Ivosidenib Shows Durable Disease Control in Advanced IDH1-Mutant Chondrosarcoma

William D. Tap, MD

Ivosidenib (Tibsovo) showed minimal toxicity, substantial 2-hydroxyglutarate (2-HG) reduction, and durable disease control in patients with chondrosarcoma, a rare primary malignancy of the bone, according to data from a phase I study.

A total of 21 patients (escalation, n = 12; expansion, n = 9) with advanced chondrosarcoma received ivosidenib. Twelve patients (57.1%) experienced grade ≥3 adverse events (AEs) and 1 event of hypophosphatemia was determined to be treatment related. Plasma 2-HG levels decreased in all patients (range, 14%-94.2%). The median progression-free survival (PFS) was 5.6 months (95% CI, 1.9-7.4 months) and the PFS rate at 6 months was 39.5%. Approximately 52% of patients experienced stable disease.

Approximately 85% of chondrosarcoma cases are of the conventional subtype, while the remaining 15% include dedifferentiated, mesenchymal, and clear-cell subtypes. Treatment options for these patients are currently limited, with surgery serving as the mainstay approach for those with localized disease. Although chemotherapy options are available for patients with dedifferentiated and mesenchymal disease subtypes, the approach has proven to have minimal benefit, and it’s altogether ineffective in those with the conventional subtype of the disease.

“A majority of patients with chondrosarcoma have subtypes that are resistant to standard chemotherapy. Therefore, novel therapies are urgently needed for patients with metastatic or locally advanced chondrosarcoma,” William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, and co-authors wrote in the study. “The observation that IDH mutations are commonly detected in chondrosarcomas offers hope that targeted mutant IDH inhibitors, such as ivosidenib, may provide a novel treatment strategy and improve outcomes for these patients.”

Of the 21 patients who enrolled, 8 patients were female, the median age was 55 years (range, 30-88), and 11 patients had received prior systemic therapy. Ivosidenib was administered orally (100 mg twice daily to 1200 mg once daily) in continuous 28-day cycles. Responses to treatment were assessed every other cycle using RECIST criteria. For dose escalation, a standard 3 + 3 design was used, and the doses evaluated were 100 mg twice daily (n =1) and 400 (n = 4), 500 (n = 11), 600, 800 (n = 3), and 1,200 mg (n = 2) once daily.

Nineteen percent of patients were still receiving treatment at the time of data cutoff. Reasons for treatment discontinuation were due to disease progression (47.6%); AEs (9.5%); death (9.5%); withdrawal by patient (4.8%); clinical progression (4.8%); and other (4.8%). Most patients (n = 14) had grade 2 or 3 chondrosarcoma at screening (grade 1 chondrosarcoma, n = 2), and 6 had dedifferentiated histology.

In patients with chondrosarcoma, ivosidenib was found to be rapidly absorbed, with a half-life ranging from 72 to 297 hours after a single dose. A steady state of disease was achieved within 14 days of dosing. The maximum 2-HG inhibition in plasma was achieved during the first 28-day cycle in patients receiving 500 mg once daily in all tumor types; no additional inhibition was reported at higher doses. Plasma 2-HG was inhibited in all patients with chondrosarcoma, with consistent and substantial inhibition (median, 56.7%; range, 14%-94.2%) after multiple doses of ivosidenib, to levels that proved consistent with those seen in healthy volunteers.

Fifty-two percent of patients achieved stable disease as the best overall response by RECIST criteria, 29% experienced disease progression, 5% had a response categorized as unknown, and 14% were not assessed. No complete responses or partial responses were reported. As of the time of data cutoff, the 3- and 6-month PFS rates were 62.1% (95% CI, 36.4%-79.9%) and 39.5% (95% CI, 17.9%-60.6%). The outcomes of patients with dedifferentiated histology were poor; only 30% of these patients were progression free at 3 months and none were by 6 months.

In contrast, the 3-, 6-, and 12- month PFS rates for those with non-dedifferentiated tumors (n = 13) were 76.9%, 53.8%, and 30.8%, respectively. A total of 28.6% of patients experienced disease progression as the best overall response, 1 of whom had an IDH2 mutation. Nineteen percent of patients have continued therapy for ≥2.5 years with a best response of stable disease.

Regarding safety, the profile of the agent in the chondrosarcoma cohort proved to be consistent with what has been observed in the cholangiocarcinoma and glioma cohorts in the study. The most common AEs observed were fatigue, diarrhea, and nausea. The most common treatment-emergent AEs in the chondrosarcoma cohort were mostly grade 1 or 2 in severity. Of the grade ≥3 AEs reported in 57.1% of patients, only 1 was determined to be related to treatment via investigator assessment, and that was hypophosphatemia (n = 1).

Additionally, 1 patient experienced an AE that led to permanent drug discontinuation (hydronephrosis at 500 mg); this event was not considered to be treatment related. Two patients had AEs that resulted in drug hold (anemia at 400 mg and confusion at 500 mg, respectively). No AEs resulted in dose reductions. Grade 1 or 2 ECG QT prolongation was reported in 23.8% of patients; however, no grade ≥3 events were observed, and no dose modifications were required for QT prolongation. Two deaths during treatment resulted from serious AEs: acute respiratory failure at 400 mg and respiratory failure at 500 mg, respectively. Both events were not determined to be related to the study treatment per investigator assessment.

“In this phase I study, ivosidenib was well tolerated in a chondrosarcoma population. A majority of AEs were consistent with those seen in other mutant IDH solid tumors in this study,” the investigators wrote. “Ivosidenib also demonstrated clinical activity…the higher PFS rates in patient without dedifferentiated histology suggest that ivosidenib may be more effective in conventional chondrosarcoma.”

The authors of the study acknowledged the limitations of using RECIST criteria to assess tumor response in patients with chondrosarcoma. They also noted that they were unable to record overall survival data in this patient cohort; as such they are unable to conclude whether there is a survival benefit with ivosidenib. Additionally, patient samples were limited for translational studies; as such, they were unable to perform longitudinal mutational analysis to determine the emergence of resistant clones throughout treatment.

“The development of ivosidenib has the potential to offer therapy to patients with mutant IDH1 chondrosarcoma who have no treatment options,” the investigators concluded. Future research should further explore the use of the agent as monotherapy or in combination in patients with advanced IDH1-mutant chondrosarcoma.

In July 2018, the FDA approved ivosidenib for the treatment of adult patients with relapsed/refractory IDH1-mutant acute myeloid leukemia AML.

This approval was expanded in May 2019 to include the first-line treatment of adult patients with IDH1-mutant AML, as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive chemotherapy.

In December 2019, the granted a breakthrough therapy designation to ivosidenib for the treatment of adult patients with relapsed/refractory myelodysplastic syndromes who harbor IDH1 mutations.

Tap WD, Villalobos VM, Cote GM, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J Clin Oncol. 2020;38:1-10. doi: 10.1200/JCO.19.02492