老药新用——ivosidenib（艾伏尼布）二线治疗胆管癌脱颖而出

Introduction: Ivosidenib is the first oral small molecule inhibitor that targets isocitrate dehydrogenase-1 (IDH1) and is currently the only investigational drug approved by the FDA to treat IDH1 mutations. The birth of AML is a milestone event in the field of AML treatment, which has a very important impact on the treatment and prognosis of AML. Now, Ivosidenib is used in the second-line treatment of cholangiocarcinoma. How did this important discovery come about? Let’s take a look below!

Cholangiocarcinoma (CCA) is a malignant tumor originating from bile duct epithelial cells. Cholangiocarcinoma has a low incidence rate, is highly heterogeneous and aggressive, and its patients have a poor prognosis. The most common types of cholangiocarcinoma are intrahepatic cholangiocarcinoma (intrahepatic CCA, iCCA), hilar cholangiocarcinoma (perihilar CCA, pCCA), and distal cholangiocarcinoma (distal CCA, dCCA). The latter two are also collectively called extrahepatic cholangiocarcinoma (extrahepatic CCA, eCCA). In recent years, the incidence and mortality of CCA have been increasing globally. According to research, as of 2019, there were approximately 400,000 new cases of CCA worldwide, of which nearly 280,000 occurred in Asia.

Current treatment status and treatment difficulties of cholangiocarcinoma

Since CCA patients (especially iCCA) have no obvious clinical symptoms in the early stage, special clinical manifestations such as night sweats, jaundice, ascites, and hepatomegaly appear only in the late stage. Based on this situation, most diseases are diagnosed in the middle and late stages. Only about 35% of patients can undergo tumor resection or liver transplantation, and recurrence is easy after surgery. The 5-year survival rate is only 5% to 15%. For CCA patients who have no indication for surgery or are not suitable for local treatment, the main treatment methods are chemotherapy and radiotherapy. Patients receiving chemotherapy often have a poor prognosis, and the median survival time is usually less than 1 year. Although external beam radiation, stereotactic radiotherapy and proton beam radiotherapy have certain therapeutic effects on CCA, due to severe adverse reactions and lack of high-level clinical evidence, the optimal radiotherapy regimen has not yet been formed. For patients with CCA that progresses too rapidly or has invasive metastasis, palliative care may be the only treatment option for such patients. This is also a major difficulty and pain point in the current field of cholangiocarcinoma treatment.

In recent years, as biological detection technology has become increasingly mature, the underlying molecular pathology of CCA has gradually emerged. Some studies have shown that CCA is highly heterogeneous. Nearly 40% of CCA patients have potential target gene mutations, which may require targeted therapy in the later stage. Therefore, the importance of molecular targeted therapy for CCA is becoming increasingly apparent.

Ivosidenib is the first oral small molecule inhibitor that targets isocitrate dehydrogenase-1 (IDH1) and is currently the only investigational drug approved by the FDA to treat IDH1 mutations. The birth of Ivosidenib is a milestone event in the field of AML treatment, which has a very important impact on the treatment and prognosis of AML. Now, Ivosidenib is used in the second-line treatment of cholangiocarcinoma. How did this important discovery come about? Please see the detailed analysis below.

Discovery - the journey of discovery of the first innovative drug ivosidenib (AG-120)

In 2012, Agios Pharmaceuticals Co., Ltd., a partner of Keystone Pharmaceuticals, screened the first small molecule inhibitor AGI-5198 targeting the IDH1 R132 mutation through high-throughput testing (HTS). Although AGI-5198 showed a strong inhibitory effect on 2-HG in the IDH1-mutated xenograft model, its poor metabolic stability and poor drug preparation have greatly limited its clinical application.

Subsequently, the researchers conducted in-depth research on the metabolites of AGI-5198. After a series of medicinal chemistry optimization steps aimed at improving metabolic clearance, they discovered a metabolically stable compound, AGI-14100, which is active at both the enzyme and cellular levels, and optimized its chemical structure multiple times.

After repeated trials, the optimal drug product ivosidenib (AG-120) was obtained (Figure 1). This product has excellent enzyme activity and cell activity, good liver microsome stability, high membrane permeability, and low efflux rate. At the same time, ivosidenib has high selectivity for IDH1 mutations, but has no inhibitory effect on wild-type and mutant IDH2. In follow-up and pharmacodynamic evaluation, ivosidenib showed good activity and safety, and is expected to be further developed as an anti-cancer drug.

Figure 1 The discovery and optimization process of Ivosidenib

Breakthrough - ivosidenib provides a new treatment option for AML patients

In June 2018, "New England" reported the interim results of a clinical trial, which included 179 patients with relapsed and refractory AML with IDH1 mutations. After applying ivosidenib, the overall patient response rate was 41.6%, and the average duration of complete response (CR) + complete response with partial hematological improvement (CRh) was 8.2 months. Of the 84 patients who were dependent on red blood cell and/or platelet transfusions, 29 (35%) were transfusion-free at day 56. Based on the results of this groundbreaking clinical trial, in July 2018, the U.S. Food and Drug Administration (FDA) approved ivosidenib for the treatment of adult patients with IDH1 mutations, becoming the world's first approved IDH1 inhibitor.

