 3 or greater adverse reaction occurs during ivosidenib monotherapy for AML or MDS, withhold ivosidenib therapy.1 When the toxicity improves to grade 2 or less, resume ivosidenib therapy at a reduced dosage of 250 mg daily; the dosage of ivosidenib may be re-escalated to 500 mg daily when the toxicity improves to grade 1 or less.1 If a grade 3 or greater adverse reaction recurs, discontinue ivosidenib therapy.1
If a grade 3 or greater adverse reaction occurs during ivosidenib therapy in combination with azacitidine for AML or during therapy for cholangiocarcinoma, withhold ivosidenib therapy.1 When the toxicity improves to grade 1 or less, or baseline, resume ivosidenib therapy at a dosage of 500 mg daily (grade 3 toxicity) or 250 mg daily (grade 4 toxicity).1 If grade 3 toxicity recurs a second time, reduce the dosage of ivosidenib to 250 mg daily until toxicity resolves, then resume dosage of 500 mg daily.1 If grade 3 toxicity recurs a third time, or grade 4 toxicity recurs, discontinue ivosidenib.1
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of ivosidenib with drugs that are potent inhibitors of CYP3A4 should be avoided, and selection of an alternative drug with less CYP3A4 inhibition potential is recommended.1 If concomitant use with a potent CYP3A4 inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of ivosidenib from 500 mg once daily to 250 mg once daily.1 When concomitant use of the potent CYP3A4 inhibitor is discontinued, the ivosidenib dosage should be returned (after at least 5 elimination half-lives of the potent CYP3A4 inhibitor) to 500 mg once daily.1
No initial dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Ivosidenib has not been studied in patients with severe hepatic impairment (Child-Pugh class C); the manufacturer states that clinicians should consider potential risks and benefits of the drug prior to initiating therapy in such patients.1
No initial dosage adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to <90 mL/minute per 1.73 m2).1, 5 Ivosidenib has not been studied in patients with severe renal impairment (eGFR <30 mL/minute per 1.73 m2) or in those requiring dialysis; the manufacturer states that clinicians should consider potential risks and benefits of the drug prior to initiating therapy in such patients.1
The manufacturer makes no special dosage recommendations for geriatric patients.1
Differentiation Syndrome in Acute Myeloid Leukemia and Myelodysplastic Syndrome
A boxed warning is included in the prescribing information of ivosidenib regarding the risk of differentiation syndrome in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).1 Differentiation syndrome, which may be life-threatening or fatal, occurred in 25% of ivosidenib-treated patients with newly diagnosed AML and 19% of ivosidenib-treated patients with relapsed or refractory AML in the AG120-C-001 study.1 Differentiation syndrome resolved following completion of therapy or temporary interruption of therapy in 86% of patients with newly diagnosed AML and 79% of those with relapsed or refractory AML who developed this condition.1 In the clinical trial of patients with relapsed or refractory MDS treated with ivosidenib, 11% of patients experienced differentiation syndrome.1 Of the 2 patients affected, both recovered after treatment or dose interruption of ivosidenib.1 Differentiation syndrome following therapy with an isocitrate dehydrogenase-1 (IDH1) inhibitor, including ivosidenib, is associated with rapid proliferation and differentiation of myeloid cells.1 In patients receiving ivosidenib, differentiation syndrome has been characterized by acute respiratory distress (dyspnea and/or hypoxia), pulmonary infiltrates, renal impairment, multiorgan dysfunction, pyrexia, pulmonary or peripheral edema, rapid weight gain, rash, hypotension, tumor lysis syndrome, leukocytosis without infectious etiology, and pleural or pericardial effusions.1, 2, 5, 6, 11, 12 Differentiation syndrome has been observed with or without concomitant leukocytosis as early as 1 day or up to 3 months after initiation of ivosidenib.1
