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    Home > Active Ingredient News > Urinary System > Prof. He Zhisong: Important Clinical Research on Urological Tumors in 2021

    Prof. He Zhisong: Important Clinical Research on Urological Tumors in 2021

    • Last Update: 2022-02-24
    • Source: Internet
    • Author: User
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    In 2021, many important progresses will be made in the field of urological tumor treatment
    .

    "NEJM Medical Frontiers" invited the team of Professor He Zhisong from the Department of Urology, Peking University First Hospital to sort out the important progress of clinical research on urological tumors in 2021
    .

    "NEJM Frontiers in Medicine" is jointly developed by Jiahui Medical Research and Education Group (J-Med) and the New England Journal of Medicine (NEJM)
    .

    As in the past three years, we will launch a review of clinical research in various important disease areas one after another, so stay tuned
    .

     He Zhisong*, Mi Yue, Tang Qi, Fan Yu, Department of Urology, Peking University First Hospital* Corresponding author Renal cancer Adjuvant therapy for clear cell renal cell carcinoma Postoperative nephrectomy is the standard of care for locally advanced renal cell carcinoma
    .

    Due to the late stage of the tumor at the time of diagnosis, nearly half of the patients experienced recurrence or metastasis after surgery and entered the stage of metastatic renal cell carcinoma
    .

    In the past, several clinical trials of adjuvant targeted therapy have been conducted for locally advanced renal cancer with high recurrence risk, including targeted drugs sunitinib (ASSURE), pazopanib (PROTECT) and axitinib (ATLAS).
    ) and other drug adjuvant therapy trials, the results were negative
    .

    Only one S-TRAC study of adjuvant sunitinib after renal cancer surgery observed a disease-free survival (DFS) benefit but no overall survival (OS) benefit in the experimental group
    .

    Therefore, for locally advanced renal cancer with high recurrence risk, neither the European Association of Urology (EAU) nor the American NCCN guidelines recommend adjuvant targeted therapy
    .

     The KEYNOTE-564 study is a randomized, double-blind, placebo-controlled phase 3 clinical trial[1] in clear cell renal cell carcinoma (postoperative pathology-proven pT2 with nuclear grade 4 or sarcomatoid differentiation, pT3 or pT4 and Patients with no evidence of residual tumor [NED] after M1 were randomized 1:1 to receive pembrolizumab (200 mg every three weeks) or placebo, with the primary endpoint of DFS
    .

    The median follow-up time of the study was 24.
    1 months, and the 24-month DFS rates were 77.
    3% in the experimental group and 68.
    1% in the control group (HR, 0.
    68; P=0.
    002), which met the primary endpoint set by the trial, i.
    e.
    support Pembrolizumab for adjuvant therapy after surgery for high-risk renal cell carcinoma
    .

    Subgroup analysis of DFS endpoints found that benefit was observed in all subgroups, with the most significant benefit in the M1 NED subgroup
    .

    The proportion of adverse reactions of grade 3 and above in the experimental group and the control group were 32.
    4% and 17.
    7%, respectively, and the incidence of serious adverse events was 20.
    5% and 11.
    3%, respectively, which was consistent with the previous pembrolizumab trial data, and there was no new safety.
    Sex signal (click for related reading: Phase 3 trial confirms that pembrolizumab significantly improves disease-free survival after adjuvant therapy for renal cancer)
    .

     The trial results were originally published in the New England Journal of Medicine (NEJM) in August 2021, and the latest data will be presented at the European Society for Medical Oncology (ESMO) annual meeting in September
    .

    At present, the U.
    S.
    Food and Drug Administration has granted priority review to pembrolizumab, which is expected to become the first immunotherapy approved in the adjuvant treatment of clear cell renal cell carcinoma
    .

    We look forward to more follow-up data showing the benefit of OS in patients
    .

                         Figure 1.
    KEYNOTE-564 disease-free survival
    .

    Figure A shows the disease-free survival of the two groups of patients; Figure B shows the results of subgroup analysis
    .

    At the same time, more similar clinical trials are being carried out, such as the IMmotion010 study on anti-PD-L1 single drug and the CheckMate 914 study on dual-immune combination, hoping to achieve positive results and provide postoperative adjuvant immunity for patients with locally advanced renal cancer.
    Treatment adds new evidence
    .

    First-line treatment of advanced clear cell carcinoma of the kidney: The KEYNOTE-426 study of targeted immunotherapy in combination with pembrolizumab is a phase 3 randomized comparison of pembrolizumab plus axitinib and sunitinib in first-line treatment of advanced clear cell carcinoma of the kidney Controlled clinical trials (RCTs) [2]
    .

