Experts interpret the research progress of ASCO advanced urothelial cancer treatment in 2021

In the 2021 American Society of Clinical Oncology (ASCO) annual meeting, in the field of urothelial cancer, more attention will be paid to bladder-preserving therapy and neoadjuvant therapy; while in the treatment of advanced urothelial cancer, immunotherapy and antibody-conjugated drugs are still centered (ADC) and other hot areas in recent years
.

Yimaitong invited Professor Sheng Xinan and Zhou Li from Peking University Cancer Hospital to review the progress of advanced urothelial cancer treatment in the 2021 ASCO conference
.

1.
Progress in immunotherapy of advanced urothelial cancer 1.
Immunotherapy represented by immune checkpoint inhibitors PD-1/L1 monoclonal antibody is the second-line treatment for advanced urothelial cancer; it is intolerable to platinum For patients with advanced urothelial cancer, immunotherapy can be an important treatment option
.

The ASCO conference updated the long-term follow-up results of several immunotherapy for the first and second-line treatment of advanced urothelial cancer
.

 The KEYNOTE052 study is a single-arm phase II study using pembrolizumab in the first-line treatment of patients with platinum intolerance
.

The ASCO meeting reported updated data with a median follow-up of 56.
3 months, and the results showed an objective response rate (ORR) and survival outcome comparable to previous reports: ORR was 28.
9%, and median duration of efficacy (DOR) was 33.
4 Months, the median overall survival (OS) was 11.
3 months
.

Among them, patients with PD-L1 expressing CPS≥10 had better efficacy.
Compared with patients with CPS<10, ORR was 47.
3% vs 20.
7%, DOR was NR vs 21.
2 months, and OS was 18.
5 vs 9.
7 months
.

Therefore, platinum can not tolerate patients with PD-L1 positive, single-drug PD-1 monoclonal antibody can obtain better curative effect
.

This is consistent with the exploratory analysis of the IMvigor130 study, in which atilizumab monotherapy in PD-L1 positive patients can significantly improve overall survival compared with gemcitabine combined with carboplatin
.

The current NCCN guidelines for the first-line immunotherapy population is still limited to patients who cannot tolerate cisplatin and are PD-L1 positive, or cannot tolerate any platinum therapy
.

The ASCO meeting reported the five-year follow-up update results of the second-line immunotherapy KEYNOTE045 study of advanced urothelial cancer
.

KEYNOTE-045 is a randomized controlled phase III clinical study of pembrolizumab and chemotherapy for the second-line treatment of advanced urothelial cancer.
This clinical study established the status of second-line immunotherapy for advanced urothelial cancer.
This year's ASCO meeting Reported the updated data of its 5-year follow-up
.

The results showed that the median OS of the pembrolizumab treatment group and the chemotherapy control group were 10.
1 months and 7.
2 months, respectively, and the ORR was 21.
9% and 11%, which were similar to previous results
.

In patients with effective immunotherapy, the duration of efficacy reached 29.
7 months, and the median OS has not yet reached, and the 3-year OS rate was 72.
9%; while in patients with stable immunotherapy (SD), the median OS was 16.
4 months.
But the 3-year OS rate is only 9.
9%
.

The 5-year follow-up once again confirmed the survival advantage of people who benefited from immunotherapy
.

2.
New immunotherapy This ASCO conference involves a variety of new treatment methods, including PD-1 monoclonal antibody combined with immunoreceptor agonists, and PD-1 monoclonal antibody combined with peptide vaccines, etc.
, which is the late stage after failure of multi-line therapy Patients with refractory urothelial cancer strive for more new treatments
.

INDUCE-1 is a clinical study exploring the safety and efficacy of feladilimab±pembrolizumab in solid tumors
.

Feladilimab is an inducible T cell costimulatory factor (ICOS) agonist antibody.
It belongs to the CD28 immunoglobulin receptor superfamily and plays an important role in T cell proliferation, survival and recognition of foreign antigens
.

Anti-tumor efficacy has been reported in melanoma and head and neck squamous cell carcinomas that failed PD-(L)1 treatment.
It may help further activate the immune response of T cells and improve the efficacy of immune checkpoint inhibitors
.

Studies have shown that ICOS is highly expressed in all stages of urothelial cancer, and the proportion of ICOShighCD4+ T cells increases after CTLA-4 treatment, which may predict a better curative effect
.

This conference reported the efficacy data in the urothelial cancer expansion cohort
.

The patients had previously received no more than 5 lines of systemic treatment, of which 14 had previously received immunotherapy and were given feladilimab monotherapy; 32 immuno-naive patients were given combination therapy
.

The results of the study showed that the ORR of feladilimab patients (PD-1 monoclonal antibody progression) was 7%, the disease control rate (DCR) was 22%, and the median OS was 14.
5 months; while the feladilimab combined with pembrolizumab treatment group ( No previous immunotherapy) ORR was 22%, DCR was 63%, and median OS was 10.
7 months
.