Manifestations of differentiation syndrome may be clinically indistinguishable from manifestations of disease progression or other acute comorbidities; therefore, differentiation syndrome should be suspected if there is no clear alternate etiology.12, 13 If signs or symptoms suggestive of differentiation syndrome occur, IV or oral corticosteroid therapy (e.g., 10 mg of dexamethasone IV every 12 hours [or equivalent]) should be initiated for at least 3 days and hemodynamic parameters should be monitored until symptoms improve.1 If concomitant leukocytosis occurs in the absence of infection, hydroxyurea therapy should be initiated according to standard practices and leukapheresis should be performed as needed.1 Signs or symptoms of differentiation syndrome may recur if systemic corticosteroid and/or hydroxyurea therapy is discontinued prematurely; therefore, corticosteroid and hydroxyurea therapy should be continued until symptoms resolve, followed by tapering of the corticosteroid and/or hydroxyurea dosage.1 If severe signs or symptoms of differentiation syndrome persist for more than 48 hours despite corticosteroid therapy, ivosidenib should be temporarily interrupted until symptoms improve to grade 2 or less.1
Other Warnings and Precautions
Prolongation of the corrected QT (QTc) interval and ventricular arrhythmias have been observed in patients receiving ivosidenib.1 The prolongation appears to occur in a plasma concentration-dependent manner.1 Following administration of ivosidenib 500 mg daily, a QTc interval change from baseline of approximately 17.2 msec has been observed at steady-state peak plasma concentrations.1 The reported incidence of QTc interval exceeding 60 msec from baseline in patients treated with ivosidenib was 14% in the AG120-C-001 study (ivosidenib monotherapy in patients with hematological malignancies), 22% in the AG120-C-009 study (ivosidenib in combination with azacitidine in patients with newly diagnosed AML), and 5% in the AG120-C-005 study (in patients with cholangiocarcinoma).1 In these studies, the reported incidence of QTc interval exceeding 500 msec was 9%, 14%, and 2%, respectively.1 These trials excluded patients with baseline uncontrolled or significant cardiovascular disease or characteristics that increased risk of QT prolongation or arrhythmic events.1
Patients with congenital long QT syndrome, congestive heart failure (CHF), or electrolyte abnormalities, and those receiving cytochrome P-450 (CYP) isoenzyme 3A4 inhibitors or drugs known to prolong the QTc interval (e.g., antiarrhythmic agents, fluoroquinolone anti-infectives, azole antifungals, type 3 serotonin [5-HT3] receptor antagonists) may be at increased risk for QT interval prolongation during ivosidenib therapy; therefore, more frequent monitoring (i.e., electrocardiograms [ECGs], serum electrolytes) may be necessary.1
Electrocardiograms should be monitored at least once weekly for the first 3 weeks of ivosidenib therapy and then at least once monthly thereafter.1 Blood chemistries also should be monitored at baseline, at least once weekly for the initial month of therapy, every other week for the next month, and then once monthly thereafter.1 Any electrolyte abnormalities that occur prior to initiation of ivosidenib therapy or during therapy should be corrected as clinically indicated.1 If QT interval prolongation occurs, temporary interruption, dosage reduction, or discontinuance of ivosidenib may be necessary, and ECGs should be monitored at least once weekly until 2 weeks following resolution of the toxicity.1
Guillain-Barré syndrome occurred in 2 of 265 patients (0.8%) receiving ivosidenib in the AG120-C-001 study.1, 5
Patients receiving ivosidenib therapy should be monitored for signs or symptoms of motor and/or sensory neuropathy (e.g., unilateral or bilateral weakness, sensory alterations, paresthesias, difficulty breathing).1 Ivosidenib therapy should be discontinued in patients who develop Guillain-Barré syndrome.1
Ivosidenib may cause fetal harm in humans based on animal findings.1 There are no available data regarding use of ivosidenib in pregnant women to inform a drug-associated risk of adverse developmental outcomes.1 In animal reproduction studies, embryofetal toxicity (e.g., decreased fetal weight, abortion) and teratogenicity (e.g., skeletal and visceral anomalies) were observed in rats and rabbits receiving ivosidenib at exposures levels approximately 2 times the human exposure at the recommended dosage.1
