NEJM: Announced Phase 3 Study Results of Ivornib Combined with Azacitidine in IDH1 Mutant AML, Significant Patient Benefit

Acute myelocytic leukemia (AML) includes all acute leukemias of non-lymphocytic origin

AML is a rapidly progressive cancer of the blood and bone marrow and is the most common type of leukemia in adults

Acute myeloid leukemia (AML) mainly affects the elderly (median age 68 years), and elderly patients and patients who cannot tolerate intensive induction chemotherapy (so-called unfit patients) can receive low-intensity non-curative regimens (such as low-dose cytidine and demethylating drugs), while in unfit patients with acute myeloid leukemia of unknown mutation status, azacitidine combined with venetoclax improved overall survival

One of the strategies to improve the prognosis of unfit AML patients is to use new drugs to target molecular lesions involved in leukemogenesis

Ivosidenib (Tosuvo), a first-in-class, oral, potent, targeted small-molecule inhibitor of IDH1 mutations, data from a Phase 1b trial of 23 newly diagnosed IDH1-mutant acute myeloid leukemia patients showed encouraging clinical activity of ivonib combined with azacitidine

Results of the Phase 3 AGILE study of ivonib combined with azacitidine in IDH1-mutant AML were published in the New England Journal of Medicine

Acute myelocytic leukemia (AML) includes all acute leukemias of non-lymphocytic origin

AML is a rapidly progressive cancer of the blood and bone marrow and is the most common type of leukemia in adults

Acute myeloid leukemia (AML) mainly affects the elderly (median age 68 years), and elderly patients and patients who cannot tolerate intensive induction chemotherapy (so-called unfit patients) can receive low-intensity non-curative regimens (such as low-dose cytidine and demethylating drugs), while in unfit patients with acute myeloid leukemia of unknown mutation status, azacitidine combined with venetoclax improved overall survival

One of the strategies to improve the prognosis of unfit AML patients is to use new drugs to target molecular lesions involved in leukemogenesis

Ivosidenib (Tosuvo), a first-in-class, oral, potent, targeted small-molecule inhibitor of IDH1 mutations, data from a Phase 1b trial of 23 newly diagnosed IDH1-mutant acute myeloid leukemia patients showed encouraging clinical activity of ivonib combined with azacitidine

Results of the Phase 3 AGILE study of ivonib combined with azacitidine in IDH1-mutant AML were published in the New England Journal of Medicine

This is a global, double-blind, randomized, placebo-controlled, phase 3 study to evaluate the efficacy of ivonib plus azacitidine versus placebo plus azacitidine in new patients not suitable for intensive induction chemotherapy Efficacy and safety in patients diagnosed with IDH1-mutant acute myeloid leukemia

Inclusion criteria for patients included: age ≥ 18 years, as detected by the US Food and Drug Administration -approved Abbott RealTime IDH1 in vitro polymerase chain reaction (PCR) assay, and a central diagnosis of previously untreated IDH1-mutant acute myeloid leukemia; No prior IDH1 inhibitor or demethylating drug therapy for myelodysplastic syndromes, ECOG performance status score of 0-2, and good liver and kidney function

The primary endpoint was EFS

Patients were enrolled between March 2018 and May 2021, and as of March 18, 2021 (data cutoff), of 295 patients screened, 146 underwent randomization (Figure 1), of which 72 were assigned to AIDS.

Baseline demographics similar (Table 1).
Fifty-four (75%) patients in the ivonib+azacitidine group had primary acute myeloid leukemia, and 18 (25%) had secondary acute myeloid leukemia.
Primary acute myeloid leukemia; 53 patients (72%) in the placebo+azacitidine group had primary acute myeloid leukemia and 21 (28%) had secondary acute myeloid leukemia .
A total of 16 patients (22%) in the ivonib+azacitidine group were at low cytogenetic risk compared with 20 (27%) in the placebo+azacitidine group .
At data cutoff, 39 patients remained on treatment (27 [38%] in the ivonib+azacitidine group and 12 [16%] in the placebo+azacitidine group) .

Primary efficacy endpoint

Time-free survival was defined as: from randomization to treatment failure (CR at 24 weeks), relapse after remission, or death from any cause, whichever occurred first
.

