Professor Wang Jianxiang: More flowers, talk about the application of geritinib in FLT3 mutation-positive AML

On February 1, 2021, Segatan® (geritinib fumarate tablets) has been officially approved by the National Medical Products Administration (NMPA) of China for the treatment of relapsed or refractory acute myeloid systems with positive FLT3 mutations Leukemia (AML).

Domestic patients have ushered in the first highly selective FLT3 inhibitor.
The excellent efficacy of geritinib alone or in combination with other drugs in multiple studies is expected to bring more choices to AML patients.

In this regard, Yimaitong invited Professor Wang Jianxiang from the Hematology Hospital of the Chinese Academy of Medical Sciences to talk about the application of geritinib in FLT3 mutation-positive AML patients.

Professor Wang Jianxiang, Chief Physician, Professor, Doctoral Supervisor, Director, National Clinical Research Center for Hematology, Vice President, Hematology Branch, Chinese Medical Doctor Association, Vice President, Chinese Medical Doctor Association, Hematology Branch, Former Chairman, Chinese Medical Association Hematology Branch, J Hematol & Oncol (IF7 .
4) Deputy Editor-in-Chief Editor-in-Chief of Chinese Journal of Hematology (2012-2016) Chairman of the Hematology and Tumor Committee of China Anti-Cancer Association (2012-2015) is extraordinary, there are many molecular mutations in "Ji" Xiangkai AML, Jirui The therapeutic target of tinib is the FLT3 mutation.
The FLT3 mutation mainly includes internal tandem repeats (FLT3-ITD) and tyrosine kinase domain point mutations (FLT3-TKD).
These two region mutations are involved in the occurrence of AML and are used in the treatment of AML.
Important target.

After years of research and development including preclinical trials, clinical phase I, II and international phase III randomized controlled studies, the small molecule compound geritinib for FLT3 has finally come out.

At the same time, because the international phase III randomized controlled study ADMIRAL showed its superiority relative to salvage chemotherapy, the drug was approved in China.

Professor Wang Jianxiang said that the listing of gerritinib means that AML patients with poor prognosis due to FLT3 mutations in the past, "Fujitailai", have a new treatment option-molecular targeted therapy.

Although geritinib is currently only suitable for refractory or relapsed AML with FLT3 mutations, it is believed that more clinical explorations will be carried out after geritinib is launched, including studies on refractory relapse, first-line treatment, and maintenance treatment to help More patients benefit.

Accurate positioning, "Rui" is unstoppable Professor Wang Jianxiang said that geritinib is a second-generation highly selective FLT3 inhibitor, and its clinical marketing has undergone rigorous evidence-based medical research.

The ADMIRAL study is an international, multi-center phase III randomized controlled study.
The results of the study show that 1, compared with the control group (FLAG [fludarabine + cytarabine + granulocyte colony stimulating factor], MEC [mitoxantrone +etoposide + cytarabine]-based traditional chemotherapy regimens), geritinib alone can significantly improve the response rate of FLT3-ITD mutant R/R AML patients (ORR 68% vs 26%) and prolong The survival time (median overall survival time of 9.
3 months vs.
5.
6 months) reached the main experimental endpoint of statistical hypothesis.
Based on the above research results, the drug was approved for marketing in China.

Together, the gold list "replaced" the name at the 2020 ASH conference, and reported a phase 1b extended cohort study that evaluated the effectiveness of geritinib combined with venecla in the treatment of relapsed or refractory FLT3 mutation-positive AML And safety.

The results show that 2, in patients with FLT3 mutation-positive AML who have received a large number of treatments (most of which have received FLT3 inhibitors or TKI treatments in the past), geritinib combined with venecla achieved extremely high bone marrow and blood primitives The cell clearance rate, modified compound complete remission (CRc) rate is as high as 83.
8%, and the long-term survival benefit is still under observation.

The study showed that the anti-leukemia activity of gerritinib combined with venecola was significantly higher than that of gerritinib alone.

The non-hematological toxicity is moderate, and the combination is well tolerated.

In addition to being combined with targeted drugs, geritinib can also be combined with traditional standard chemotherapy regimens.

The CRc rate of gerritinib combined with 3+7 induction chemotherapy in the treatment of FLT3 mutant AML patients is 81.
6%, the median overall survival has not yet reached, and is well tolerated3. In addition, there is also a phase 3 open randomized trial showing that the combination of geritinib and azacitidine in the treatment of FLT3 mutant AML that is not suitable for intensive induction chemotherapy, the CRc rate of the safety cohort was 67%4.

Professor Wang said that in addition to combining other targeted drugs, intensive chemotherapy, and demethylation drugs, geritinib has a lot of room for exploration, such as maintenance therapy and consolidation therapy in combination with high-dose cytarabine.

As a lesson from the car, the incomparable "ni" geritinib belongs to a new generation of FLT3 inhibitors, not only effective against FLT3-ITD, but also effective against FLT3-TKD mutations, and the concentration required for gerritinib to inhibit FLT3 mutations in vitro Very low, the IC50 value is only 0.
29nM.

A meta-analysis was reported at the 2020 ASH meeting, which included patients who had previously used FLT3 inhibitors (Sorafenib, Midostaurin) in the CHRYSALIS study and the ADMIRAL study.
After these patients received geritinib treatment, CRc The rate can reach 42% (CHRYSALIS study) or even higher (48%, ADMIRAL study)5.

Therefore, the new generation of geritinib is still an effective treatment option for patients who have used the first generation of FLT3 inhibitors with weaker efficacy in the past.

In addition, a multi-center retrospective study also analyzed the efficacy of geritinib in patients who had previously used FLT3 inhibitors.

The results showed that the CRc was 51.
4%, and the curative effect was similar to the above results, which was unanimously affirmed by the academic community.

Summary The listing of FLT3 inhibitors provides clinicians with powerful weapons and new treatment options when faced with refractory AML cases.

We also look forward to more explorations in future clinical trials, such as applying geritinib to induction therapy, consolidation therapy, and maintenance therapy to overcome the poor prognosis of patients with FLT3 mutations, and further improve the efficacy of these patients, thereby Fundamentally improve the survival and prognosis of these patients, and then bring significant changes to the field of AML.

References: 1.
Perl AE, et al.
N Engl J Med.
2019;381(18):1728-1740.
2.
Daver N,et al.
2020 ASH.
Oral:333.
3.
Keith W,et al.
2020 ASH.
Oral :24.
4.
Eunice S,et al.
2020 ASH.
Oral:27.
5.
Alexander E,et al.
2020 ASH.
Oral:334.
6.
Numan Y,et al.
2020 ASH.
Oral:262.
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