On February 9, the world's first isotrate dehydrogenase-1 (IDH1) inhibitor, Avonib, was officially approved by the State Drug Administration (NMPA) for the treatment of patients with recurrent IDH1 mutations in China or refractory acute myeloid leukemia (R/R AML), which is expected to open up a new pattern of treatment for IDH1 mutation R/R AML in China.
Due to the excellent clinical efficacy and good safety of the Global Key Research AG120-C-0011,2 China Bridging Registered Trial, CS3010-101 Study 3, NMPA accepted the new drug listing application (NDA) of Avonib after only half a year. On this occasion, Professor Jiang Erlie of the Hospital of Hematology of the Chinese Academy of Medical Sciences is specially invited to make wonderful interpretations and comments on the global key research AG120-C-001 and its China Bridging Registration Test - CS3010-101 Research!
Professor Jiang Erlie
- Chief Physician, Doctoral Supervisor
- Director of stem cell transplantation center of Hematology Hospital, Chinese Academy of Medical Sciences
- Deputy Leader of the Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association
- Deputy Leader of hematopoietic stem cell transplantation and cell therapy group of hematogenetic oncology professional committee of Chinese Anti-Cancer Association
- Member of hematology branch of China Association for the Promotion of International Exchanges in Healthcare
- Member of the Academic Working Committee on Transplant Infection of the Hematology Branch of the Chinese Geriatrics Association
- Vice Chairman of Tianjin Society of Blood and Regenerative Medicine
- Hematology Committee member of Tianjin Anti-Aging Society
- Hematology Branch of Tianjin Medical Association and Society of Integrative Traditional and Western Medicine
- Member of Organ Transplantation Branch of Tianjin Medical Association
- Member of hematology Physician Branch of Tianjin Medical Doctor Association
Avonib's global pivotal study AG120-C-001
Research background
Isocitric acid dehydrogenase-1 (IDH1) mutations can be detected in about 6% to 10% of patients with AML. Avonib (AG-120) is a small molecule inhibitor that orally targets IDH1 mutations.
Research methodology
The AG120-C-001 study is a phase I dose escalation and dose-scaling study of avonib monotherapy to evaluate the efficacy and safety of avonib in the treatment of patients with IDH1 mutation AML. The main therapeutic group is R/R AML patients, 500 mg of avonib orally daily, followed up for at least 6 months.
Research results
A total of 258 patients were treated with avonib, of which 179 were R/R AML patients. In 125 patients with R/R AML who received 500 mg of avonib daily and had data from at least 6 months of follow-up data, complete remission and partial haematological recovery (CR/CRh) were 31.8% (95% confidence interval, 25.1-39.2), CR rate was 24.0% (95% confidence interval, 18.0-31.0), objective response rate (ORR) was 41.9% (95% confidence interval, 34.6-49.5), CR/ The median duration of CRh was 8.2 months (95% confidence interval, 5.6-12.0) and the median time to CR/CRh was 2 months (95% confidence interval, 0.9-5.6) (Table 1). After a median follow-up of 15.3 months, the median OS for patients with CR+CRh was 18.8 months (Figure 1). Of the 84 patients with baseline transfusion dependence, 29 (35%) achieved non-transfusion dependence, and patients in remission had a lower incidence of infection and febrile neutropenia than patients without remission. Of the patients who reached CR or CRh, 23% cleared the IDH1 mutation from bone marrow monocytes (BMMCs).
Table 1. Hematologic remission and duration of remission in patients treated with 500 mg of avonib daily
Figure 1: Survival of optimal remission for avonib treatment
In patients with R/R AML, adverse events associated with ≥3 treatment were prolonged QT interval (7.8%), differentiation syndrome (3.9%), anemia (2.2%), thrombocytopenia or decreased platelet count (3.4%), leukocytosis (1.7%) (Table 2), and were managed with standard care and dose adjustment of Avonib.
Table 2. ≥ treatment-related adverse events of grade 3
Conclusions of the study
In patients with IDH1 mutation R/R AML, ivonib receiving 500 mg daily can achieve induced lasting remission, non-transfusion dependence is observed in all remission categories in patients with transfusion dependence at baseline, febrile neutropenia and frequency of infection are reduced in patients who respond, and patients are well tolerated, with 23% of CR/CRh patients achieving molecular response.
Avonib China Bridging Study CS3010-101
There are currently no IDH1 inhibitors in China that target IDH1 mutation aML. Here, the China Bridging Study CS3010-101 reports for the first time clinical data of Avonib in patients with IDIH1 mutation R/R AML in China.
A total of 30 adult patients with mutations in the IDH1 R132 gene were included in the study. All subjects received 500 mg of avonib once daily for a cycle of 28 days with no intervals between cycles. The primary endpoint was pharmacokinetics (PK), with key secondary endpoints including safety and efficacy (Figure 2).
Figure 2. CS3010-101 Study Design
As of 20 May 2021, a total of 30 patients have been treated, of which 9 are still being treated.
Pharmacokinetic characteristics: for single and repeated administration of 500 mg, the median Tmax was 3.98 hours and 2.00 hours, respectively, after one repeated administration per day, the geometric mean CL/F was 6.25 L/h, and no obvious drug accumulation was seen when steady state was reached. The inter-individual variability of exposure (Cmax and AUC) in Chinese patients was moderate.