Among them, PD-L1 positive and ICOS positive people had better OS than negative patients
.

 TAS0313 is a new cancer peptide vaccine containing 12 cytotoxic T cell epitopes
.

This conference reported the results of a phase Ib/II clinical study of TAS0313 combined with pembrolizumab in the treatment of advanced urothelial carcinoma
.

Cohort 1 had previously failed platinum therapy but had not received immunotherapy.
The ORR of 36 patients was 33.
3%, the DCR was 66.
7%, the median progression-free survival (PFS) was 5.
0 months, and the median OS had not yet reached, 1 The annual OS rate is 74.
3%
.

Cohort 2 was enrolled in 10 patients who had progressed from previous immunotherapy, and 5 patients got SD, and no patients got complete remission (CR) or partial remission (PR)
.

Combination therapy only increased the incidence of local injection reactions and fever
.

This treatment plan may be considered for further research in patients who have not previously received immunotherapy
.

2.
Advances in the treatment of advanced urothelial cancer antibody-conjugated drugs.
Antibody conjugated drugs are a breakthrough in the field of advanced urothelial cancer drug treatment in recent years.
The US FDA has successively approved EV and SG for immunization with previous platinum-based and immune checkpoint inhibitors.
The treatment of metastatic urothelial carcinoma after treatment failure is still a hot topic in this meeting
.

1.
Antibody-conjugated drug monotherapy The current ASCO conference announced the latest updated efficacy data of the EV201 study cohort 2.
This study is the second-line treatment of EV for the platinum-intolerant population after the previous immunotherapy has failed
.

The 2021 ASCO-GU meeting has announced preliminary results, and the ASCO meeting announced the latest follow-up data
.

The results showed that the ORR was 51%, the median DOR was 13.
8 months, the median PFS and OS were 6.
7 months (95%CI: 5.
0-8.
3) and 16.
1 months (95%CI: 11.
3-24.
1), compared with this year The ASCO-GU conference reports are consistent
.

In addition, this conference also announced the results of the RC48-C009 research
.

The anti-HER2 antibody conjugate drug RC48-ADC (Vedicitumumab) independently developed by Rongchang Biotechnology in China has previously reported excellent efficacy in advanced urothelial cancer after failure of standard chemotherapy at the 2019 ASCO conference
.

The RC48-C009 study enrolled patients with locally advanced or metastatic urothelial cancer who had progressed after previous conventional chemotherapy treatments and were HER2 positive (ICH3+ or 2+), by Professor Guo Jun from Peking University Cancer Hospital and Chinese Academy of Medical Sciences Cancer Hospital Prof.
Zhou Aiping jointly led the development of phase II clinical research in a national multi-center
.

Compared with the previous RC48-C005 study, the enrollment of this study is more stringent, requiring all patients who have received all current effective chemotherapy (including gemcitabine, platinum, paclitaxel, etc.
) have failed
.

Among 64 patients, the proportion of patients who received ≥2 line system therapy was 85.
9%.
The ORR of RC48-ADC treatment was 50.
0%, the DCR was 76.
6%, the median PFS was 5.
1 months, and the median DOR was 8.
3 months.
In most cases of third-line treatment, the median OS of patients reached 14.
2 months
.

Each subgroup has obvious benefits, and the incidence of serious adverse events is only 6.
3%
.

2.
Antibody-conjugated drugs combined with immunotherapy EV103 is a phase 1b study of the first-line application of EV combined with pembrolizumab in platinum intolerant populations
.

At last year's ASCO conference, a significant effect was reported.
This ASCO conference updated the results of the study with a follow-up of 24.
9 months
.

The most common treatment-related adverse reactions among the 45 enrolled patients were peripheral sensory neuropathy (56%, 4%≥G3), fatigue (51%, 11%≥G3) and alopecia (49%).
The incidence of serious adverse events The rate was 15.
6%, 11 patients discontinued treatment due to treatment-related adverse reactions (24.
4%), and 1 treatment-related death was due to multiple organ failure
.

The confirmed ORR was 73.
3%, of which the CR rate was 17.
8%, and the DCR was 93.
3%; the ORR of patients with liver metastases was 57.
1%, the median DOR was 25.
6 months, the median PFS was 12.
3 months, and the median OS had not yet been reached, 2 The annual OS rate is 56.
3%
.

This treatment combination has been certified by the US FDA as a breakthrough therapy because of its excellent efficacy data.
The first-line full-population EV302 study of EV combined with pembrolizumab compared to standard chemotherapy is underway
.

The RC48-C014 study is a phase Ib/II clinical study exploring the efficacy and safety of RC48-ADC combined with PD-1 monoclonal antibody in patients with locally advanced or metastatic urothelial cancer.
The ASCO meeting first reported the preliminary efficacy
.