Patients should be apprised of the potential hazard to the fetus if ivosidenib is used during pregnancy.1
It is not known whether ivosidenib or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to ivosidenib in nursing infants, women should be advised to discontinue nursing during ivosidenib therapy and for at least 1 month after the last dose.1 The effects of the drug on nursing infants or on the production of milk are unknown.1
Safety and efficacy of ivosidenib have not been established in pediatric patients.1
In clinical studies of ivosidenib in the treatment of AML and MDS, 75% of ivosidenib-treated patients were ≥65 years of age and 35% were ≥75 years of age.1
In the study of ivosidenib for the treatment of cholangiocarcinoma, 37% of patients were ≥65 years of age and 11% were ≥75 years of age.1
No overall differences in effectiveness or safety were observed between patients ≥65 years of age and younger patients.1
Following administration of a single 500-mg dose of ivosidenib, AUC and peak plasma concentration of ivosidenib were not substantially altered in individuals with mild hepatic impairment (Child-Pugh class A).1, 18 In patients with moderate hepatic impairment (Child-Pugh class B), AUC and peak plasma concentration of ivosidenib decreased by 28 and 44%, respectively, compared with individuals with normal hepatic function.1, 18 The pharmacokinetic profile of ivosidenib has not been established in patients with severe hepatic impairment (Child-Pugh class C).1
In a population pharmacokinetic analysis, mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to less than 90 mL/minute per 1.73 m2) did not have clinically important effects on systemic exposure to ivosidenib.1, 5 The pharmacokinetic profile of ivosidenib has not been established in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m2) and those requiring dialysis.1, 5
The most common adverse reactions including laboratory abnormalities (≥25%) with ivosidenib in patients with AML are decreased leukocytes, diarrhea, decreased hemoglobin, decreased platelets, increased glucose, fatigue, increased alkaline phosphatase, edema, decreased potassium, nausea, vomiting, decreased phosphate, decreased appetite, decreased sodium, leukocytosis, decreased magnesium, increased aspartate aminotransferase, arthralgia, dyspnea, increased uric acid, abdominal pain, increased creatinine, mucositis, rash, QT prolongation, differentiation syndrome, decreased calcium, decreased neutrophils, and myalgia.1
The most common adverse reactions including laboratory abnormalities (≥25%) with ivosidenib in patients with relapsed or refractory MDS are increased creatinine, decreased hemoglobin, arthralgia, decreased albumin, increased aspartate aminotransferase, fatigue, diarrhea, cough, decreased sodium, mucositis, decreased appetite, myalgia, decreased phosphate, pruritus, and rash.1
The most common adverse reactions (≥15%) in patients with cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.1 The most common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are decreased hemoglobin, increased aspartate aminotransferase, and increased bilirubin.1
Ivosidenib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1
In vitro studies indicate that ivosidenib is an inducer of CYP3A4 resulting in induction of its own metabolism.1, 5 In vitro, the drug also has the potential to induce CYP isoenzymes 2B6, 2C8, and 2C9.1
In vitro, ivosidenib is an inhibitor of P-glycoprotein (P-gp) and organic anion transporter (OAT) 3, but does not inhibit breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and organic cation transporter (OCT) 2 at clinically relevant concentrations.1 In vitro, the drug is a substrate for P-gp, but is not a substrate for BCRP, OATP1B1, or OATP1B3.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of ivosidenib with moderate or potent inhibitors of CYP3A4 may increase systemic exposure to ivosidenib and increase the risk of toxicity (e.g., prolongation of QT interval).1 When the potent CYP3A4 inhibitor itraconazole (200 mg once daily for 18 days) was administered concomitantly with ivosidenib (single 250-mg dose) in healthy individuals, AUC of ivosidenib was increased by 269% and peak plasma concentrations were unchanged.1, 5, 16 Simulations suggest that concomitant use of ivosidenib (single 500-mg dose) and the moderate CYP3A4 inhibitor fluconazole (400 mg on day 1, then 200 mg once daily for 29 days) would result in a 173% increase in AUC of ivosidenib and unchanged peak plasma concentrations; however, concomitant use of ivosidenib (500 mg once daily for 15 days) and fluconazole (400 mg on day 1, then 200 mg once daily for 14 days) may increase AUC and peak plasma concentration of ivosidenib by 190 and 152%, respectively, at steady state.1, 5
