The first domestic prescription of infigratinib: how is the treatment for patients with intrahepatic cholangiocarcinoma?

Most patients with cholangiocarcinoma are diagnosed with advanced disease, lose the chance of radical surgery, and have a poor prognosis
.

Activating fusions, rearrangements, translocations and gene amplifications of FGFR are closely related to the occurrence of various cancers

FDA approves FGFR-targeted drug pemigatinib for cholangiocarcinoma

On December 8, 2021, the Hainan Provincial Drug Administration approved the application for approval of the import of infigratinib, a drug urgently needed for clinical use (Qiong Yao Jian Zhuan [2021] No.
619), and the first clinical patient in China was reported in Hainan on December 15, 2021.
The Boao Lecheng Medical Pilot Zone began to use this product
.

This is also the first prescription for infigratinib outside North America

Lancet Gastroenterol Hepatol: Efficacy and Safety of Infigratinib in FGFR2 Fusion or Rearranged Advanced Cholangiocarcinoma

The case sharing in this issue is a case of FGFR2 fusion intrahepatic cholangiocarcinoma patient with postoperative recurrence and lung metastasis brought by Director Li Jiangfeng of Boao Super Hospital
.

After the first-line chemotherapy progressed, the patient progressed again with multi-line treatment of targeted and immune drugs.

Li Jiangfeng, Director of Boao Super Hospital, Professor Mou Haibo, Hangzhou Shulan Hospital

Surgery and postoperative adjuvant chemotherapy

Surgery and postoperative adjuvant chemotherapy

The patient is a 54-year-old female who underwent "liver cancer resection + cholecystectomy + abdominal lymph node dissection" on 2017-03-17.
The postoperative pathology showed moderately differentiated cholangiocarcinoma, stage PT3N1M0 stage IVa, and the gene test result was FGFR2 fusion
.

From April to July 2017, the patient received 8 courses of adjuvant chemotherapy with "gemcitabine + oxaliplatin" after chemotherapy, and from August to September 2017, she received 4 courses of "gemcitabine + capecitabine" chemotherapy due to high fever after chemotherapy

What you see under the mirror:

1.
One gallbladder, 9*3.
3*37.
5px, there are many small golden polyps in the gallbladder wall, 2.
5px in diameter

2.
Group 5 lymph nodes are adipose tissue

3.
Group 12 lymph nodes are adipose tissue

4.
One specimen of partial liver resection, size 19*13*125px, a huge gray-white mass, size 12*6*162.
5px, was seen around the mass, 1.
5*30px, and free liver tissue, size 4 *3*37.
5px

Pathological diagnosis:

1.
Moderately differentiated cholangiocarcinoma (left half liver), tumor size 12*6*162.
5px, close to liver capsule, vascular recurrence (-), nerve recurrence (-)
.

2.
The margins are negative
.

3.
Chronic cholecystitis with cholesterol polyps
.

4.
12 pieces (group 3), 0/12 pieces (group 7), 0/3 pieces (group 8), 3/4 pieces (group 7, 8, 9), (group 12) ) 0/1 and (group 13) Q/4 lymph nodes showed cancer metastasis, among which (group 5) lymph node was adipose tissue, and there was 1 cancer nodule in the lymph nodes (group 7, 8, and 9)
.

Immunohistochemistry: Glypican-3(-), FDL(-), FD1(-), Hepatocyte(-), CD34((vascular+), CK7(+), CK19(+), Ki-67(+3 0 %), F53 (+20%), CDX2 (-), CK8/18 (+), CK20 (-)
.

(Report time: 2017-03-27 14: 28: 14) Immunohistochemistry: 2017001869-13: MLH1(+), FMS2(+), MSH2(+), MSH6(+)

△ Postoperative pathology and genetic testing report

Postoperative recurrence with pulmonary metastasis

Postoperative recurrence with pulmonary metastasis

The re-examination on 2019-1-5 showed bilateral lung metastasis.
On 2019-01-26, the GS regimen (gemcitabine + Seggio) chemotherapy + bevacizumab treatment was started.
Due to intolerance of adverse reactions after chemotherapy, on 2019- 2-16 cases were changed to (gemcitabine + capecitabine) chemotherapy + bevacizumab for 4 courses of treatment, the curative effect was stable, and regular observation was made
.

Started to change to Anlotinib for long-term maintenance therapy on 2019-5-8.

This is a patient with postoperative intrahepatic cholangiocarcinoma with distant metastasis (lung) and abnormal FGFR2 fusion
.