Efficacy: Among the 30 assessable patients, the secondary efficacy endpoint CR+CRh rate was 36.7% (11/30), and 11 patients achieved CR. The estimated sustained response rate for CR+CRh at 12 months was 90.9%, and the median time to CR/CRh was 3.68 months (95% confidence interval, 1.0-6.5) (Figure 3). Two patients (6.7%) received hematopoietic stem cell transplantation after reaching CR or CRh. The overall median overall survival (OS) was 9.1 months, and the median OS in patients with CR/CRh had not been reached.
Figure 3: Duration of treatment and optimal objective response of avonib
Safety: adverse events (TEAEs) during treatment were reported in all patients. Fourteen (46.7%) patients reported ≥ grade 3 treatment-related TEAEs, the most common being decreased platelet count (36.7%), anemia (33.3%), and neutrophil count (33.3%). Observation of the blood picture of the patients after the treatment of avonib over time, no bone marrow suppression was found. In addition to this, adverse events that lead to serious consequences such as tapering, interruption and discontinuation of the drug are not common. Overall, avonib was safe, no unintended adverse events were found, the proportion of adverse events of particular concern was not higher than that of the AG120-C-001 study, and after treatment, it could be effectively controlled and mitigated without adverse consequences.
The PK, safety and efficacy data observed by Avonib in patients with IDH1 mutation R/R AML in China are comparable to those observed in the key study AG120-C-001 conducted in the United States and France, and are well tolerated, can induce lasting remission, have clinical benefits, and are expected to meet the medical needs of such patient populations in China.
Expert reviews
AML is the most common type of leukemia in adults, and the disease progresses rapidly4. Most patients relapse despite remission, tend to develop relapsing/refractory AML, and have a poorer prognosis in patients with R/R AML5. Multiple studies have shown IDH1 mutations in patients with AML and are associated with a poor prognosis6. IDH1 mutations are involved in the development of AML, which not only has a prognostic cue effect on AML, but also serves as a therapeutic target for AML. IDH1 inhibitors have broad application prospects in patients with IDH1 mutation R/R AML.
Avonib is the first small molecule inhibitor to target the IDH1 mutation, and its efficacy and safety in patients with the IH1 mutation R/R AML have been confirmed in a multicenter, single-arm, open-label Phase I clinical trial (AG120-C-001). The AG120-C-001 study showed that the IDH1 inhibitor avonib treated the IDH1 mutation R/R AML with an ORR of 41.9%, a CR+CRh rate of 31.8%, a CR+CRh rate of 24%, an overall median OS of 8.8 months, and a median OS of 18.8 months for patients with CR/CRh, and a good safety profile of avonib during treatment1. Therefore, in July 2018, the U.S. Food and Drug Administration (FDA) approved avonib for the treatment of adult patients with IDH1 mutation R/R AML. Based on this breakthrough research result, from the 2018 V2 edition to the 2021 V3 edition of the NCCN AML guidelines, the ivonib is recommended for the treatment of patients with IDH1 mutation R/R AML, and so far avonib is the only recommended treatment regimen for patients with IDH1 mutation R/R AML7,8.
The CS3010-101 study, as a key global study AG120-C-001, also showed excellent efficacy and good safety of Avonib in the treatment of patients with IDH1 mutation R/R AML in China. Among the 30 assessable patients, the main efficacy endpoint CR+CRh rate was 36.7% (11/30, 11 patients all achieved CR), the overall median OS was 9.1 months, the median OS in patients with CR/CRh was not yet reached, and the safety was good, no unexpected adverse events were found, and the proportion of adverse events of special concern was not higher than that of the AG120-C-001 study. With its excellent performance among Chinese patients, Avonib was selected for the 2020 edition of the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Malignant Haematology 9. The 2021 CSCO Guidelines for the Diagnosis and Treatment of Malignant Haematology also recommend avonib for the treatment of patients with IDH1 mutation R/R AML10. In addition, the 2021 guidelines for the diagnosis and treatment of recurrent refractory acute myeloid leukemia in China (2021 edition) also recommend that avonib be used for R/R AML treatment11.
Recently, based on the excellent clinical efficacy and good safety of CS3010-101 in the Chinese bridging study CS3010-101, Avonib was approved by NMPA for the treatment of patients with IDH1 mutation R/R AML, becoming the only drug in China that was approved by NMPA to target the treatment of IDH1 mutation R/R AML. It is expected that it will be widely used in patients with IDH1 mutation R/R AML in China, and open up a new pattern of treatment of IDH1 mutation R/R AML in China.
bibliography:
1. Dinardo CD, et al. New England Journal of Medicine 2018;378(25):2386-2398.
2. Pollyea DA, et al. Abstract #7000. Presented at the 2018 ASCO Annual Meeting, June 2, 2018; Chicago, IL.
3. M. Sun, et al. Annals of Oncology (2021) 32 (suppl_5): S773-S785.
4. Beyar-Katz O, Gill S. Clin Cancer Res. 2018 Nov 15;24(22):5502-5515.
5. Montesinos P, et al. Ann Hematol. 2019 Nov;98(11):2467-2483.
6. Pirozzi CJ, Yan H. Nat Rev Clin Oncol. 2021 Oct;18(10):645-661.
7. NCCN Clinical practice guidelines in oncology: Acute Myeloid Leukemia（2018.V2）.
8. NCCN Clinical practice guidelines in oncology: Acute Myeloid Leukemia（2021.V3）
9. Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Malignant Hematology 2020.
10. Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Malignant Hematology 2021.
11. Guidelines for the Diagnosis and Treatment of Relapsed refractory acute myeloid leukemia in China (2021 edition).
Approval number: NPM-CN-HEMA-028-20230209