Efficacy of Ivosidenib + azacitidine in patients with acute myeloid leukemia

On March 8, 2022, the US FDA accepted the supplemental New Drug Application (sNDA) submitted by Tibsovo, an IDH1 inhibitor, in combination with azacitidine for the treatment of naïve acute myeloid patients with IDH1 mutations Leukemia (AML) patients.

Previously, in July 2018, the FDA approved Tibsovo for the treatment of patients with relapsed or refractory (R/R) IDH1-mutated AML.

In May 2019, the FDA approved a supplemental New Drug Application for Tibsovo for the treatment of newly diagnosed IDH1-mutated AML patients 75 years of age and older who cannot receive intensive chemotherapy due to other comorbidities.

On August 26, 2021, the FDA approved the expanded indication of Tibsovo for the treatment of locally advanced or metastatic cholangiocarcinoma in previously treated adult patients with IDH1 mutations. Tibsovo is the first targeted therapy approved to treat this patient population.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an estimated annual incidence of more than 30,000 new cases in China. AML usually progresses rapidly, and most patients eventually become resistant to treatment or relapse, developing relapsed or refractory acute myeloid leukemia (R/R AML). R/R AML has a poor prognosis, the five-year survival rate is about 27%.

Some AML patients carry isocitrate dehydrogenase-1 (IDH1) mutation. The IDH1 mutant enzyme leads to the accumulation of abnormal metabolites and blocks normal blood stem cell differentiation, which is responsible for the occurrence and development of AML. one of the mechanisms. By blocking the activity of the IDH1 mutant enzyme, it can promote the differentiation of AML cells, thereby exerting an anti-tumor effect. The IDH1 mutation rate in Chinese AML patients is approximately 6-10%.

Tibsovo is a potent oral targeted inhibitor for IDH1-mutated cancers. IDH1 is a metabolic enzyme whose gene mutations are present in a variety of tumors including acute myeloid leukemia, cholangiocarcinoma, and glioma.

Trade name: Tibsovo

Generic name:Ivosidenib (Ivosidenib vornib)

Target: IDH-1

First US approval: July 2018

First Approved in China: Not Approved

Approved Indication: IDH-1 Mutated Acute Myeloid Leukemia (AML) , Cholangiocarcinoma

Recommended dose: 500mg each time, once daily, with or without meals

Storage conditions:20-25°C

Clinical Data

This NDA is supported by the Phase III AGILE study (NCT03173248). Between March 19, 2018, and March 18, 2021, a total of 146 patients were randomized (1:1) to Tibsovo+azacitidine (n=72) or azacitidine+placebo (n=74 )therapy group.

The primary endpoint of the trial is event-free survival (EFS), and key secondary endpoints include complete response (CR) rate, overall survival (OS), CR + partial hematologic recovery (CRh) rate, and objective response rate (ORR).

The data showed that the Tibsovo + azacitidine treatment group significantly improved patients’ event-free survival (EFS) compared with the azacitidine + placebo treatment group (HR 0.33; 95%, Confidence interval: 0.16-0.69; P = .0011). In addition, Tibsovo + azacitidine treatment group also significantly improved overall survival (OS) compared with azacitidine + placebo treatment group, with a median OS of 24.0 months vs 7.9 months /strong> (HR 0.44; 95% confidence interval: 0.27-0.73; P = .0005).

Other data showed that the objective response rate (ORR) of Tibsovo + azacitidine treatment group vs azacitidine + placebo treatment group was 62.5% vs 18.9% ( P < .0001).

In addition, the median time to complete remission (CR) was 4.3 months vs 3.8 months in both groups. In addition, the CR+CRh rate was 52.8% VS 17.6% (P < .0001). At a median of 24 weeks, the CR rates in both groups were 37.5% vs 10.8%.

Adverse Reactions

In terms of safety, the most common all-grade adverse reactions included: nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), fever (33.8% vs 39.7%), anemia strong> (31.0% VS 28.8%), febrile neutropenia (28.2% VS 34.2%), thrombocytopenia (28.2% VS 20.5%), constipation (26.8% VS 52.1%), pneumonia (23.9% VS 31.5 %).

The most common grade 3 or higher adverse reactions included: febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0 %), thrombocytopenia (23.9% vs 20.5%), and pneumonitis (22.5% vs 28.8%).

Conclusion

Tibsovo is the first therapy targeting cancer metabolism, and the combination of azacytidine improves event-free survival and overall survival in previously untreated patients with IDH1-mutant AML. lifetime. In addition, the US FDA also granted this sNDA priority review status, which can shorten the review time from 10 months to 6 months.

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