Moving forward at full speed - ivosidenib (ivosidenib) is developed in China and is expected to benefit more patients

Among the AML therapeutic drugs currently on the market in China, none are truly effective for AML patients with IDH1 mutations. In order to meet the urgent needs of domestic IDH1 mutated AML patients, CStone reached an exclusive cooperation with Agios in 2018 and obtained the clinical development and commercialization and licensing agreement of ivosidenib in China. Moreover, we are currently making every effort to promote the clinical research and development of ivosidenib in China. We look forward to the results of these studies and hope that ivosidenib can be put into use in China as soon as possible to benefit more Chinese patients.

ivosidenib approved for new indication - second-line treatment of cholangiocarcinoma

Recently, "Lancet Oncology" published an article about the Phase III clinical trial ClarlDHy of ivosidenib (AG-120). ClarlDHy is a clinical trial of late-stage chemotherapy for IDH-1 mutated cholangiocarcinoma. Research shows that Ivosidenib can significantly improve the quality of life of patients with cholangiocarcinoma, extend overall survival (OS) by 10.8 months, and reduce the risk of death by 66.5%.

The ClarlDHy trial is a multi-center, randomized, double-blind, placebo-controlled Phase III clinical trial. The study subjects of this trial were 185 patients with progressive cholangiocarcinoma (who had received 1-2 systemic treatments before taking ivosidenib), all of whom carried IDH-1 gene mutations. The primary endpoint of the trial is progression-free survival (PFS), and the secondary endpoints are overall survival (OS), objective response rate (ORR), etc.

Results: PFS in the ivosidenib group was: 2.7 months, and that in the placebo group was 1.4 months (P<0.001). The 6-month progression-free survival rate in the ivosidenib group was 32%, and the 12-month progression-free survival rate was 22%. OS was 10.8 months in the ivosidenib group and 9.7 months in the placebo group (P = 0.06). Disease control: 53% vs 28%. Median duration of development was 2.6 months (IQR 1.4–6.0) versus 16 months (1.1–2.7). The incidence rate of grade 3 and above adverse reactions was 30% vs 22%.

Safety of ivosidenib

In terms of safety, common adverse events (TEAEs) during treatment in the ivosidenib group included: nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), and occasionally prolongation of the qt interval on electrocardiogram. The incidence of grade 3 or above adverse events was 46% in the ivosidenib group and 36% in the placebo group. There were no treatment-related deaths in either group. In addition, patients in the ivosidenib group had better quality of life.

The importance of ivosidenib compared to other cholangiocarcinoma drugs

The overall efficacy of ivosidenib is slightly lower than that of FGFR inhibitors. However, considering the non-overlapping nature of IDH and FGFR2 mutations, the development of IDH inhibitors is still of irreplaceable importance for the subgroup of patients harboring IDH mutations.

Ivosidenib is well tolerated compared with other drugs for the treatment of cholangiocarcinoma. The most common treatment-emergent adverse events in patients receiving ivosidenib were low-grade diarrhea, nausea, and fatigue. Rates of treatment discontinuation or dose reduction were low. Although the findings reported here are specific to patients with IDH1-mutated advanced cholangiocarcinoma, which represents only a small subset of the disease population, the incidence of intrahepatic cholangiocarcinoma is increasing internationally and represents an area of ​​growing unmet need. RPSFT-adjusted data showed a significant improvement in overall survival with ivosidenib compared with placebo. In the absence of an established effective alternative, there is no reason to deny ivosidenib to patients receiving placebo.

In conclusion, ivosidenib treatment significantly improved crossover-adjusted progression-free survival and overall survival with a favorable safety profile in patients with advanced IDH1-mutant cholangiocarcinoma who progressed on standard chemotherapy. Clinical studies of ivosidenib demonstrate feasibility and clinical benefit in targeting molecularly defined subgroups of cholangiocarcinoma and warrant tumor mutation profiling as a new standard of care in this heterogeneous disease.

Summary and Outlook

ivosidenib has been approved for the treatment of relapsed or refractory AML with IDH-1 mutations. With the further development of clinical trials of ivosidenib, ivosidenib is expected to play a more important role in the field of cholangiocarcinoma and bring new hope to patients with IDH-1 mutations in cholangiocarcinoma. Currently, ivosidenib has been included in NCCN guidelines as a second-line treatment option for IDH-1-mutated cholangiocarcinoma. At the recently concluded 2021 China Clinical Oncology (CSCO) conference, in the guidelines for the diagnosis and treatment of biliary tract tumors, patients with IDH-1 mutations were also recommended to take ivosidenib (Level III expert recommendation, Class 1A evidence). The author hopes that ivosidenib can be approved for early market use and benefit more patients.

References [1] Banales J M, Marin J J G, Lamarca A, et al. Cholangiocarcinoma2020: the next horizon in mechanisms and management[J]. Nat RevGastroenterol Hepatol, 2020, 17(9): 557-588. [2] Informa PLC. Datamonitor Healthcare[DB/OL]. [2020-09-11]. . [3] Krasinskas A M. Cholangiocarcinoma[J]. Surg Pathol Clin, 2018,11(2): 403-429. [4] Rizvi S, Khan S A, Hallemeier C L, et al. Cholangiocarcinomaevolving concepts and therapeutic strategies[J]. Nat Rev ClinOncol, 2018, 15(2): 95-111. [5] Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliarytract cancer[J]. Nat Genet, 2015, 47(9): 1003-1010. [6] Blechacz B. Cholangiocarcinoma: current knowledge and new developments[J]. Gut Liver, 2017, 11(1): 13-26.

Note: Copyright statement, the copyright of all text, pictures and video materials on this website with the source "Medical Companion Travel" indicated belongs to the Medical Companion Travel website. Without authorization, any media, website or individual may not reproduce it, otherwise they will be held legally responsible. When obtaining written authorization for reprinting, the source "Medical Companion Travel" must be indicated. The purpose of reprinting articles on this website is to transmit information, and the reprinted content does not represent the position of this website. If it is involved, please contact our website for deletion.