The median follow-up was 12.
4 months
.
Event-free survival was significantly longer in the ivonib+azacitidine group than in the placebo+azacitidine group (hazard ratio for treatment failure, relapse after remission, or death, 0.
33; 95% confidence interval [CI], 0.
16– 0.
69; P = 0.
002) (Fig.
2A)
.
Since more than half of patients in both groups did not achieve complete remission at week 24, median EFS was the same in both groups (0.
03 months for both); The event-free rate was 20% at 12 months compared to 12% at 12 months, with an estimated event-free rate of 40% at 6 months and 37% at 12 months in the ivonib+azacitidine group
.
The EFS benefit in each subgroup is shown in Figure 2C
.

The CR rate at 24 weeks was 38% in the evonib + azacitidine group compared to 11% in the placebo + azacitidine group; and the event-free survival of patients with CR at 24 weeks was also in favor of ivonib + Azacitidine group
.
The authors also performed a sensitivity analysis of event-free survival, with treatment failure defined as lack of complete response after at least 24 weeks of treatment, complete response with incomplete hematologic recovery, or morphological clearance of leukemia cells in the bone marrow; according to this definition, ivonib Median event-free survival was 22.
9 months in the + azacitidine group compared with 4.
1 months in the placebo + and azacitidine groups
.

secondary endpoint

A total of 74 deaths (28 [39%] in the ivonib + azacitidine group and 46 [62%] in the placebo + azacitidine group), with median OS of 24.
0 months and 7.
9 months, respectively (hazard ratio for death, 0.
44; 95% CI, 0.
27 to 0.
73; P = 0.
001) (Figure 2B)
.
The OS benefit in each subgroup is shown in the figure below
.

Hematologic remission, duration of remission, and time to remission are shown in Table 2
.
Of the 72 patients, 34 (47%) in the ivonib + azacitidine group and 11 of 74 (15%) in the placebo + azacitidine group achieved a CR (P < 0.
001); The median duration of response in CR was 11.
2 months in the former group and 11.
2 months in the placebo+azacitidine group
.
Among patients in complete remission, the estimated probability of maintaining a complete remission at 12 months was 88% in the ivonib+azacitidine group compared with 36% in the placebo+azacitidine group
.
The median time to CR was 4.
3 months in the ivonib+azacitidine group and 3.
8 months in the placebo+azacitidine group
.
Complete remission/complete remission with partial hematologic recovery was achieved in 38 patients (53%) in the ivonib+azacitidine group versus 13 (18%) in the placebo+azacitidine group (P<0.
001)
.
The ORR in the two groups was 62% and 19%, respectively (P < 0.
001), and the median DOR was 22.
1 months and 9.
2 months, respectively; the median treatment duration was 6.
0 months and 2.
8 months
.

hematology improvement

In patients with red blood cell and/or platelet transfusion dependence at baseline, the ivonib plus azacitidine group (46%) converted to transfusion-independent compared with placebo and azacitidine (18%).
ratio was higher (P = 0.
006)
.

Conversion results

The median variant allele frequency of IDH1 mutations in bone marrow aspirate at baseline was 36.
8% in the ivonib + azacitidine group and 35.
5% in the placebo + azacitidine group, and the variant allele frequency of IDH1 mutations Remission in the two groups could not be predicted
.

Of the 120 patients for which the sample was available (58 in the ivonib+azacitidine group and 62 in the placebo+azacitidine group), all patients carried at least one mutation in another gene, DNMT3A, SRSF2, and RUNX1 was the most common in both groups, and among other mutations of interest, including RTK pathway mutations (FLT3, KIT, KRAS, NRAS, and PTPN11) and TP53, was more common in the ivonib+azacitidine group than placebo+azacitidine Cytidine CR rates were higher
.

IDH1 mutation clearance was assessed in bone marrow monocytes, defined as no IDH1 mutation detected at one or more time points during treatment
.
Among patients with sample-available CR/CR with partial hematologic recovery, 17 (52%) of 33 patients in the ivonib + azacitidine group had IDH1 mutation clearance, compared with placebo + azacitidine The IDH1 mutation was cleared in 3 of 10 patients (30%) in the zacitidine group
.
Among patients with data on IDH1 mutation clearance in bone marrow mononuclear cells, 14/43 patients (33%) in the ivonib + azacitidine group had IDH1 mutation clearance with complete remission, compared to placebo + azacitidine The cytidine group was 2/31 (6%) (P=0.
009)
.