    The 2019 American Genitourinary Oncology Symposium (ASCO-GU) published its findings for the first time, promoting the first-line treatment of advanced renal cancer to enter the era of immune combined targeted therapy
    .

    The 2021 American Society of Clinical Oncology (ASCO) annual meeting announced the results of the study with a median follow-up of 42.
    8 months [3]
    .

    Subgroup analysis based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score shows progression-free survival (PFS) of pembrolizumab combined with axitinib in the low-risk group compared with sunitinib No significant benefit was achieved, but the intermediate and high risk group benefited; the low-risk group also did not achieve significant OS benefit, with 42-month OS rates of 72.
    3% and 73% (HR, 1.
    17) in the two groups, respectively (HR, 1.
    17); and the intermediate and high risk group still showed Long-term survival benefit, the 42-month OS rates in the two groups were 50.
    6% and 37.
    6% (HR, 0.
    64)
    .

    The long-term follow-up data suggest that pembrolizumab combined with axitinib can significantly improve PFS and OS in high-risk patients with IMDC
    .

    Figure 2.
    KEYNOTE-426 trial outcomes
    .

    In addition, the CLEAR study is also a phase 3 RCT of first-line target-immune combination therapy for advanced renal clear cell carcinoma [4], which compared lenvatinib combined with pembrolizumab, lenvatinib combined with everolimus and su Nitinib
    .

    In April 2021, NEJM published preliminary data from the trial
    .

     Both PFS and OS were significantly prolonged in the lenvatinib plus pembrolizumab group compared with the sunitinib group
    .

    In addition, according to the IMDC risk stratification analysis, the median PFS in the intermediate and high-risk groups was 22.
    1 and 5.
    9 months in the lenvatinib plus pembrolizumab group compared with the sunitinib group (HR, 0.
    36; 95 % CI, 0.
    28-0.
    47), 28.
    1 and 12.
    9 months in the low-risk group (HR, 0.
    41; 95% CI, 0.
    28-0.
    62)
    .

    The median OS of different risk groups has not been reached, but the HR was 0.
    58 (95% CI, 0.
    42-0.
    80) in the intermediate-high risk group and 1.
    15 (95% CI, 0.
    55-2.
    40) in the low-risk group
    .

    The ORR of the middle-high-risk group was 72.
    4% vs.
    28.
    8%, and the ORR of the low-risk group was 68.
    2% vs.
    50.
    8%, respectively
    .

    Similar to the KEYNOTE-426 study, the combination of lenvatinib and pembrolizumab did not improve OS in low-risk groups, but showed significant benefit in intermediate and high-risk groups
    .

    The CheckMate 9ER study is a phase 3 RCT comparing nivolumab in combination with cabozantinib and sunitinib in the first-line treatment of advanced renal cancer [5]
    .

    Results published in NEJM in March 2021 showed that nivolumab combined with cabozantinib significantly improved PFS (16.
    6 months vs.
    8.
    3 months) and ORR (55.
    7% vs.
    27.
    1 months) compared with sunitinib treatment.
    %)
    .

     The 2021 ASCO annual meeting updated the data of the trial with a median follow-up of 23.
    5 months [6]
    .

    Median PFS was 17.
    0 and 8.
    3 months in the nivolumab plus cabozantinib group and 8.
    3 months in the sunitinib group, respectively (HR, 0.
    52; 95% CI, 0.
    43-0.
    64; P<0.
    0001), and ORRs were 54.
    8% and 28.
    4%
    .

    The median OS of patients in the two groups was not reached and 29.
    5 months, respectively (HR, 0.
    66; 95% CI, 0.
    50-0.
    87; P=0.
    0034)
    .

    Divided into subgroups according to IMDC risk stratification (low, medium and high group), number of organs involved (≥1 vs.
    1), and sum of target lesion diameters (<72.
    1 mm vs.
    ≥72.
    1 mm), the researchers found that in all subgroups, Both nivolumab and cabozantinib significantly improved PFS, but no OS was observed in the IMDC intermediate/low risk population, 1 organ involvement population, and population with small tumor volume (diameter and <72.
    1 mm) benefit
    .

     Late-line treatment of advanced clear cell renal cell carcinoma At present, the first-line treatment options for patients with metastatic clear cell carcinoma of the kidney are relatively abundant, but the prognosis of patients after the disease progresses again is not optimistic
    .

    The existing metastatic clear cell carcinoma after-line treatment is mainly divided into four types: mTOR inhibitor, TKI, PD-1 antibody and targeted/immune combination therapy [7]
    .