The study included first-line treatment populations who had failed previous treatment or were unwilling to receive platinum-based chemotherapy, including patients with low HER2 expression, regardless of PD-L1 expression status
.

Among the 17 patients who underwent at least one effectiveness evaluation, 16 patients achieved objective remission (94.
1%, 95% CI: 71.
31%, 99.
85%), 3 patients achieved CR, and 13 patients achieved PR; among them, no previous treatment All 10 patients who underwent any treatment achieved CR or PR, and the ORR reached 100%.
Among the other 7 patients who had previously received platinum-based therapy, 6 achieved CR or PR, and the ORR reached 85.
7%, which also showed excellent efficacy.

.

The overall adverse reactions are relatively controllable.
The incidence of grade 3-4 adverse reactions is 31.
6%, including fatigue and elevated transaminases.
The clinical research is still ongoing
.

3.
Progress in targeted therapy for advanced urothelial carcinoma 1.
ATR inhibitor Berzosertib is a telangiectatic ataxia and Rad3-related protein (ATR) inhibitor
.

The mechanism of action of gemcitabine and cisplatin is to induce DNA damage, while ATR interferes with DNA repair
.

The synergistic anti-tumor effect of the combination of the two has been observed in preclinical studies, and the efficacy has been reported in high-grade serous ovarian cancer and small cell lung cancer
.

This ASCO conference reported a phase II clinical study of berzosertib combined with GC regimen and GC regimen alone for the first-line treatment of advanced urothelial cancer
.

The results showed that the PFS of the two groups were close at 8.
0 months, but the response rate (RR, 54% vs 63%) and OS (14.
4 vs 19.
8 months) of the combined group were worse than the standard treatment group
.

Research suggests that GC chemotherapy combined with ATR inhibitor berzosertib is not superior to standard GC chemotherapy
.

2.
The FGFR inhibitor FORT-2 study is a first-line treatment of rogaratinib combined with atilizumab in the first-line treatment of cisplatin intolerance, FGFR1/3 mRNA overexpression, locally advanced or metastatic urothelial cancer patients with stage Ib/II Research
.

The ASCO conference last year reported that the maximum tolerated dose (MTD) was 600mg of rogaratinib Bid combined with 1200mg of atelizumab.
The conference updated the efficacy data and safety information of this dose group
.

The ORR of 24 patients with evaluable curative effect was 58%, and the DCR was 83%, of which 13% achieved CR; among 16 patients with negative or low expression of PD-L1 and no mutation in FGFR3, the ORR was still 56%
.

The most common adverse reactions were diarrhea (65%), hyperphosphatemia (58%), fatigue (42%), urinary tract infection (38%), elevated transaminase and anorexia (31%).
23% of patients were caused by Treatment-related adverse reactions were discontinued.
The adverse reactions related to rogaratinib were hyperphosphatemia (58%) and retinal pigment layer detachment (4%)
.

This study provides a new treatment strategy for patients with FGFR gene changes, and proposes a new way to screen the treatment population with mRNA
.

3.
Anti-vascular targeted therapy.
In addition, immune combined anti-vascular targeted therapy has also been explored in urothelial cancer in recent years, including ativizumab combined with cabozinib (ORR 27), which was reported in the previous ASCO conference.
%), and nivolumab ± ipilimumab combined with cabozantinib (ORR 42.
4%), both showed promising anti-tumor activity
.

This conference reported the results of the Phase II study of Hengrui's Carrelizumab combined with Famitinib in advanced renal cell carcinoma and unresectable urothelial carcinoma
.

The study enrolled 33 patients with advanced urothelial carcinoma who had not been treated with more than two-line treatments.
The ORR was 33.
3%, the DCR was 60.
6%, and the median PFS was 6.
4 months
.

Subgroup analysis showed that bladder cancer has more obvious benefits than upper urothelial cancer, with higher ORR (43.
8% vs 25%) and longer PFS (8.
1 vs 2.
2 months)
.

Adverse reactions are relatively controllable.
The incidence of grade 3-4 adverse reactions is 63.
5%, which mainly include hypertension, thrombocytopenia, proteinuria, anemia and hand-foot syndrome
.

This study provides a basis for domestic urothelial cancer patients to choose immune combined anti-vascular targeted therapy
.

4.
Summary The above is a summary of the latest advances in the treatment of advanced urothelial cancer at the ASCO Conference in 2021, involving immunotherapy, antibody-conjugated drugs, and a variety of combined treatment methods
.

The treatment of advanced urothelial cancer has continuously made breakthroughs.
A number of domestic studies have been selected, especially in the anti-HER2 treatment of urothelial cancer, which is at the forefront of the world
.

Domestic antibody conjugate drugs targeting HER2 will be launched soon, bringing new treatment options for these patients
.

The clinical research of antibody-conjugated drugs combined with immunotherapy is underway, and it has initially shown excellent anti-tumor activity, which may change the treatment pattern of advanced urothelial carcinoma in the future
.