The diagnosis is clear, and after repeated chemotherapy, targeted and immunotherapy, the disease control is not satisfactory.

FGFR2 inhibitor targeted therapy

FGFR2 inhibitor targeted therapy

In December 2021, the patient was admitted to the Boao Lecheng Medical Pilot Area, with an ECOG score of 1 and a tumor marker-carbohydrate antigen (CA19-9) of 47.
41U/ml
.

On December 15, 2021, "Infigratinib 125mg qd" treatment was performed.

△CT examination: comparison of lung metastases before and after treatment

Summary of diagnosis and treatment

Summary of diagnosis and treatment

△ Overview of the treatment of this patient

FGFR2 - opening the era of targeted therapy for cholangiocarcinoma

FGFR2 - opening the era of targeted therapy for cholangiocarcinoma

Most patients with cholangiocarcinoma are usually diagnosed at an advanced stage that is no longer treatable by surgery and has a poor prognosis
.
Activating fusions, rearrangements, translocations and gene amplifications of FGFR are closely related to the occurrence of various cancers
.
Among them, FGFR2 mutation is one of the most common driver genes in patients with cholangiocarcinoma
.

In recent years, with the further understanding of the molecular pathogenesis of cholangiocarcinoma and the success of clinical trials related to targeted and immunotherapy, new options and hopes have emerged for the treatment of patients with advanced cholangiocarcinoma
.
The cascade of fibroblast growth factor FGF (fibroblast growth factor) and its receptor FGFR (fibroblast growth factor receptor) is involved in multiple intracellular signaling pathways that regulate cell proliferation, tumor growth, angiogenesis and proliferation
.
FGFR consists of 4 distinct subtypes
.
In tumors, FGFR, as an oncogene, is involved in multiple steps of tumorigenesis and development, by inducing mitogenic and survival signals, promoting tumor cell invasion and metastasis, promoting epithelial-mesenchymal transition, promoting angiogenesis, and participating in tumor recurrence and drug resistance
.
Dysregulation of FGFR signaling leads to the development, proliferation and metastasis of cancer
.

Results of a study that sequenced 4853 tumor tissue samples revealed FGF–FGFR genetic variants in 7.
1% of all tumor samples
.
Of these, FGFR2 gene fusion/activating mutations were found in 15% of intrahepatic cholangiocarcinoma samples7
.

Infigratinib, a highly selective FGFR2 inhibitor, in patients with advanced, previously treated cholangiocarcinoma, with high efficacy and durable responses

Infigratinib, a highly selective FGFR2 inhibitor, in patients with advanced, previously treated cholangiocarcinoma, with high efficacy and durable responses

Infigratinib Capsule is a selective ATP-competitive tyrosine kinase inhibitor of FGFR1-3 that inhibits the growth of multiple types of tumors driven by FGFR gene amplification, fusion and mutation
.

Up to now, 13 Phase I, 3 Phase II and 2 Phase III clinical studies have been conducted around the world to evaluate the pharmacokinetics, efficacy and safety of Infigratinib in patients with various solid tumors
.
Among them, a phase II clinical study (Study 2204) evaluating infigratinib monotherapy in patients with locally advanced unresectable or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement mutations who failed previous first-line therapy Among the 108 ≥ second-line patients enrolled, including 83 (77%) patients with FGFR2 fusion mutations, 58 (54%) patients had previously received more than second-line therapy
.
The objective response rate (ORR) obtained by independent efficacy evaluation was 23.
1% (95% confidence interval, 15.
6%-32.
2%), including 1 complete response (CR) and 24 partial responses (PR)
.
The median progression-free survival (PFS) was 7.
3 months (95% confidence interval 5.
6-7.
6 months)
.
Further analysis showed that among 50 second-line patients, ORR was 34% ((95% CI: 21.
2, 48.
8)); among 58 third-line and above patients (3-8 previous treatment regimens), ORR was 13.
8% (95% CI: 6.
1, 25.
4)
.
The results of the study confirmed the efficacy of Infigratinib in the treatment of patients with FGFR2 gene fusion or rearrangement of cholangiocarcinoma [3]
.
The full text of the findings has been published in the journal Lancet Gastroenterol Hepatol in 2021 [4]
.

Based on the results of this study, on December 2, 2020, the US FDA accepted the New Drug Application for Infigratinib (BGJ398) and granted the drug priority review status
.
Infigratinib received accelerated FDA approval in May 2021 for the treatment of previously treated, unresectable locally advanced or metastatic disease with fibroblast growth receptor factor 2 (FGFR2) fusions or other rearranged mutations of adult patients with cholangiocarcinoma
.

