In a phase I study reported in the Journal of Clinical Oncology, William D. Tap, MD, and colleagues found that the selective mutant-IDH1 inhibitor ivosidenib produced no objective responses but resulted in durable disease control in a cohort of patients with advanced chondrosarcoma.
William D. Tap, MD
As noted by the investigators, mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas and result in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG).
Study Details
The analysis included 21 patients (12 in the dose-escalation phase, 9 in the dose-expansion phase) with chondrosarcoma from a total of 168 patients with mutant-IDH1 advanced solid tumors enrolled in the study. Patients received oral ivosidenib in doses ranging from 100 mg twice daily to 1,200 mg once daily in continuous 28-day cycles. Prior systemic therapy had been received by 11 of the 21 patients with chondrosarcoma.
Responses
No maximum tolerated dose was established in the entire patient population, with no dose-limiting toxicities being observed.
KEY POINTS
- No objective responses occurred; durable disease control was observed in some patients.
- Treatment was well tolerated.
No objective responses were observed. Stable disease was observed in 11 patients (52%). Four patients (19%) with best response of stable disease have remained on therapy for ≥ 2.5 years.
As of data cutoff, median progression-free survival among all 21 patients was 5.6 months. Progression-free survival was 62% at 3 months and 40% at 6 months among all patients, including rates of 77% and 54% among 13 patients with known nondedifferentiated tumors and 30% and 0% among 6 with known dedifferentiated tumors, respectively. Plasma 2-HG levels decreased in all patients (range = 14%–94%) to levels seen in healthy individuals.
Adverse Events
The most common adverse events of any grade included diarrhea (43%), nausea (33%), fatigue (29%), and peripheral edema (24%). Grade 1 or 2 QT prolongation occurred in five patients (24%). Grade ≥ 3 adverse events were observed in 12 patients (57%), including hypophosphatemia, peripheral edema, pain in extremity, increased alkaline phosphatase, and anemia.
No dose reductions were required for adverse events. Adverse events led to death in two patients (both due to respiratory failure), with neither death considered related to study treatment.
The investigators concluded, “In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control. Future studies of ivosidenib monotherapy or rational combination approaches should be considered in patients with advanced mutant-IDH1 chondrosarcoma.”
Jonathan C. Trent, MD, PhD, of Sylvester Comprehensive Cancer Center, University of Miami Health System, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by a grant from the National Cancer Institute and by Agios Pharmaceuticals. For full disclosures of the study authors, visit ascopubs.org.
