Tibsovo (Ivosidenib) FDA Approved for Advanced or Metastatic Cholangiocarcinoma and IDH1 Mutation

Cholangiocarcinoma (CCA) is an aggressive cancer of the bile duct that forms inside the liver (ie, intrahepatic) or outside the liver (ie, extrahepatic, including perihilar and distal tumors).^1,2 Individuals with colitis or certain liver diseases may have an increased risk for CCA.² Although the precise incidence of CCA is unknown, an estimated 8000 new cases of CCA are diagnosed annually in the United States.¹ It is likely, however, that this number is higher, because CCA is difficult to diagnose and may be misclassified at times.¹

The average age at diagnosis of patients with intrahepatic CCA is 70 years and for those with extrahepatic CCA, 72 years.¹

The 5-year relative survival rate is 25% for patients diagnosed with localized intrahepatic CCA and 15% for extrahepatic CCA. But the 5-year relative survival rate is only 2% for those diagnosed with metastatic CCA.³ Advanced CCA can invade the adjacent lymph nodes, adjacent liver, and the portal vein.² Although distant metastasis is uncommon, CCA can lead to peritoneal metastases or to hematogenous hepatic metastases.²

The treatment of CCA generally includes surgery, chemotherapy, radiation therapy, and most recently, targeted therapy, for patients with specific genomic alterations.⁴ For patients with advanced or metastatic CCA, the treatment options remain limited.²

The understanding of the role of biomarkers in CCA is increasing. The National Comprehensive Cancer Network guidelines for hepatobiliary cancers now recognize the need for molecular profiling to identify any genomic mutations or other alterations—including FGFR2-3, IDH1-2, and KRAS—in patients with advanced CCA. Molecular profiling, using US Food and Drug Administration (FDA)-approved tests, is necessary today to identify patients who may be eligible to receive one of the new targeted agents recently approved by the FDA.⁴

Approximately 18% of CCA cases in the United States harbor an IDH1 mutation.⁵ Recently, a new oral therapy that targets the IDH1 mutation was approved for the treatment of patients with advanced or metastatic CCA and IDH1 mutation.⁶

FDA Approves Oral Ivosidenib for CCA and IDH1 Mutation

On August 25, 2021, the FDA accelerated the approval of a new indication for ivosidenib (Tibsovo; Servier Pharmaceuticals), an oral IDH1 inhibitor, for the treatment of patients with locally advanced or previously treated metastatic CCA and an IDH1 mutation, as detected by an FDA-approved test, the Oncomine Dx Target Test companion diagnostic, which was approved on the same day.⁶ The FDA granted ivosidenib an orphan drug designation for this indication.⁶

“Patients living with IDH1-mutated cholangiocarcinoma, especially those whose disease progresses following chemotherapy, are in urgent need of new treatment options,”⁷ said Rachna T. Shroff, MD, MS, Associate Professor of Medicine, University of Arizona, and Chief of GI Medical Oncology, University of Arizona Cancer Center, Tucson, commenting on the approval of ivosidenib for CCA.

“In addition to an acceptable safety profile, Tibsovo demonstrated an impressive, significant benefit in progression-free survival, underscoring its importance as a new option for patients battling this aggressive cancer,”⁷ Dr Shroff added.

Ivosidenib is the first targeted therapy to receive FDA approval for the treatment of patients with CCA and IDH1 mutation.⁷ It was initially approved in 2018 for relapsed or refractory acute myeloid leukemia (AML), and in 2019 it received an expanded indication for newly diagnosed AML in patients aged ≥75 years or in patients with comorbidities that preclude the use of intensive induction chemotherapy.⁸

Mechanism of Action

Ivosidenib, a small-molecule agent, is a targeted inhibitor of the mutated IDH1 enzyme. Susceptible IDH1 mutations lead to increased levels of 2-hydroxyglutarate (2-HG).⁸ The IDH1 R132C substitution occurs most often in CCA and in several other cancer types.⁹ Ivosidenib was shown to reduce 2-HG levels in patient-derived xenograft intrahepatic CCA models with IDH1 R132C substitution.⁸

