CUA 2022 Professor Huang Jian: Precise targeting + combination therapy, the future battle of bladder cancer should be fought like this

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The 29th National Urology Conference (CUA2022), hosted by the Chinese Medical Association and the Urology Branch of the Chinese Medical Association (CUA), organized by the Shanghai Medical Association, and co-organized by Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine, was held
online on December 08-11, 2022 。 This year's annual meeting has set up 14 sub-venues such as tumor, stone, minimally invasive, urinary control, andrology, nursing, kidney transplantation, pediatric urology and laser, covering all aspects of the field of urology, comprehensively and deeply displaying and discussing the new progress and new technologies in the diagnosis and treatment of diseases in the industry, and will present a wonderful urology event
for everyone.
At the meeting, Professor Huang Jian from Sun Yat-sen Memorial Hospital of Sun Yat-sen University introduced the current situation and future of bladder cancer medical treatment for us.

- Professor Wong Kin -

Director of the Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Professor, Chief Physician, Doctoral Supervisor

Chairman of the Urology Branch of the Chinese Medical Association

Vice President of Medical Robot Physician Branch of Chinese Medical Doctor Association

Leader of Oncology Group, Urology Branch of Chinese Medical Association

Vice President of the Urology and Andrology Devices Professional Committee of China Medical Device Industry Association

Editor-in-chief of the Chinese Guidelines for the Diagnosis and Treatment of Urology and Andrological Diseases

Editor-in-Chief of the Chinese Journal of Urology

Associate editor of Chinese Journal of Laparoscopic Urology and Journal of Minimally Invasive Urology

Editorial board member of International Journal of Urology, Asian Journal of Urology, Journal of Endourology and other magazines

With the advent of molecularly targeted drugs and antibody drug conjugates (ADCs), the efficacy of bladder tumors has been greatly improved
.
Professor Huang Jian predicts that the main treatment strategy for bladder cancer in the future is combination + precision targeted therapy
.

Molecularly targeted drugs

FGFR gene alterations are quite common in bladder cancer, with an incidence of up to 60% in non-muscle-invasive bladder cancer (NMIBC) and 15%-20% in advanced urothelial carcinoma, where FGFR mutations and fusions drive tumorigenesis
.
Erdatinib is a small molecule, highly selective pan-FGFR tyrosine kinase inhibitor, which can block the downstream pathway of tumor cells and lead to apoptosis, and is currently the only approved targeted therapy for bladder cancer
.

Professor Huang Jian introduced that the BLC2001 study related to erdaltinib (phase II.
, multicenter, open-label) included patients with metastatic and unresectable locally advanced urothelial carcinoma
with FGFR fusion or mutation.
After 2 years of treatment and follow-up, the objective response rate (ORR) was 40%, the disease control rate (DCR) was 79%, and the median duration of response (DoR) was 6.
0 months
.
The results of this study have established the therapeutic position
of erdatinib in bladder cancer.
Fortunately, in addition to erdatinib, there are 46 clinical studies on molecular targeted therapy for bladder cancer on the clinical trial website, involving multi-stage, multi-target, and multi-pathway
.
Among them, the research involving HER-2 antibodies, PARP inhibitors, PI3K/AKT/mTOR inhibitors, MetAP2 inhibitors and other drugs may bring us promising results
.

ADC drugs

At present, the available ADC drugs for bladder cancer at home and abroad include vedicitumab (HER-2 target), Enfortumab vedotin (EV, ennozumab, Nectin-4 target) and sacituzumab govitecan (SG, gosatuzumab, target TROP-2).

The clinical use of drugs varies depending on the target
.
For example, the expression rates of Nectin-4 and TROP-2 in bladder cancer can reach 83% and 80%, respectively, and the corresponding targeted drugs do not need to be screened during clinical use.
However, the overexpression rate of HER-2 in bladder cancer is only 12.
4%, so patients who are positive for HER-2 need to be screened for treatment
.
Professor Huang Jian mentioned that the clinical application of the above three drugs in bladder cancer has been inventoried, and these studies have achieved satisfactory results (as shown in the figure below).