Quality of Life

In all quality of life EORTC QLQ-C30 subscales, the results favored the ivonib + azacitidine group
.
The decline in initial quality of life in both groups was consistent with time to remission, but from cycle 5 to cycle 19, health-related quality of life in the ivonib + azacitidine group was similar to baseline or Improvement from baseline occurred in neither the placebo nor azacitidine groups
.

safety

A summary of common adverse events is shown in Table 3.
A total of 66/71 patients (93%) in the ivonib + azacitidine group experienced grade ≥ 3 adverse events, and a total of 69/73 patients (95%) in the placebo + azacitidine group.
) grade ≥ 3 adverse events occurred
.
Grade ≥3 adverse events that occurred in more than 15% of both groups included: febrile neutropenia (28% in the ivonib+azacitidine group and 34% in the placebo+azacitidine group) , anemia (25% and 26%, respectively), neutropenia (27% and 16%, respectively), thrombocytopenia (24% and 21%, respectively), and pneumonia (23% and 29%, respectively)
.

The percentage of patients with any grade infection was 28% in the ivonib + azacitidine group compared with 49% in the placebo + azacitidine group; and over time, only ivonib + azacitidine An increase in absolute neutrophil counts from baseline was observed in the azacitidine group, especially during the first cycle
.

The rate of bleeding events was higher in the ivonib+azacitidine group than in the placebo+azacitidine group (41% vs.
29%); the percentage of patients with any grade of differentiation syndrome was 14% (No events of grade ≥4), 8% in the placebo + azacitidine group (including 1 case of grade 4 events), all cases were treated with glucocorticoids, diuretics, hydroxyurea, etc.
; ivonib + azacitidine The median time to any grade of differentiation syndrome in the zacitidine group was 19.
5 days
.
No deaths due to differentiation syndrome were observed in either group
.

Adverse events leading to discontinuation of both trial drugs occurred in 19 patients in both groups: the most common were pulmonary embolism in the ivonib + azacitidine group (two [3%]) and placebo + azacitidine Pneumonia in the cytidine group (4 cases [5%])
.
Adverse events leading to dose reductions for both trial drugs occurred in only 4 patients (6%) in the ivonib+azacitidine group
.

The median relative dose intensity of ivonib or placebo was 98.
4% in the ivonib + azacitidine group and 97.
7% in the placebo + azacitidine group; median relative dose of azacitidine strength, 92.
5% and 95.
2%, respectively
.

Adverse events leading to discontinuation of both trial drugs occurred in 37 patients (52%) in the ivonib + azacitidine group and in 28 patients (38%) in the placebo + azacitidine group, the most common cause of dosing discontinuation Adverse events included neutropenia (23% in the ivonib+azacitidine group and 4% in the placebo+azacitidine group), febrile neutropenia (10% and 8%, respectively) and infectious pneumonia (8% and 7%)
.
0 patients (14%) in the ivonib+azacitidine group and 21 (29%) in the placebo+azacitidine group died from adverse events
.

This phase 3 study showed that ivonib plus azacitidine had similar adverse events to both alone in acute leukemia, was effective in prolonging event-free survival, increasing complete remission, and prolonging the elderly or otherwise unsuitable for induction chemotherapy OS in IDH1-mutant acute myeloid leukemia patients
.
The benefit of targeting the mutant IDH1 protein was underscored by the finding that durable and deep responses occurred in patients treated with ivonib plus azacitidine, with multiple clearance of IDH1 mutations
.
In terms of safety, overall, ivonib combined with azacitidine rarely stopped treatment due to toxic effects
.

Jianxin Yang, Chief Medical Officer of CStone Pharmaceuticals, said: "We are very pleased to see the excellent data of the AGILE Phase III AML study published in the New England Journal of Medicine, which fully demonstrates the high degree of the research results and academic value in the world's authoritative academic journals.
Approved
.
The prognosis of IDH1-mutant AML patients is poor, especially for IDH1-mutant naïve AML patients without intensive chemotherapy
.
Tosuvo® combined with azacitidine therapy is expected to bring new treatment options for these patients
.
We plan to We will communicate with the National Medical Products Administration (NMPA) of China and look forward to bringing this innovative therapy to more Chinese patients as soon as possible
.
"

About the AGILE Phase III AML Study (NCT03173248)

The AGILE study is a global Phase III, multicenter, double-blind, randomized, placebo-controlled clinical trial evaluating evonib plus azacitidine versus placebo plus azacitidine in patients not eligible for intense chemotherapy Efficacy and safety in patients with newly diagnosed AML
.
The primary endpoint of the study was EFS, defined as the time from randomization to treatment failure, relapse after remission, or death from any cause, whichever occurred first
.
Treatment failure was defined as the failure of a patient to achieve a CR until week 24
.