By blocking the IDH1 mutation, ivosidenib induces myeloid differentiation in vitro and in vivo. In blood samples from patients with an IDH1 mutation, ivosidenib was shown to decrease 2-HG levels ex vivo, reduce blast counts, and increase the proportion of mature myeloid cells.⁸

Dosing and Administration

The recommended dose of ivosidenib is 500 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Ivosidenib should not be administered with a high-fat meal.⁸

Ivosidenib is available as 250-mg tablets.⁸

Pivotal Clinical Trial: ClarIDHy

The efficacy of ivosidenib in patients with CCA was assessed in the ClarIDHy study (or Study AG120-C-005), a randomized, double-blind, placebo-controlled, multicenter clinical trial that included 185 adults with locally advanced or metastatic CCA and an IDH1 mutation whose disease had progressed after previous therapy (at least 1 but no more than 2 previous therapies).¹⁰ The patients were randomized to ivosidenib 500 mg orally once daily or to placebo, administered in continuous 28-day cycles, until disease progression or unacceptable adverse events. Patients were stratified according to the number of therapies they received previously (1 or 2). Patients randomized to the placebo arm were permitted to cross over to the ivosidenib arm after radiographic evidence of disease progression.¹⁰

The median age of enrolled patients was 62 years; 37% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 62% had an ECOG performance status of 1. At diagnosis, 91% of patients had intrahepatic CCA and 92% had metastatic disease; 47% received 2 previous lines of treatment.¹⁰ Overall, 70% of patients had an R132C mutation, and the remainder had other R132 mutations.¹⁰

As shown in the Table, patients who received ivosidenib achieved a significant improvement in progression-free survival (PFS).^8,10 At the median follow-up of 6.9 months, 82% (50/61) of patients who received placebo had an event (ie, progressive disease or death) compared with 61% (76/124) of patients who received ivosidenib (Table).^8,10

The median PFS for the ivosidenib arm was 2.7 months versus 1.4 months in the placebo arm (95% confidence interval [CI], 1.6-4.2 vs 1.4-1.6).¹⁰ The median overall survival was 10.3 months for ivosidenib-treated patients versus 7.5 months for the placebo arm, without adjusting for crossover (95% CI, 7.8-12.4 vs 4.8-11.1).⁸

Among the patients who received ivosidenib, 32% (95% CI, 23-42) and 22% (95% CI, 13-32) remained free of disease progression or death at 6 months and 12 months, respectively, compared with none in the placebo arm.¹⁰

Adverse Reactions

The most common (≥20%) adverse events in the study in patients with CCA who received ivosidenib were fatigue (43%), nausea (41%), abdominal pain (35%), diarrhea (35%), cough (27%), decreased appetite (24%), ascites (23%), vomiting (23%), anemia (18%), and rash (15%).⁸

The most common (≥10%) laboratory abnormalities in patients with CCA who received ivosidenib were reduced hemoglobin (40%), increased aspartate aminotransferase (34%), and increased bilirubin level (30%).⁸

Serious adverse reactions were reported in 34% of patients treated with ivosidenib and included ≥2% of patients who had pneumonia, hyperbilirubinemia, ascites, and cholestatic jaundice.

Fatal adverse events occurred in 4.9% of patients receiving ivosidenib, including sepsis (1.6%), as well as pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (each 0.8%). Ivosidenib was permanently discontinued in 7% of patients; acute kidney injury was the most common (1.6%) event leading to treatment discontinuation.⁸

Ivosidenib has no contraindications.⁸

Drug Interactions

Coadministration of ivosidenib with strong or moderate cytochrome (CY) P3A4 inhibitors can increase the plasma concentrations of ivosidenib, thereby increasing the risk for corrected QT (QTc)-interval prolongation. If concomitant use of strong CYP3A4 inhibitors is unavoidable, a dose reduction to 250 mg ivosidenib is recommended, and the patient should be monitored for prolongation of QTc interval.⁸

