Professor Han Sujun: Research progress and direction of muscle-invasive bladder cancer

On January 8, the "2022 Beijing Urological Cancer Youth Forum" was successfully held by the Youth Committee of the Urology and Male Genital Oncology Committee of the Beijing Anti-Cancer Association and the Beijing Medical Award Foundation
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During the meeting, Professor Han Sujun from Cancer Hospital, Chinese Academy of Medical Sciences shared the progress and future research directions of muscle-invasive bladder cancer (MIBC)
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The medical pulse is organized as follows for the readers
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Expert Profile Professor Han Sujun National Cancer Center of Urology, Cancer Hospital, Chinese Academy of Medical Sciences/Deputy Chief Physician of Urology Department, Cancer Hospital, Chinese Academy of Medical Sciences Member and Secretary General of the Urological Oncology Special Committee of Beijing Cancer Prevention and Control Society Member and Secretary General of the Youth Committee of Beijing Urological Society Committee Member, Beijing Medical Association Urology Branch, Digital Urology Group Member, Photodynamic Society, China Anti-Cancer Association Research progress in neoadjuvant therapy for MIBC Based on class I evidence, cisplatin-based neoadjuvant therapy is the standard treatment for MIBC.
The complete remission (pCR) rate is 25% to 38%, which can improve the overall survival (OS) rate of patients by 5% to 8%
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However, the improvement of pCR with platinum-containing neoadjuvant chemotherapy is relatively limited, and there is no neoadjuvant treatment option for cisplatin-intolerant patients
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Guideline recommendation: cisplatin-based neoadjuvant chemotherapy Combined growth factor supportive therapy (3 or 4 cycles); GC regimen (gemcitabine plus cisplatin) (4 cycles); other recommended regimens: CMV (cisplatin, methotrexate, and vinblastine) (3 cycles)2 Neoadjuvant chemotherapy recommended by EAU 2021 Bladder Cancer Guidelines: For patients with T2-4a and CN0M0, cisplatin-based neoadjuvant chemotherapy is recommended (strong recommendation); patients who are not suitable for cisplatin-based combination chemotherapy are not given neoadjuvant chemotherapy.
Adjuvant chemotherapy (strong recommendation); neoadjuvant immunotherapy (strong recommendation) should only be considered under clinical trial conditions
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Research progress of cisplatin-intolerant population For cisplatin-intolerant population, the current research on neoadjuvant immunotherapy (PURE-01 [pembrolizumab], ABACUS [atezolizumab], NABUCCO[] Nivolumab + ipilimumab], NCT02812420 [durvalumab + tremelimumab]) showed the pCR rate of immune checkpoint inhibitor/dual immune neoadjuvant therapy in platinum-intolerant MIBC 31%~46%
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Research progress in cisplatin-resistant populations For cisplatin-resistant populations, four phase II studies have shown that durvalizumab + GC, atezolizumab + GC, pembrolizumab + GC, The pCR rates (pT0) of nivolumab + GC in platinum-resistant MIBC were 34%, 44%, 36%, and 34%, respectively
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Recently, Chinese researchers also conducted a single-arm, multi-center exploratory phase II clinical study to evaluate the efficacy of camrelizumab + GC for neoadjuvant treatment of locally advanced bladder cancer
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The enrolled patients were cT2-T4a N0-1M0 locally advanced urothelial carcinoma, ECOG score of 0-1, cisplatin resistance, and the primary endpoint was pCR rate
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The results showed that as of July 10, 2021, 17 patients had completed the primary efficacy evaluation, and the ratios of cT2/cT3-4/cN+ were 52.
9%, 47.
1%, and 5.
9%, respectively, and 9 patients (52.
9%) achieved pCR (52.
9%).
pT0N0), 10 patients (58.
8%) achieved pathological downstaging (≤pT1N0); PD-L1 (CPS≥10) patients had a pCR rate of 33% (1/3), and PD-L1 (CPS<10) patients had a pCR rate of 63% (5/8); the median time from the last medication to surgery was 4.
71 weeks, no patients had delayed surgery due to adverse events, and no unexpected surgical complications occurred
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The incidence of grade 3 and above adverse events was 44.