Because of the potential for moderate (e.g., fluconazole) and potent (e.g., itraconazole) CYP3A4 inhibitors to increase exposure to ivosidenib, selection of an alternative drug with less CYP3A4 inhibition potential should be considered.1 If concomitant use of a potent CYP3A4 inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of ivosidenib from 500 mg once daily to 250 mg once daily.1 When concomitant use of the potent CYP3A4 inhibitor is discontinued, the ivosidenib dosage should be returned (after at least 5 elimination half-lives of the potent CYP3A4 inhibitor) to 500 mg once daily.1 Patients receiving ivosidenib concomitantly with moderate or potent CYP3A4 inhibitors should be monitored for signs of ivosidenib toxicity (i.e., QT interval prolongation).1
Concomitant use of ivosidenib with potent inducers of CYP3A4 may decrease ivosidenib plasma concentrations.1 Simulations suggest that concomitant use of ivosidenib (500 mg once daily) and the potent CYP3A4 inducer rifampin (600 mg once daily for 15 days) may decrease AUC and peak plasma concentration of ivosidenib by 33 and 19%, respectively.1, 5
Concomitant use of ivosidenib with potent CYP3A4 inducers (e.g., rifampin) should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of ivosidenib with sensitive CYP3A4 substrates may decrease plasma concentrations of the substrate drug and decrease therapeutic efficacy of the drug.1 5 Simulations also suggest that concomitant use of ivosidenib and CYP3A4 substrates such as itraconazole may result in a clinically important decrease of systemic exposure to itraconazole at steady state.1
Concomitant use of ivosidenib with sensitive substrates of CYP3A4 should be avoided, and selection of an alternative drug should be considered.1, 5 If concomitant use with sensitive substrates of CYP3A4 cannot be avoided, patients should be monitored for loss of efficacy of the substrate drug.1 Because concomitant use of ivosidenib with itraconazole or ketoconazole (CYP3A4 substrates) may decrease antifungal efficacy of itraconazole or ketoconazole, the manufacturer states that concomitant use of ivosidenib with itraconazole or ketoconazole is not recommended.1
Ivosidenib has the potential to induce CYP2C9 and may decrease plasma concentrations of drugs that are sensitive substrates of CYP2C9 (e.g., warfarin).1, 5
Concomitant use of ivosidenib with sensitive substrates of CYP2C9 should be avoided, and selection of an alternative drug should be considered.1 If concomitant use with sensitive substrates of CYP2C9 cannot be avoided, patients should be monitored for loss of efficacy of the substrate drug.1
Drugs that Prolong QT Interval
Because ivosidenib has been associated with QT interval prolongation, concomitant use of ivosidenib with other drugs known to prolong the QT interval (e.g., antiarrhythmic agents, fluoroquinolone anti-infectives, azole antifungals, type 3 serotonin [5-HT3] receptor antagonists) should be avoided, and selection of an alternative drug should be considered.1 If concomitant use of drugs known to prolong the QT interval cannot be avoided, ECGs and serum electrolytes should be monitored more frequently.1
Concomitant use of ivosidenib with hormonal contraceptives may result in decreased plasma concentrations of the hormonal contraceptive and decreased contraceptive efficacy.1 The manufacturer states that an alternative nonhormonal contraceptive should be considered during ivosidenib therapy.1
Drugs Affecting Gastric Acidity
Concomitant administration of ivosidenib and drugs that increase the pH of the upper GI tract (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) did not result in observable clinically significant differences in pharmacokinetics.1
