Strong and strong combination, go to the new course to focus on advanced urothelial cancer immunocombination therapy

preface

In recent years, the treatment of advanced urothelial carcinoma drugs has made rapid progress, including immune checkpoint inhibitors, FGFR kinase inhibitors and a number of antibody-conjugated drugs have been approved for clinical use

Expert profile

Professor Chen Junxing

• Deputy Director of the Department of Urology, First Affiliated Hospital of Sun Yat-sen University, Chief Physician, Doctoral Supervisor

• Visiting Scholar at Massachusetts General Hospital (MGH), Harvard University, USA

• He is a member of the Laser Science Group of the Urology Branch of the Chinese Medical Association

• He is a member of the Laser Science Group of the Urology Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Urology Branch of the Chinese Society of Sexology

• Standing Committee Member of Urology Branch of Guangdong Medical Association and Deputy Head of Oncology Group

• Standing Committee Member of Urology Branch of Guangdong Medical Doctor Association

• Vice Chairman of the Urology Committee of Guangdong Association of Integrative Traditional Chinese and Western Medicine

• Vice Chairman of the Renal Surgery Branch of Guangdong Genitourinary Association

• Vice Chairman of the Men's Health Management Branch of Guangdong Genitourinary Association

• Member of the Professional Committee of Genitourinary Oncology of Guangdong Anti-Cancer Association

• Vice Chairman of Andrology Professional Committee of Guangdong Geriatric Health Care Association

Siege – healing dilemmas, limited benefits, seeking breakthroughs

Urothelial carcinoma (UC) is one of the most common malignancies of the genitourinary system, originating in all urinary tract transitional epitheliums including the renal pelvis, ureters, bladder, and urethra, with vesicouropathic carcinoma being the most common

At present, platinum-based chemotherapy regimens are still the most important first-line treatment options in clinical practice, and the clinical prognosis of patients with disease progression after first-line treatment is still poor and treatment options are limited

A retrospective study from Yuhuangding Hospital in Yantai showed the clinical efficacy and adverse events of PD-1 inhibitors in real clinical practice ^{Chinese mainland [12].}

Nearly 1/2 of the patients enrolled in the study had not received previous drug therapy, 55 patients with an ECOG score of 0 (47%), and 36 patients receiving PD-1 single-agent combination chemotherapy (31%), the results of the study showed that the total population had an ORR of 28% (PD-1 single-agent 24%, PD-1 combined chemotherapy 36%), which was comparable to the previously reported second-line ICI single-agent efficacy, and no complete response (CR) was observed, as detailed in Table 2<>

These studies show that although the clinical efficacy of PD-1 monotherapy combined with chemotherapy is better than that of PD-1 monotherapy, the high incidence of adverse events (AEs) caused by combination therapy requires concern

Table 1 Patient baseline features

Table 2 Efficacy of PD-1 monotherapy or combination therapy

Based on the results of the JAVELIN Bladder study, NCCN guidelines recommend first-line maintenance therapy for patients with advanced UC who have reached at least a stable state of disease after first-line platinum-containing chemotherapy ^[13

Siege – new drugs, increased benefits, more options

In recent years, new drugs have emerged, bringing more options

Edatinib is a small-molerate, highly selective, potent pan-FGFR(1 to 4) tyrosine kinase inhibitor (TKI

Figure 1 BLC2001 findings

In addition, a variety of antibody-drug conjugates (ADCs) have emerged, further improving the clinical benefits
for patients with advanced UC.

RC48-ADC treated patients with HER2+ locally advanced or metastatic UC who had previously failed first-line and above systemic chemotherapy with an ORR of 51.
2% and mOS of 13.
9 months, and the most common treatment-related adverse events (TRAE) included hypoesthesia (60.
5%), hair loss (55.
8%), and leukopenia (55.
8%) ^[16]； Sacituzumab Govitecan (SG) in the treatment of patients with metastatic UC who advanced after platinum chemotherapy and ICI treatment had an ORR of 27% and mOS of 10.
9 months, but attention was paid to the management of adverse effects, particularly severe neutropenia and severe diarrhea ^[17,18]; Enfortumab Vedotin (EV) is used in patients with locally advanced or metastatic UC who have previously undergone platinum-containing chemotherapy and ICI therapy, with an ORR of 40.
6% and mOS of 12.
88 months [¹⁹], but attention needs to be paid to the management of adverse effects, particularly severe and fatal skin adverse reactions (including Stevens Johnson syndrome [SJS]) and toxic epidermal necrolysis [TEN]) ^[20]
。

Breaking the city - the combination of strong and powerful, without quitting, the future can be expected

Given the excellent efficacy of immunocombination therapy in other solid tumors, several studies have attempted to explore the clinical application
of ICI combined with novel therapeutic drugs in advanced UC.