Application of ADC drugs in MIBC

In addition, the layout of ADC drugs is still moving forward, and EVs have also been studied
in neoadjuvant therapy for muscle-invasive bladder cancer (MIBC).
The EV-103 study (Cohort H) enrolled 22 patients with MIBC (T2-T4a) who received EV neoadjuvant therapy for 12 weeks and underwent surgery
1-3 months after the end of treatment.
The results showed that the pathological complete response rate of patients reached 36.
4%, the pathological reduction rate reached 50%, and the efficacy of single agent was even better than that of traditional GC chemotherapy
.

Application of ADC drugs in NMIBC

Professor Huang Jian's team has conducted some explorations and studies on the efficacy of ADC drugs in NMIBC, and a preclinical study revealed that after vedicitumab perfusion therapy in mouse models of bladder cancer, tumor control in both the low-dose and high-dose groups was better than that of the control group
.
Based on this, Professor Huang Jian led a multicenter clinical study using vedicitumab intravesical perfusion in the treatment of MIBC patients with HER-2 expression and BCG failure, which is being enrolled, and we look forward to the publication
of the follow-up results of the study.

Immunotherapy combination

Professor Huang Jian mentioned that immunotherapy + chemotherapy has become a popular choice for the treatment of bladder cancer, and has good results in advanced bladder cancer treatment, maintenance therapy, and neoadjuvant therapy, and many studies of immune + targeted therapy are underway, including PD-1/PD-L1 inhibitor + ADC, PD-1/PD-L1 inhibitor + RTK inhibitor, PD-1/PD-L1 inhibitor + FGFR inhibitor and so on
.

Molecular targeting + immunotherapy

The NORSE study used erdatinib plus immunotherapy in patients with mUC who were not candidates for cisplatin therapy with FGFR gene
alterations.
Studies have shown that combination regimens achieve an ORR of 68% compared with erdatinib alone (ORR of 33%), with significantly better efficacy
.

ADC+ immunotherapy

Similarly, there are many studies on ADC+ immunotherapy for advanced bladder cancer, such as an ORR of 34% for SG+ pembrolizumab second-line therapy; The ORR of first-line treatment with EV+ pembrolizumab reached 64.
5%; The ORR of first-line treatment of vedicitumab + teripulimab reached 73.
9%, and tumor shrinkage was significant after treatment, and the results were satisfactory
.
In addition, Professor Huang Jian's team has also carried out a study using vedicitumab combined with teripulimab in the treatment of patients with cT2-T4aNxM0 bladder urothelial carcinoma who express cisplatin intolerance with HER-2, which is being enrolled
.

In addition to the targeted combination immunotherapy mentioned above, there are many combination regimens for targeted drugs, such as dual targets (tucatinib + trastuzumab), targeted + ADC (EV + erdatinib), targeted + chemotherapy (bevacizumab + GC), and so on
.

R&D of innovative targeted drugs

Multi-omics approach to find new targets

In addition to seeking treatment options on the basis of existing ones, attention should also be paid to the research and development
of innovative drugs.
Based on transcriptome and proteome screening, Professor Huang Jian's team found that bladder cancer metastasis has VEGF-C dependent and VEGF-C non-dependent pathways, and has found some targets through preclinical research, which provides new targets and new treatments
for blocking the metastasis of bladder cancer.

Targeted drug carriers

Targeted therapy of drugs is better realized through new carriers, such as perfusion therapy for bladder cancer through drug delivery systems, including pH-responsive nanodrug delivery systems, glutathione (GSH)-responsive nanodrug delivery systems, enzyme-responsive nanodrug delivery systems, and hypoxia-responsive nanodrug delivery systems
.
The use of these systems for bladder instillation therapy can increase the permeability and adhesion of drugs, better realize targeted therapy of drugs, and improve the efficacy
of bladder instillation.

summary

Finally, Professor Huang Jian summarized the treatment development of bladder cancer as follows: With the development and application of targeted drugs, ADC drugs and innovative drugs, the means of precision treatment of bladder cancer are becoming more and more abundant; The combination of multiple regimens further improved the efficacy
of bladder cancer treatment.
Precision combat + multi-program combination will change the clinical treatment pattern of bladder cancer and bring a better tomorrow to patients!