    Representative drugs are everolimus, axitinib/cabozantinib/lenvatinib, nivolumab, and lenvatinib combined with everolimus
    .

    In the phase 2/3 clinical trial of the above treatment regimen, the PFS of patients in the experimental group was 4.
    6, 8.
    3/7.
    4/7.
    4, 4.
    6 and 14.
    6 months, respectively
    .

    Although the data between the different trials cannot be directly compared, it can be seen from the data from the three cohorts (lenvatinib/everolimus/lenvatinib+everolimus) of the Study 205 study and the results of other studies , The efficacy of TKI combined with mTOR inhibitor is outstanding, and mTOR inhibitor combined with targeted therapy may become the treatment trend of metastatic clear cell renal cell carcinoma
    .

     Vorolanib (CM082) is a multi-target receptor tyrosine kinase inhibitor jointly developed at home and abroad, the main targets are vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor ( PDGFR)
    etc.

    The CONCEPT study is a phase 3 RCT comparing voronib combined with everolimus, voronib monotherapy and everolimus monotherapy in the treatment of advanced renal cancer after failure of previous targeted drug therapy [8]
    .

    Patients were randomized in a 1:1:1 ratio to receive voronib monotherapy, everolimus monotherapy, or a combination of the two
    .

    The primary endpoint was PFS, and secondary endpoints included OS, ORR, and safety
    .

     The CONCEPT study enrolled 399 patients from November 2016 to June 2019
    .

    At data cutoff (October 23, 2020), median PFS was significantly longer in the combination arm than in the everolimus monotherapy arm (10.
    0 months vs.
    6.
    4 months; HR, 0.
    70; 95% CI, 0.
    52-0.
    94 ; P=0.
    0171), while the median PFS in the voronib monotherapy arm was comparable to that in the everolimus monotherapy arm (6.
    4 months vs.
    6.
    4 months; HR, 0.
    94; 95% CI, 0.
    69-1.
    24; P =0.
    6856)
    .

    The OS data is immature, the OS of the combination therapy group, everolimus monotherapy group and voronib monotherapy group were 30.
    4, 25.
    4 and 30.
    5 months, respectively, and the ORRs of the three groups of patients were 24.
    8%, 8.
    3% and 24.
    8%, respectively.
    10.
    5%
    .

     Figure 3.
    Progression-free survival in the CONCEPT trial
    .

    It should be pointed out that CONCEPT is the first phase 3 RCT carried out by the domestic urological oncology community
    .

    The results confirmed that the second-line treatment of voronib combined with everolimus in patients with advanced clear cell carcinoma who had failed previous VEGF-TKI therapy was safe and effective
    .

    We look forward to the publication of follow-up data and results from the study
    .

     Targeted therapy for advanced non-clear cell carcinoma Renal collecting duct carcinoma is a very rare (about 1% of renal cell carcinoma) pathological type with poor prognosis and a median survival of about 1 year
    .

    Current treatment options for advanced renal collecting duct carcinoma are limited
    .

    The only phase 2 clinical trial currently enrolled 23 patients with metastatic renal collecting duct carcinoma to evaluate the clinical efficacy of gemcitabine combined with platinum-based chemotherapy [9]
    .

    RESULTS: The patient's ORR was 26%, PFS was 7.
    1 months, and OS was 10.
    5 months
    .

     A prospective, single-center, phase 2 BONSAI trial was reported at the 2021 ASCO Annual Meeting to explore the efficacy of cabozantinib in the first-line treatment of metastatic renal collecting duct carcinoma [10]
    .

    A total of 25 patients were enrolled in the trial and received oral cabozantinib (60 mg once daily) until disease progression or intolerance
    .

    RESULTS: Among the 23 patients who completed treatment, the ORR was 35%, of which 6 had stable disease, 1 had a complete response, and 7 had a partial response
    .

    Median PFS was 6 months
    .

    The BONSAI study met its primary endpoint, showing favorable efficacy and acceptable adverse effects of cabozantinib in patients with metastatic renal collecting duct carcinoma
    .

    Investigators are analyzing serial peripheral blood mononuclear cell (PBMC) profiles during treatment to assess local and systemic tumor immunomodulatory activity of cabozantinib
    .

    They will also present well-established findings based on mutational spectrum and genetic profiling
    .

     Figure 4.
    Objective response rates in the BONSAI trial
    .

    The KEYNOTE-427 study of immunotherapy in advanced non-clear cell carcinoma is a single-arm, open-label phase 2 trial of pembrolizumab in the first-line treatment of metastatic non-clear cell carcinoma [11]
    .