The coadministration of ivosidenib with strong CYP3A4 inducers should be avoided, because coadministration can decrease the plasma concentrations of ivosidenib.⁸

The coadministration of ivosidenib with QTc-prolonging drugs increases the risk for QTc-interval prolongation and should be avoided; if coadministration is unavoidable, the patient should be monitored for QTc-interval prolongation.⁸

Use in Specific Populations

Data are not available regarding the use of ivosidenib during pregnancy, but the use of ivosidenib during pregnancy carries a risk for fetal harm.⁸

No data are available on the effects of ivosidenib on human milk production or on the breastfed child. Women should be advised not to breastfeed during ivosidenib treatment and for at least 1 month after the last dose.⁸

In clinical studies, no overall differences in the efficacy or safety of ivosidenib were observed between patients younger and older than age 65 years.⁸

No modification of the starting dose of ivosidenib is required in patients with mild or moderate renal impairment. For patients with preexisting severe renal impairment or those who require dialysis, the risks and benefits should be considered before initiating ivosidenib treatment.⁸

No modification of the ivosidenib starting dose is required for patients with mild or moderate hepatic impairment. In patients with preexisting severe hepatic impairment, the risks and benefits should be weighed before initiating ivosidenib treatment.⁸

Warnings and Precautions

Patients receiving ivosidenib should be monitored with electrocardiogram (ECG) and electrolyte laboratory tests for QTc-interval prolongation and ventricular arrhythmias. Obtain an ECG before initiating ivosidenib and at least once weekly for the first 3 weeks of treatment, then at least once monthly for the duration of treatment. If QTc-interval prolongation occurs, a dose reduction or withholding of ivosidenib is recommended, depending on the severity.⁸

Guillain-Barré syndrome was reported in less than 1% (2/258) of patients with AML and IDH1 mutation who received ivosidenib in ClarIDHy. Patients should be monitored for new signs and symptoms of motor and/or sensory neuropathy; ivosidenib should be permanently discontinued in patients with Guillain-Barré syndrome.⁸

Conclusion

The approval of a new indication for ivosidenib, an IDH1 inhibitor for patients with previously treated, locally advanced or metastatic CCA and an IDH1 mutation, provides a new oral option and the first targeted therapy for a patient population whose treatment options are limited. In the ClarIDHy study, ivosidenib demonstrated a statistically significant improvement in PFS in patients with this rare type of biliary tract cancer.

References

1. American Cancer Society. Key statistics for bile duct cancer. Updated July 3, 2018. www.cancer.org/cancer/bile-duct-cancer/about/key-statistics.html. Accessed September 13, 2021.
2. National Cancer Institute. Bile duct cancer (cholangiocarcinoma) treatment (PDQ)–health professional version. Updated September 10, 2021. www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq. Accessed September 13, 2021.
3. American Cancer Society. Survival rates for bile duct cancer. Updated January 27, 2021. www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html. Accessed September 14, 2021.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Hepatobiliary Cancers. Version 4.2021. August 26, 2021. www.nccn.org/professionals/physician_gls/pdf/hepatobiliary. Accessed September 14, 2021.
5. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019;10:751-765.
6. US Food and Drug Administration. FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. August 25, 2021. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma. Accessed September 14, 2021.
7. Servier Pharmaceuticals. Servier announces FDA approval of Tibsovo (ivosidenib tablets) in IDH1-mutated cholangiocarcinoma. August 25, 2021. www.servier.us/tibsovo_fda_approval_idh1-mutated_cca. Accessed September 10, 2021.
8. Tibsovo (ivosidenib tablets), for oral use [prescribing information]. Servier Pharmaceuticals; August 2021. www.tibsovopro.com/pdf/prescribinginformation.pdf. Accessed September 14, 2021.
9. My Cancer Genome. Biomarkers: IDH1 R132C. www.mycancergenome.org/content/alteration/idh1-r132c/. Accessed September 14, 2021.
10. 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;21:796-807. Erratum in: Lancet Oncol. 2020;21:e462.