Big Coffee Review-Professor Jiang Erlie: The first-in-class drug Avonib was approved for marketing in China, and its key research AG120-C-001 and China bridging research CS3010-101 were analyzed

On February 9, the world's first isocitrate dehydrogenase-1 (IDH1) inhibitor, ivonib, was officially approved by the National Medical Products Administration (NMPA) for the treatment of recurrent or difficult IDH1 mutations in China.
It is expected to open up a new pattern for the treatment of IDH1-mutated R/R AML in China
.

Due to the excellent clinical efficacy and good safety of the CS3010-101 study 3 of the global pivotal study AG120-C-0011,2's Chinese bridging registration trial, the NMPA accepted the New Drug Application (NDA) of evonib within half a year.
approval
.

On this occasion, Professor Jiang Erlie from the Hospital of Hematology, Chinese Academy of Medical Sciences was specially invited to give a wonderful interpretation and comment on the global key research AG120-C-001 and its Chinese bridging registration trial-CS3010-101 research! Professor Jiang Erlie Chief Physician, Doctoral Supervisor Director of Stem Cell Transplantation Center, Hematology Hospital, Chinese Academy of Medical Sciences Member of the Hematology Branch of the China Association for the Promotion of International Exchanges in Healthcare, Member of the Transplant Infection Academic Working Committee of the Hematology Branch of the Chinese Geriatrics Association, Vice Chairman of the Tianjin Society of Hematology and Regenerative Medicine, Standing Committee Member of the Hematology Professional Committee of the Tianjin Anti-aging Society, Tianjin Medical Committee, member of the Hematology Branch of the Association of Integrative Chinese and Western Medicine, member of the Tianjin Medical Association Organ Transplantation Branch, member of the Tianjin Medical Association Hematologist Branch, Avonib Global Key Research AG120-C-001 Research Background About 6%-10% Isocitrate dehydrogenase-1 (IDH1) mutations can be detected in AML patients
.

Ivornib (AG-120) is an oral small-molecule inhibitor targeting mutations in IDH1
.

Research Methods The AG120-C-001 study is a Phase I dose-escalation and dose-expansion study of ivonib monotherapy to evaluate the efficacy and safety of ivonib in patients with IDH1-mutant AML
.

The main efficacy population was R/R AML patients who received 500 mg of ivonib orally daily and were followed up for at least 6 months
.

A total of 258 patients received ivonib, 179 of whom had R/R AML
.

In 125 patients with R/R AML who received 500 mg daily ivonib and had at least 6 months of follow-up data, complete remission and partial hematologic recovery (CR/CRh) was 31.
8% (95% confidence interval, 25.
1- 39.
2), the CR rate was 24.
0% (95% confidence interval, 18.
0-31.
0), the objective response rate (ORR) was 41.
9% (95% confidence interval, 34.
6-49.
5), and the median duration of CR/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 who achieved CR+CRh was 18.
8 months (Figure 1)
.

Of the 84 patients who were transfusion-dependent at baseline, 29 (35%) achieved transfusion independence, and those who responded had lower rates of infection and febrile neutropenia than those who did not
.

Among patients who achieved CR or CRh, 23% cleared myeloid mononuclear cells (BMMCs) for IDH1 mutations
.

Table 1.
Hematologic Response and Duration of Response in Patients Treated with Ivonib 500 mg Daily The adverse events reported were QT interval prolongation (7.
8%), differentiation syndrome (3.
9%), anemia (2.
2%), thrombocytopenia or decreased platelet count (3.
4%), leukocytosis (1.
7%) (Table 2), and passed Both standard-of-care treatment and dose adjustment of ivonib can be managed
.

 Table 2.
Conclusions from the Study of Grade ≥3 Treatment-Related Adverse Events In patients with IDH1-mutant R/R AML, 500 mg of ivonib daily induces durable remission, and patients with transfusion dependence at baseline were in all remission categories Transfusion independence was observed in all patients, and febrile neutropenia and infection frequency were reduced in remission patients, and were well tolerated, with 23% of CR/CRh patients achieving molecular remission
.

Avonib China Bridge Study CS3010-101 Background There is currently no IDH1 inhibitor for IDH1-mutant AML in China
.

Here, the Chinese bridging study CS3010-101 is the first to report clinical data of ivonib in Chinese IDH1-mutant R/R AML patients
.

Methods: A total of 30 adult R/R AML patients with IDH1 R132 mutation were included in this study
.

All subjects received continuous oral administration of 500 mg of ivonib once daily in a 28-day cycle with no interval between cycles
.

The primary endpoint was pharmacokinetics (PK), with key secondary endpoints including safety and efficacy (Figure 2)
.

Figure 2.
CS3010-101 Study Design Study Results As of May 20, 2021, a total of 30 patients have been treated, of which 9 patients are still receiving treatment
.

Pharmacokinetic profile: Median Tmax was 3.
98 hours and 2.
00 hours for single and repeated dosing of 500 mg, respectively.
After repeated once-daily dosing, the geometric mean CL/F was 6.
25 L/h.
See obvious drug accumulation
.

The interindividual variability of exposure (Cmax and AUC) in Chinese patients was moderate
.