Ivosidenib, a potent and selective inhibitor of isocitrate dehydrogenase-1 (IDH1), is an antineoplastic agent.1, 2, 5, 6, 7, 8, 14, 15 Isocitrate dehydrogenases (IDH) are metabolic enzymes in the citric acid cycle responsible for the oxidative decarboxylation of isocitrate to α-ketoglutarate, which is essential for normal cellular processes.5, 6, 7, 9 Approximately 6-16% of acute myeloid leukemia (AML) cases carry IDH1 mutations.2, 5, 6 IDH1 mutations cause a reduction of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate, which competitively inhibits α-ketoglutarate-dependent dioxygenases resulting in epigenetic dysregulation and subsequent histone and DNA hypermethylation and differentiation arrest of hematopoietic stem cells.2, 6, 8, 9, 10, 14
Susceptible IDH1 mutations are defined as those resulting in increased 2-hydroxyglutarate levels in the leukemic cells and where efficacy of ivosidenib is predicted by clinically meaningful remissions at the recommended dosage of ivosidenib and/or inhibition of IDH1 mutation activity is expected at ivosidenib concentrations sustainable at the recommended dosage.1 The most common ivosidenib-susceptible IDH1 mutations are R132C and R132H substitution mutations.1 In vitro studies indicate that ivosidenib inhibits IDH1 with R132C, R132H, R132G, R132L, or R132S mutation at much lower concentrations than IDH1 wild-type enzymes.1, 5, 8
Ivosidenib has demonstrated decreased 2-hydroxyglutarate levels and induction of myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH1 mutation and in mouse models of intra-hepatic cholangiocarcinoma.1 Ivosidenib also has demonstrated decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH1 mutation.1 The clinical importance of persistent IDH1 mutations in patients who achieve complete remission has not been established; however, persistent IDH1 mutations may indicate continued differentiation of abnormal myeloblast cells into mature granulocytes.2
Peak plasma concentrations and AUC of ivosidenib are less than dose proportional over the dosage range of 200-1200 mg daily.1 Following oral administration of a single dose, median time to peak plasma concentrations of ivosidenib is approximately 2-3 hours.1 Following repeated administration of ivosidenib, steady-state concentrations of the drug are achieved in 14 days and accumulation of the drug is observed (approximately 1.2- to 1.9-fold increases in AUC and peak plasma concentrations).1 Pharmacokinetics of ivosidenib at steady state in patients with newly diagnosed AML, patients with relapsed or refractory AML, and patients with relapsed or refractory MDS are similar, and are lower in patients with cholangiocarcinoma.1 Administration of ivosidenib (single 500-mg dose) with a high-fat meal (approximately 900-1000 calories with 500-600 calories from fat) increased peak plasma concentrations and AUC of ivosidenib by 98 and approximately 25%, respectively, in healthy individuals compared with administration in the fasted state; administration of ivosidenib with a high-fat meal should be avoided.1, 5, 16
Ivosidenib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by N -dealkylation and hydrolysis.1 Following oral administration of a radiolabeled dose of the drug, unchanged ivosidenib accounted for greater than 92% of plasma total radioactivity.1, 17 In vitro, ivosidenib is highly bound (92-96%) to plasma proteins.1 The terminal half-life at steady state of ivosidenib is 129, 58, 98, and 96 hours in patients with cholangiocarcinoma, relapsed or refractory AML, newly diagnosed AML in combination with azacitidine, and relapsed or refractory MDS, respectively.1 Following administration of a radiolabeled dose of ivosidenib, 77% of the radioactivity was recovered in feces (67% of the dose as unchanged drug) and 17% was recovered in urine (10% of the dose as unchanged drug).1, 17
Clearance of ivosidenib does not appear to be affected substantially by age (18-89 years), sex, race, body weight (38-150 kg), or Eastern Cooperative Oncology Group (ECOG) performance status.1, 5
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Ivosidenib can only be obtained through designated specialty pharmacies and distributors.3 Contact manufacturer for additional information.3
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg | Servier Pharmaceuticals |