4%, and the safety was consistent with previous reports
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The comparison of camrelizumab combined with GC neoadjuvant therapy for MIBC and previous data is based on the good data obtained in the previous period.
Professor Xing Nianzeng led the follow-up randomized controlled study
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The study plans to enroll 106 patients who will receive either camrelizumab + GC or GC regimens
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Looking forward to the publication of the research results
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Can bladder-sparing therapy be performed in patients who achieve CR with neoadjuvant therapy? Researchers have carried out several studies
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HCRN GU 16-257 Study The HCRN GU 16-257 study is a Phase II study evaluating transurethral resection of bladder tumor (TURB-t) + GC + nivolumab + selective bladder preservation in patients with MIBC 's curative effect
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The study, presented at the 2021 ASCO Congress, included platinum-resistant cT2-4aN0M0 bladder cancer patients who received 4 cycles of GC + nivolumab after TURBT, and patients who achieved clinical complete remission (cCR) received nivolumab.
Resistant to maintenance therapy, the other patients underwent radical cystectomy (RC)
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The primary endpoints were cCR rate and the ability of cCR to predict 2-year metastasis-free survival, and secondary endpoints were the effect of gene mutation on cCR
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RESULTS: A total of 76 patients were included in the study, and the cCR rate was 48%, a result similar to the neoadjuvant study
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In situ recurrence of cCR patients was 26% (8/31), 6 patients underwent surgery, and the initial bladder retention rate was 36%
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High TMB (≥10 mut/Mb [P=0.
02]) or ERCC2 mutation (p=0.
02) was associated with cCR or pT0
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The study used immunocombination therapy and individualized treatment for patients with different outcomes, which reflects the current precision medical stratification and whole-process management of MIBC treatment
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NCT02621151 Study bladder-sparing triple therapy (TMT) is the clinical standard treatment for local MIBC.
Pembrolizumab has shown activity in the neoadjuvant treatment of MIBC, and its combination with TMT is expected to improve the efficacy
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A multicenter phase II study (NCT02621151) evaluated the efficacy of pembrolizumab + TURB + (pembrolizumab + gemcitabine) + radiotherapy (RT) (quadruple therapy) in MIBC
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The study included patients who did not accept or could not tolerate RC surgery.
The enrolled patients first received pembrolizumab for 2-3 weeks, followed by maximizing TURB, and then received whole bladder RT + gemcitabine + pembrolizumab
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The primary endpoint was 2-year bladder-preserving disease-free survival (BIDFS)
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The results showed that the 12-week CR rate was 83%, and the 1-year BIDFS rate was 77%
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It can be seen that combined therapy, especially the addition of TMT to radiotherapy, can improve the local control rate
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The IMMUNOPRESERVE-SOGUG study combines bladder-sparing therapy as an alternative to radical cystectomy
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The IMMUNOPRESERVE-SOGUG study is a phase II study to explore the feasibility and efficacy of TURB + dual-immune combination (durvalumab + trimetimumab) + RT in the bladder-preserving treatment of MIBC
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The study included patients with cT2-4aN0M0 stage who did not receive or were intolerant of RC surgery, and were given TURBT first, then durvalumab + tremelimumab (Q4W, 3 cycles), and conventional fractionated radiotherapy was started 2 weeks later.
(Pelvic: 46Gy; Bladder: 64-66Gy), bladder preservation was given to patients without residual tumor (TURB assessment); patients with residual tumor or recurrence received salvage cystectomy, and the primary endpoint was CR rate
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The results showed that 26 patients achieved complete remission (CR), the CR rate was 81%, and the 6-month complete bladder disease-free survival (DFS) and OS rates were 76% and 93%, respectively
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This study also reflects immunocombination therapy and individualized stratified therapy for MIBC patients
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The above three studies showed that the cCR rates of the HCRN GU 16-257 study, NCT02621151, and IMMUNOPRESERVE-SOGUG study were 48%, 83%, and 81%, respectively; bladder retention rates were 36%, 77% (1 year), and 76%.
(6 months)
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After adding radiotherapy, the cCR rate has been significantly improved.