Efficacy: Among 30 evaluable patients, the secondary efficacy endpoint CR+CRh rate was 36.
7% (11/30), and 11 patients achieved CR
.

The estimated 12-month CR+CRh sustained response rate was 90.
9%, and the median time to CR/CRh was 3.
68 months (95% confidence interval, 1.
0-6.
5) (Figure 3)
.

Two (6.
7%) patients received hematopoietic stem cell transplantation after achieving CR or CRh
.

The overall median overall survival (OS) was 9.
1 months, and the median OS in CR/CRh patients has not been reached
.

Figure 3.
Ivonib treatment duration and best objective response safety: All patients reported on-treatment adverse events (TEAEs)
.

Grade ≥3 treatment-related TEAEs were reported in 14 (46.
7%) patients, the most common being decreased platelet count (36.
7%), anemia (33.
3%), and decreased neutrophil count (33.
3%)
.

Observing the trend of changes in the blood count of patients after ivonib treatment over time, no bone marrow suppression was found
.

In addition, adverse events leading to serious consequences such as dose reduction, interruption and discontinuation were uncommon
.

Overall, ivonib has good safety, no unexpected adverse events were found, and the proportion of adverse events of special concern was not higher than that in the AG120-C-001 study, and it could be effectively controlled and alleviated after treatment, without causing Adverse consequences
.

Study Conclusions The PK, safety, and efficacy data observed with ivonib in Chinese IDH1-mutant R/R AML patients were comparable to those observed in the pivotal study AG120-C-001 in the United States and France, and were tolerated It has good properties, can induce durable remission, has clinical benefits, and is expected to meet the medical needs of this patient population in China
.

Expert Comments AML is the most common type of adult leukemia, and the disease progresses rapidly 4
.

Most patients still relapse after remission and are prone to develop relapsed/refractory AML, and patients with R/R AML have a poor prognosis5
.

Multiple studies have shown that IDH1 mutations are associated with poor prognosis in AML patients 6
.

IDH1 mutation is involved in the occurrence and development of AML, not only has a prognostic role in AML, but also can be used as a therapeutic target for AML
.

IDH1 inhibitors hold great promise in patients with IDH1-mutated R/R AML
.

Ivornib is the first small-molecule inhibitor targeting IDH1 mutations, and its efficacy and safety in patients with IDH1-mutated R/R AML are in a multicenter, single-arm, open-label Phase I clinical trial (AG120-C- 001) was confirmed
.

The AG120-C-001 study showed that the IDH1 inhibitor ivonib in the treatment of IDH1-mutant R/R AML had an ORR of 41.
9%, a CR+CRh rate of 31.
8%, a CR rate of 24%, and an overall median OS of 8.
8 months , the median OS of patients who achieved CR/CRh was 18.
8 months, and ivonib had a good safety profile during treatment 1
.

Therefore, in July 2018, the U.
S.
Food and Drug Administration (FDA) approved ivonib for the treatment of adult patients with IDH1-mutated R/R AML
.

Based on this breakthrough research results, from the 2018 V2 version to the 2021 V3 version of the NCCN AML diagnosis and treatment guidelines, avonib is recommended for the treatment of IDH1-mutated R/R AML patients, and so far avonib is IDH1-mutated R/R The only recommended treatment regimen for patients with AML7,8
.

The CS3010-101 study, as the Chinese bridging registration trial of the global pivotal study AG120-C-001, also showed the excellent efficacy and good safety of ivonib in the treatment of Chinese IDH1-mutated R/R AML patients
.

Among 30 evaluable patients, the primary efficacy endpoint CR+CRh rate was 36.
7% (11/30, all 11 patients achieved CR), and the overall median OS was 9.
1 months, the median OS for patients who achieved CR/CRh It has not yet been achieved, and the safety is good, no unexpected adverse events were found, and the proportion of adverse events of special concern was not higher than that in the AG120-C-001 study
.

Due to its excellent performance in Chinese patients, avonib was selected into the 2020 edition of the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Hematological Malignancies 9
.

The 2021 CSCO guidelines for the diagnosis and treatment of hematological malignancies also recommend ivonib for the treatment of patients with IDH1-mutated R/R AML 10
.

In addition, the Chinese guidelines for the diagnosis and treatment of relapsed and refractory acute myeloid leukemia (2021 edition) released in 2021 also recommend ivonib for the treatment of R/R AML11
.

A few days ago, based on the excellent clinical efficacy and good safety in the Chinese bridging study CS3010-101, ivonib was approved by the NMPA for the treatment of IDH1-mutated R/R AML patients, becoming the only targeted therapy approved by the NMPA in China Drugs for IDH1-mutated R/R AML
.

We look forward to its wide application in Chinese IDH1-mutated R/R AML patients, opening up a new pattern of IDH1-mutated R/R AML treatment in China
.

References: 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 hematological malignancies 2020.
10.
Chinese Society of Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Hematological Malignancies 2021.
11.
China Guidelines for the Diagnosis and Treatment of Relapsed and Refractory Acute Myeloid Leukemia (2021 Edition).
Approval No.
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