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On December 2~4, the 2022 European Society of Medical Oncology Asia Annual Meeting (ESMO Asia 2022) was held
in Singapore in the form of offline and online.
There are two studies of tislelizumab presented in the form of oral presentations or posters in the urological oncology session of this conference, one of which is the HOPE-03 study
by Professor Zhang Peng and Professor Shen Yali from West China Hospital of Sichuan University.
We invited the principal investigators of the study, Professor Zhang Peng and Professor Shen Yali of West China Hospital of Sichuan University, to give us a glimpse of the HOPE-03 study
.
1
Research background
In China, bladder cancer is one of the most common diseases in urology, and its incidence and mortality rank firstamong urinary tumors.
Of patients with bladder cancer, approximately 30% have muscle-invasive bladder cancer (MIBC).
Preoperative platinum-based neoadjuvant chemotherapy has been shown to lower tumor staging and improve 5-year survival1
.
Limitations of neoadjuvant chemotherapy for MIBC
Neoadjuvant platinum-containing chemotherapy improves 5-year survival in patients with MIBC by approximately 8%2.
Current NCCN guideline 3 recommends cisplatin-based neoadjuvant chemotherapy
.
However, due to the advanced age of patients, poor physical status, poor renal function, and concerns about the toxicity of chemotherapy drugs, the overall use rate of neoadjuvant chemotherapy in MIBC patients is low, only 18.
1%2
.
Immune checkpoint inhibitors in neoadjuvant therapy with MIBC
Significant benefits have been achieved
With the rise of tumor immunotherapy, immunotherapy has developed by leaps and bounds in the field of urothelial carcinoma, and the exploration of indications for bladder cancer by immune checkpoint inhibitors has been moved from second-line therapy to first-line treatment, and clinical trials have gradually been carried out in the fields of adjuvant therapy, neoadjuvant therapy, combined with other regimens, and non-muscle-invasive bladder cancer2。 The PURE-01 study is a prospective, single-arm phase II trial that investigated the efficacy of neoadjuvant immunotherapy in patients with MIBC with a pathologically complete response rate (pCR) of 37% and a pathologic reduction rate (<pT2N0) of 55%.
<b21>
The ABACUS study is a multicenter, single-arm phase II trial to explore the efficacy and safety
of neoadjuvant atezolizumab in patients with MIBC.
PCR was achieved in 31% of 88 evaluable patients, 1-year recurrence-free survival was 79%, and radiographic response and progression before radical resection were 22% and 16%, respectively2.
As these two studies progressed, neoadjuvant immunotherapy began to enter the clinic
.
ADC therapy began to enter the clinic
Vidicitumab (RC48) is an ADC drugthat targets HER2.
RC48 is MMAE, a synthetic derivative of sea rabbit toxin 10, which belongs to tubulin inhibitors, which effectively inhibit mitosis by inhibiting tubulin polymerization, thereby achieving the purpose of anti-tumor4
.
It was granted breakthrough designation
for the treatment of metastatic urothelial carcinoma (mUC) by the FDA in 2020.
In studies, RC48ADC demonstrated good efficacy and manageable safety in patients with locally advanced or mUC who were HER2-positive5
.
2
Study design
The HOPE-3 study is a multicenter, single-arm, open-label phase Ib/II clinical study led by Professor Zhang Peng and Professor Shen Yali, a subspecialty MDT team of urological oncology and bladder in West China Hospital, aiming to explore the efficacy and safety of vedicitumab combined with tislelizumab as neoadjuvant therapy in patients with HER2-positive locally progressive MIBC, hoping to improve the tumor response rate of patients and obtain long-term survival benefits through the combination therapy of the two.In order to explore a treatment pathway with better anti-tumor efficacy and fewer side effects than commonly used chemotherapy regimens for neoadjuvant therapy in patients with HER2-positive bladder cancer, the study design is shown in Figure 1
.
The main inclusion criteria of the studies were pathological and impact diagnosis of muscle-invasive bladder cancer with cT2-4b N0-3 M0-1a; Immunohistochemistry showed HER2 3+ or 2+ or 1+; Have not received systemic therapy
before.
The phase I study used a 3+3 dose climbing test, with tislelizumab 200mg on days 1 and 22, and RC48 on days 1, 15, and 29 with an interval of 6 weeks for a total of 2 cycles
.
The RC48 dose was 1.
5 mg/kg
in three patients.
In the phase II study, the regimen was the same as before, and RC48 was dosed after Phase Ib exploration
.
After neoadjuvant therapy, the efficacy is evaluated, and radical cystectomy or bladder-sparing therapy
is used according to the patient's wishes.
Follow-up after treatment until disease progression or study ends
.
The primary endpoints were clinical complete response rate (cCR, T0/Ta/Tis), pCR, and safety
.
Secondary endpoints were overall survival (OS), survival without local recurrence (LRFS), survival without distant metastases (DMFS), and quality of life score (FACT-G).
Figure 1 HOPE-03 study design
3
Study results
Of the 51 patients planned to be included in the HOPE-03 study, 6 patients have been included so far, and enrollment is ongoing.