1. Servier Pharmaceuticals LLC. Tibsovo® (ivosidenib) tablets prescribing information. Boston, MA; 2023 Oct.
2. DiNardo CD, Stein EM, de Botton S et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med . 2018; 378(25):2386-98. [PubMed 29860938]
3. Servier Pharmaceuticals LLC. Servier One Patient support services. From Servier One for Healthcare Professionals website. Accessed 2022 Oct 13. [Web]
4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2022 Oct 13. [Web]
5. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211192Orig1s000: Multi-discipline review. From FDA website. [Web]
6. Norsworthy KJ, Luo L, Hsu V et al. FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation. Clin Cancer Res . 2019 Jan 28; :1-5. [PubMed 30692099]
7. Dhillon S. Ivosidenib: First Global Approval. Drugs . 2018; 78:1509-16. [PubMed 30209701]
8. Popovici-Muller J, Lemieux RM, Artin E et al. Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med Chem Lett . 2018; 9:300-5. [PubMed 29670690]
9. Buege MJ, DiPippo AJ, DiNardo CD. Evolving Treatment Strategies for Elderly Leukemia Patients with IDH Mutations. Cancers (Basel) . 2018; 10:1-20. [PubMed 29882807]
10. Perl AE. The role of targeted therapy in the management of patients with AML. Blood Adv . 2017; 1:2281-2294. [PubMed 29296877]
11. Norsworthy KJ, Mulkey F, Ward AF et al. Incidence of Differentiation Syndrome with Ivosidenib (IVO) and Enasidenib (ENA) for Treatment of Patients with Relapsed or Refractory (R/R) Isocitrate Dehydrogenase (IDH)1- or IDH2-Mutated Acute Myeloid Leukemia (AML): A Systematic Analysis By the U.S. Food and Drug Administration (FDA). Blood . 2018; 132:288.
12. Birenda KC, DiNardo CD. Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120. Clin Lymphoma Myeloma Leuk . 2016; 16:460-5. [PubMed 27245312]
13. Fathi AT, DiNardo CD, Kline I et al. Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study. JAMA Oncol . 2018; [PubMed 29346478]
14. Bohl SR, Bullinger L, Rücker FG. New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise. Int J Mol Sci . 2019; 20 [PubMed 31018543]
15. Nassereddine S, Lap CJ, Tabbara IA. Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy. Onco Targets Ther . 2019; 12:303-308. [PubMed 30643428]
16. Dai D, Yang H, Nabhan S et al. Effect of itraconazole, food, and ethnic origin on the pharmacokinetics of ivosidenib in healthy subjects. Eur J Clin Pharmacol . 2019; [PubMed 31011758]
17. Prakash C, Fan B, Altaf S et al. Pharmacokinetics, absorption, metabolism, and excretion of [C]ivosidenib (AG-120) in healthy male subjects. Cancer Chemother Pharmacol . 2019; 83:837-848. [PubMed 30758648]
18. Fan B, Dai D, Cohen M et al. Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants. Clin Pharmacol Drug Dev . 2020; [PubMed 32648303]
19. 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.
20. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol . 2020;21(6):796-807.
21. 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.
22. National Cancer Institute. Acute Myeloid Leukemia Treatment (PDQ®)-Health Professional Version. From NIH website. Accessed 2022, Jul 19. [Web]
23. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv . 2020 11;4(15):3528-3549.
100. Nasany RA, de la Fuente MI. Therapies for IDH-mutant gliomas. Curr Neurol Neurosci Rep . 2023;23:225-33.
101. Mellinghoff IK, Ellingson BM, Touat M, et al. Ivosidenib in isocitrate dehydrogenase 1-mutated advanced glioma. J Clin Oncol . 2020;38:3398-406.
102. Mellinghoff IK, Lu M, Wen PY, et al. Vorasidenib and ivosidenib in IDH1-mutant low-grade gliomas: a randomized, perioperative phase 1 trial. Nature Med . 2023;29:615-22.
103. Kamson DO, Puri S, Sang Y, et al. Impact of frontline ivosidenib on volumetric growth patterns in isocitrate dehydrogenase-mutant astrocytic and oligodendroglial tumors. Clin Cancer Res . 2023;29:4863-9.
104. Lam K, Lin HY, Williford G, et al. Ivosidenib off-label use for IDH mutant gliomas: the MD Anderson Cancer Center real life experience. J Clin Oncol . 2023;41(16 Suppl):e14022.