Tumor response in △2204 study[2]

Combined with the cases shared this time, the patient is a postoperative recurrence and metastasis of cholangiocarcinoma, combined with lung metastasis, and has received multiple lines of chemotherapy and anti-angiogenesis therapy, and the follow-up treatment is very difficult
.
Since no FGFR2 inhibitor has been approved for marketing in China, when the disease progresses, anti-vascular combined immunotherapy is used, but after 7 cycles of treatment, the lung metastases are still progressing, and the adverse reaction of diarrhea is serious
.
In view of the fact that the global innovative drug FGFR2 inhibitor Infigratinib has been approved for marketing by the FDA, and the "Interim Regulations on the Administration of Imported Drugs Urgently Needed for Clinical Medicine in the Boao Lecheng International Medical Tourism Pilot Area of ​​Hainan Province" mentioned: "Specific medical institutions in the pilot area have imported drugs due to urgent clinical needs.
Drugs that have been approved for marketing in the United States, the European Union, Japan and other countries or regions, but which have not been approved and registered in China and cannot be replaced by domestically registered products, can be used legally in the pioneer area
.
” Therefore, through the implementation of this regulation, the availability of drugs has greatly improved It can effectively fill the domestic FGFR2 mutant cholangiocarcinoma second-line and above treatment gaps, and provide effective treatment methods for this type of patients
.
This patient obtained a significant anti-tumor effect from infigratinib treatment, the lesions were significantly reduced, the curative effect reached PR, the length and diameter of the tumor target lesions were reduced by 52%, and the non-target lesions (lungs) were also significantly reduced, and the safety was good
.
The clinical practice results further verified the efficacy of Infigratinib in FGFR2 fusion cholangiocarcinoma
.

Currently, the patient is still receiving infigratinib treatment, and she is expected to achieve PFS and overall survival (OS) outcomes consistent with or even surpassing the clinical trial
.
We expect Infigratinib to benefit more Chinese cholangiocarcinoma patients with FGFR2 fusions or other rearrangements
.
For cholangiocarcinomas with FGFR2 fusions or other rearrangements, we also very much expect that FGFR2 inhibitors combined with other treatments can further improve the efficacy of these patients
.
In addition, FGFR2 mutations in other tumors are also worthy of attention
.

references:

[1] ASCO GI 2021, Abstract #265.

[2] Milind Javle, et al.
Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study.
Lancet Gastroenterol Hepatol 2021 ; 6:803-15.

[3] Ann Transl Med 2020;8(20):1290 | http://dx.
doi.
org/10.
21037/atm-20-5118

[4] Su et al.
A comprehensive pan-cancer study of fibroblast growth factor receptor aberrations in Chinese cancer patients.
Ann Transl Med .
2020;8(20):1290

Doctor of Medicine, Director of Medical Oncology, Chief Physician

Member of CSCO Gastric Cancer Expert Committee

Member of CSCO Integrative Medicine Expert Committee

Executive Director of Zhejiang Anti-Cancer Association

Member of the Standing Committee of the Liver Microcirculation Professional Committee of the Chinese Microcirculation Association

Member of the Standing Committee of Oncology Professional Committee of China Association of Non-Public Medical Institutions

Member of the Standing Committee of the Professional Committee of Precise Diagnosis and Treatment of Cancer, Zhejiang Anti-Cancer Association

Member of the Professional Committee of Precision Cancer Therapy of Zhejiang Medical Doctor Association

Member of the Oncology MDT Professional Committee of Zhejiang Medical Doctor Association

Member of the Professional Committee of Precision Cancer Diagnosis and Treatment of Zhejiang Mathematical Association

Member of Precision Medicine Branch of Zhejiang Translational Medicine Society

Member of the Professional Committee of Clinical Pharmacology of Zhejiang Pharmacological Society

Member of Science Popularization Working Committee of Zhejiang Anti-Cancer Association

Member of the Professional Committee of Tumor Rehabilitation Promotion of Zhejiang Population and Health Association

Member of the Liver Transplantation Group of the Organ Transplantation Branch of the Chinese Medical Association

Member of the Organ Protection Professional Committee of the National Medical Trauma Center

Member of the Surgery Committee of Hainan Medical Association

Member of the Professional Committee of Hepatobiliary and Pancreatic Cancer of Hubei Anti-Cancer Association

Member of the Hernia and Abdominal Surgery Group of the Surgical Committee of Hainan Medical Association

Source: Editorial Department of "Tumor Watch"

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