At present, 4 patients have been evaluated for efficacy, including imaging and transurethral bladder multi-site biopsy
.
Among them, 3 cases were T0 and 1 case was Tis, and the current clinical complete response rate (cCR) reached 100% (4 patients were evaluated by the primary endpoint), which brings clinical confidence and hope
.
The clinical response of the six patients is shown
in Table 1.
Table 1 Efficacy of 6 patients
Security results
The safety events were mainly immune and ADC drug-related adverse reactions such as elevated liver enzymes, rash, and paresthesia, and there were no new adverse reactions, and most of them were grade 1 and 2, and the safety was controllable.
One patient developed an immune-related adverse event, grade 2 myositis, which led to treatment discontinuation
.
Three patients developed RC48-ADc-related toxicities, including grade 1 aminotransferase elevation, grade 1 erythema, and grade 1 paresthesias
.
There were no treatment-related cases
leading to drug reduction.
Expert reviews
Expert profiles
Professor Zhang Peng
West China Hospital, Sichuan University
Chief physician, medical doctor, master supervisor
In 2006, he received a doctorate degree in urology, and was a member of the Standing Committee of the Urology Special Committee of the Chinese Medical Association
Member of the Oncology Group of the Urologist Branch of the Chinese Medical Doctor Association
Youth member of the Urology Committee of the Chinese Anti-Cancer Association
Member of the Bladder Cancer Group of the Urology Committee of the Chinese Anti-Cancer Association
Member of the Urology Professional Committee of the Integrative Medicine Physician Branch of the Chinese Medical Doctor Association
Member of the Urology Group of the Minimally Non-invasive Medicine Committee of the Chinese Medical Doctor Association
Member and Secretary of Urology Branch of Sichuan Medical Association
Leader of the individualized treatment group of bladder cancer of the Urology Branch of Sichuan Medical Doctor Association
Member of the Urogenital Oncology Professional Committee of Sichuan Anti-Cancer Association
Member of the Standing Committee of the Urology Branch of Sichuan Rehabilitation Physicians Association
Member of Urology Branch of Sichuan Medical Doctor Association and leader of the secretary group
Member of the Urology Professional Committee of Sichuan Geriatric Association
Member of Sichuan Prostate Cancer CRPC Group
Member of Sichuan Plateau Medical Association
Member of the Standing Committee of the Urology Special Committee of Chengdu High-tech Medical Association
Member of the European Association of Urology
Senior Visiting Scholar, Beth Israel Cancer Center, Harvard Medical School
Senior Visiting Scholar, Urological Oncology Center, University of Strasbourg, France
Trainer of Minimally Invasive Training Center, Urology Branch of Chinese Medical Association
Invited Corresponding Editor of the Young Experts Editorial Board of the Chinese Chronicle of Urology and Oncology
Expert profiles
Professor Shen Yali
Professor of Abdominal Oncology, West China Hospital, Sichuan University
Chief physician, master tutor
Member of Gastroenterology Group, Radiotherapy Branch of Chinese Medical Association
Member of the Urogenital Tumor Committee of the Chinese Anti-Cancer Association
Member of the Cancer Artificial Intelligence Special Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Artificial Intelligence and Big Data Committee of Sichuan Cancer Society
Vice Chairman of the Urological Oncology Committee of Sichuan Cancer Society
Member of the Individualized Treatment Group of Bladder Cancer of the Urological Oncology Committee of Sichuan Medical Doctor Association
Member of the Geriatric Cancer Treatment Professional Committee of Sichuan Anti-Cancer Society
Member of the Multidisciplinary Committee of Oncology Treatment of Sichuan Medical Promotion Association
Expert reviews
The HOPE-03 study is a novel exploration of ADC drug combined with tislelizumab in patients with HER2-positive locally advanced MIBC, and the current results show good efficacy and controllable safety, and we look forward to continuing this result
in the final study.
References
1.
Research progress in molecular typing to guide the treatment of muscle-invasive bladder cancer.
Journal of Clinical Urology, 2021, 36(8): 668-671
2.
Research progress of immune checkpoint inhibitors in neoadjuvant immunotherapy for muscle-invasive bladder cancer.
Journal of Modern Urology.
2022,27(8):700-706
3.
NCCN 2022 V2
4.
2002 IIT Tianxin, L et, al.
ASCO 2022 CUA 2022 BGB-A317-2002-IIT study
5.
Peyton CC, et al.
JAMA Oncol .
2018
6.
Urol Oncol.
2022 Oct 2021 EU.
Christian Pfister.
Vesper
7.
BLASST Gupta S, et al.
GU ASCO 2020
8.
LCCC1520 Tracy L.
RoseJ , et al.
JCO 2021
9.
MSKCC Funt SA, et al.
J Clin Oncol 39,2021(suppl 15; abstr 4517).
10.
Cris Cancer Res Treat 2022 Oct 6
11.
Hcrn 2020 ASCO
12.
Safety consensus on clinical application of urothelial carcinoma antibody conjugate.
Modern Journal of Urology.
2022,27(8):628-634
13.
HOPE-03 study
Reviser: Yuna
Typesetting: Yuna
Execution: Rudolf
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