Studies have shown that ICI in combination with chemotherapy, inter-ICI combination, and ICI combined with antivascular therapy have not shown a significant survival benefit ^[21,22,23] (see Table 3< of >), and these immunocombination regimens are not recommended as first-line treatment
in patients with advanced UC.

It also suggests that screening the dominant population of immunotherapy through biomarkers, exploring ICI in combination with other novel drugs, or optimizing the current advanced UC treatment pattern
.

Table 3 OS results of different immunization combination regimens

Recent preliminary studies of multiple ADC drugs combined with ICI therapy have shown improvement in ORR ^[19,24,25] (see <Figure 2>), because the adverse reactions of ADC monotherapy are more prominent, such as SJS and TEN of EV, severe neutropenia and severe diarrhea of SG, so when ADC drugs are combined with ICI, it is necessary to focus on the management
of adverse reactions.

Figure 2 Results of EV-103 study, TROPHY-U-01 study, RC48-C014 study

In addition, the first results of the 2021 ESMO Annual Meeting Phase 2 NORRES study showed that patients with advanced UC who had not previously received systematic treatment and were not suitable for cisplatin therapy had an ORR of 68%, a disease control rate (DCR) rate of 90%, and a duration of relief (DOR) of 6.
9 months in patients with advanced UC who were not candidates for cisplatin therapy ^[26]
。
At the same time, the safety profile of Edatinib in combination with Cetrelimab is consistent with udatinib monotherapy and with the known safety profile of approved anti-PD-1 therapy ^[26].

Figure 3 NORSE findings

Expert reviews

Expert profile

Professor Yao Xin

• Director of the Department of Urology, Tianjin Medical University Cancer Hospital

• He is the chairman of the Professional Committee of Urogenital Male Genital Oncology of the Chinese Anti-Cancer Association

• He is the chairman-designate of the Kidney Cancer Committee of the Chinese Society of Clinical Oncology

• Vice Chairman of Urothelial Cancer Committee of Chinese Society of Clinical Oncology

• Chairman of the Special Committee of Urogenital Male Generative Tumors of Tianjin Anti-Cancer Association

• Member of the Board of Directors of the Chinese Society of Clinical Oncology (CSCO).
  

• He is a member of the Urology Branch of the Chinese Medical Association

• Deputy Director of the Urinary Oncology Collaborative Group (UCOG) of China Cancer Hospital

• Leader of the Urothelial Cancer Guidelines Writing Group of the Chinese Anti-Cancer Association

• Deputy leader of the kidney cancer guideline writing team of the Chinese Medical Association

• He is a member of the editorial
  boards of Chinese Journal of Urology, Chinese Journal of Endocrinology Surgery, Journal of Robotic Surgery, Journal of Minimally Invasive Urology, etc.
  
  

Urothelial carcinoma is a malignant tumor with a high heterogeneity and a poor clinical prognosis in advanced patients with a low 5-year
survival rate.

At present, the first-line standard treatment regimen for advanced UC is still platinum-containing chemotherapy, and ICI has gradually become one of the
second-line treatment options.

Several previous clinical studies and real-world retrospective studies suggest that ICI monotherapy is clinically ineffective for second-line treatment regimens
.

The clinical application of the FGFR inhibitor erdatinib and several new ADC drugs has further improved the clinical benefit of patients with advanced UC while providing more treatment options
.

The response to ICI depends largely on the type of tumor immune microenvironment of advanced UC, and studies have shown that only some advanced UC is an immunoinflammatory phenotype (i.
e.
, hot tumor).


The novel drug transforms immunotherapy "cold tumors" into "hot tumors" by inducing tumor-specific cell death, promoting the release of tumor-specific antigens, activating immune cells in the microenvironment
.

Based on this theoretical basis, a number of studies are exploring the clinical benefits of FGFR inhibitors erdaltinib and multiple ADC drugs combined with ICI in patients with advanced UC, and the preliminary results suggest a significant improvement in the objective response rate, but it is still necessary to continue to pay attention to the long-term survival benefit and adverse effects
.

In short, the exploration of new treatments for advanced UC has never stopped, and precise-sequential therapy and combination therapy are the two main research directions of advanced UC, which are expected to prolong the survival benefits and improve the quality of
life of patients with advanced UC.

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