Key secondary endpoints included: CR rate, defined as the proportion of subjects achieving CR; OS, defined as the time from the date of randomization to the date of death from any cause; CR and CR with partial hematologic recovery (CRh) rates, Defined as the proportion of subjects achieving CR or CRh; ORR, defined as subjects achieving CR, CR with incomplete hematologic recovery (CRi/CRp), partial response (PR), or morphologic leukemia-free status (MLFS) proportion
.

About Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is a rapidly progressive cancer of the blood and bone marrow and is the most common type of leukemia in adults
.
In the United States, there are about 20,000 new cases each year, and 43,000 new cases each year in Europe
.
^[1,2,7] In China, there are about 75,300 new cases of leukemia every year, of which AML patients account for about 59%
.
The incidence of AML increases significantly with age, with a median age of diagnosis of approximately 68 years
.
^[1] Most patients who do not respond to chemotherapy will progress to relapsed or refractory AML ^[3] , and the five-year survival rate of patients is about 29.
5%
.
^[1] For 6-10% of patients with AML, IDH1 enzyme mutation blocks normal blood stem cell differentiation, leading to acute leukemia
.
^[4]

About Tosuvo® ⁽ Avoni Tablets)

Tosuvo® is an oral targeted inhibitor of IDH1 mutant ^enzymes
.
Topsuvo®  has been approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with IDH1 susceptibility ^mutations
.

In 2020, Topsuwo was included in the "List of Overseas New Drugs Urgently Needed in Clinical Medicine (The Third Batch)" by the Center for Drug Evaluation of the State Drug Administration of China, and obtained the qualification for fast-track review and approval
.
At the same time, as the first potent and highly selective oral IDH1 inhibitor of its kind in the world, Topsuvo was selected into the 2020 edition of the "CSCO Guidelines for the Diagnosis and Treatment of Hematologic Malignancies " due to its clear clinical advantages .

Tosuvo® is approved by the U.
S.
Food and Drug Administration ( FDA ⁾ for the monotherapy of adult patients with relapsed or refractory acute myeloid leukemia harboring an IDH1 susceptibility mutation identified by an FDA-approved test and aged ≥ Adult patients with newly diagnosed AML with a susceptibility mutation in IDH1 who are 75 years old or cannot receive intensive chemotherapy because of other comorbidities .
^{In 2021} , Topsuvo® is approved as the first and only targeted therapy for the treatment of patients with previously treated IDH1-mutated locally advanced or metastatic cholangiocarcinoma diagnosed by an FDA-approved test .

The U.
S.
FDA has successively granted Topsuvo® in combination with ^azacitidine “Breakthrough Therapy” designation for the treatment of newly diagnosed adults with AML who are at least 75 years of age or who cannot receive intensive chemotherapy due to other comorbidities and carry an IDH1 susceptibility mutation patients, and ivonib "Breakthrough Therapy" designation for the treatment of adult patients with relapsed/refractory myelodysplastic syndromes (MDS) harboring IDH1 susceptibility mutations
.

About CStone

CStone Pharmaceuticals (SEHK: 2616) is a biopharmaceutical company focused on the research, development and commercialization of innovative immuno -oncology and precision medicines to meet the high medical needs of cancer patients in China and around the world
.
Founded in late 2015, CStone has assembled a world-class management team with extensive experience in new drug R&D, clinical research and commercial operations
.
With tumor immunotherapy combination therapy as the core, the company has established a rich product pipeline consisting of 15 tumor candidates
.
At present, CStone has obtained approvals for seven new drug marketing applications for four innovative drugs
.
Several late-stage drug candidates are in pivotal clinical trials or registration stages
.
CStone's vision is to become a world-renowned biopharmaceutical company leading the way in the fight against cancer
.

references

Pau Montesinos, et al.
Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia.
N Engl J Med .
2022 Apr 21;386(16):1519-1531.
doi: 10.
1056/NEJMoa2117344.