The results of the study need to be further verified, and more research results are expected
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Future Exploration Currently, a number of studies are exploring the efficacy of chemoradiotherapy + immunotherapy in bladder-sparing therapy
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Phase III SWOG/NRG 1806 is currently enrolling to explore the efficacy of atezolizumab + concurrent chemoradiotherapy (CRT) vs CRT for bladder preservation
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Phase III KEYONTE-992 is also currently being enrolled to evaluate the efficacy of pembrolizumab plus CRT vs CRT
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Looking forward to more updates on bladder preservation strategies
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MIBC adjuvant therapy research progress CheckMate274 study IMvigor010 study is the first phase III clinical study evaluating MIBC adjuvant immunotherapy, and the result is negative
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The CheckMate274 study showed positive results and improved DFS in patients
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CheckMate274 is a multicenter, randomized, double-blind, phase III study evaluating nivolumab versus placebo in high-risk muscle-invasive urothelial carcinoma after radical resection
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The study included 709 patients with high-risk muscle-invasive urothelial carcinoma, including pT2-T4a or node-positive patients after neoadjuvant chemotherapy and pT3-4 and node-positive patients who were not suitable/refused to receive neoadjuvant cisplatin chemotherapy
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The results showed that the median DFS of the nivolumab group and the placebo group was 21 months and 10.
9 months, respectively (HR=0.
7, P<0.
001); among patients with PD-L1≥1, the median DFS of the two groups was Not reached and 10.
8 months respectively (HR = 0.
53, P < 0.
001), the DFS improved more significantly
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Professor Han emphasized that individualized treatment is required in clinical practice, and not every patient needs to receive a new treatment regimen, and each additional treatment regimen will increase adverse reactions
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The subgroup analysis of the CheckMate274 study showed that for patients with good physical status, adjuvant immunotherapy can be preferred; bladder cancer (lower urinary tract tumor) can be preferred, lymph node positive, previous platinum-containing neoadjuvant chemotherapy, PD-L1 positive (PD-L1 positive) -L1 ≥ 1%) are more likely to benefit from adjuvant therapy
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IMvigor010 Study Phase III IMvigor010 study explored the efficacy of atezolizumab adjuvant therapy in high-risk muscle-invasive urothelial carcinoma
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Atezolizumab did not improve DFS and OS in patients in the ITT population
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However, further analysis found that ctDNA has good prognostic and predictive value: the prognosis (DFS, OS) of ctDNA-negative patients is better than that of ctDNA-positive patients; ctDNA-positive patients can benefit from adjuvant immunotherapy, while ctDNA-negative patients cannot.

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DFS and OS in patients stratified by ctDNA ctDNA clearance was 18.
18% and 3.
8% in the atezolizumab and placebo groups, respectively (P=0.
00408)
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The study also found that the DFS of ctDNA-positive and negative patients was better than that of non-negative patients, and the survival benefit of ctDNA-negative patients receiving atezolizumab was the most obvious
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The IMvigor011 study is based on the above findings of the IMvigor010 study.
The researchers carried out the IMvigor011 study.
The researchers announced the design plan at the 2021 ESMO Congress.
The study aims to evaluate atezolizumab versus placebo for ctDNA-positive high-risk MIBC after surgery efficacy of adjuvant therapy
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The study included patients with positive ctDNA within 21 months after cystectomy
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Research on precise stratification guidance like the IMvigor011 study is the future direction of development
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Future Exploration In addition, for the perioperative treatment of MIBC, there is a new “sandwich” model of neoadjuvant therapy + adjuvant therapy, which also reflects the current “individualized + combined + whole-course management” treatment model, including KEYNOTE-866 ( Cisplatin-resistant MIBC patients) and the KEYNOTE-905 study (cisplatin-intolerant MIBC patients), looking forward to the announcement of the study results
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Conclusion MIBC treatment goals: prolong survival, improve quality of life, improve cure rate, and improve bladder retention rate
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MIBC treatment direction: first, combined treatment, including drug combination, different treatment methods and MDT discussion; second, individualized treatment is precise treatment; third, whole process management is an important direction of bladder preservation treatment
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