    The primary endpoint is ORR, and secondary endpoints include OS, PFS, and duration of response (DOR)
    .

    The results showed that the ORR was 26.
    7% in the overall population, 32.
    1% in the low-risk subgroup, and 24.
    1% in the intermediate/high-risk subgroup
    .

    Median PFS was 4.
    2 months in the overall population, 5.
    3 months in the low-risk subgroup, and 4.
    0 months in the intermediate/high-risk subgroup
    .

    The median OS for the overall population was 28.
    9 months, not yet reached in the low-risk subgroup and 24.
    5 months in the intermediate/high-risk subgroup
    .

    The median DOR for the overall population was 29.
    0 months, 11.
    0 months for the low-risk subgroup, and 29.
    0 months for the intermediate/high-risk subgroup
    .

    Target lesion diameter was reduced in 59.
    4% of patients, and ≥80% in 16.
    4% of the population
    .

    Based on the results of KEYNOTE-427, investigators are conducting the KEYNOTE-B61 trial to evaluate the efficacy and safety of pembrolizumab combined with lenvatinib in first-line treatment of advanced non-clear cell carcinoma
    .

                                          It is expected that postoperative adjuvant pembrolizumab can improve the prognosis of patients with high-risk RCC, especially in patients with no measurable lesions after resection of metastatic lesions
    .

    The positive results of multiple targeted combined immunotherapy clinical trials have brought light to the treatment of patients with advanced renal cancer, but it should be noted that the treatment regimens for patients with different risk stratifications need to be treated differently
    .

    Target-immune combination therapy has limited benefit in low-risk IMDC patients with a small number/volume burden of lesions
    .

    Targeted combination therapy may become a trend in the late-line treatment of metastatic clear cell renal cancer, while targeted therapy and immunotherapy for metastatic non-clear cell renal cancer are still actively explored
    .

    According to the different disease states of patients, choosing the best drug compatibility scheme is the direction of future efforts
    .

     Neoadjuvant therapy for perioperative treatment of urothelial carcinoma has been a research hotspot in recent years, and it will shine in major conferences in 2020.
    From immune single drug, dual immune combination to immune combination chemotherapy, various new Adjuvant treatment options are endless
    .

    In contrast, relatively few studies have been reported on neoadjuvant therapy this year
    .

     1.
    Avelumab in combination with chemotherapy (AURA) The AURA study reported at the 2021 ESMO Annual Meeting is an immune-based neoadjuvant chemotherapy combination regimen for the treatment of non-metastatic muscle-invasive bladder cancer (MIBC, cT2-4aN0 -2M0) phase 2 trial to explore the efficacy of avelumab combined with different chemotherapy regimens in MIBC [12]
    .

     The trial is divided into cohort 1 (cisplatin-resistant) and cohort 2 (cisplatin-intolerant), with results from cohort 1 reported this year
    .

    In cohort 1, patients received avelumab plus gemcitabine, cisplatin (GC) chemotherapy or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) chemotherapy, respectively
    .

    The primary endpoint was pathological complete response rate (ypT0/is/aN0, pCR), and secondary endpoints were pathological downstaging rate (<ypT2N0) and safety
    .

     The trial included 56 cisplatin-resistant patients, mostly T2 stage
    .

    The results showed that the overall population pathological complete response rate (pCR) was 57%, of which pT0 patients reached 38%
    .

    The pCR rate in the population receiving the dd-MVAC plus avelumab regimen was better than that of the GC plus avelumab regimen, 61% and 54%, respectively, but not statistically different
    .

     Figure 5.
    AURA trial outcomes
    .

    The most common grade 3/4 adverse reactions were thrombocytopenia (29%), acute renal impairment (18%), neutropenia (14%), and anemia (13%)
    .

    None of the patients required glucocorticoid therapy due to immune-related adverse reactions, and none of the patients affected subsequent surgical treatment because of treatment-related adverse reactions
    .

    Platinum-based chemotherapy combined with immunotherapy is a research hotspot in the field of neoadjuvant therapy at home and abroad.
    It can achieve a high pathological complete remission rate and have a good tolerance
    .

    We look forward to follow-up findings that can demonstrate improved tumor outcomes
    .

     2.
    GC regimen (POUT) The first reported POUT trial in 2018 opened a new chapter in postoperative adjuvant chemotherapy for upper urinary tract cancer
    .

    A total of 261 patients with upper urinary tract cancer who underwent full-length nephroureterectomy were enrolled in the POUT trial, and were randomized 1:1 to receive GC regimen adjuvant chemotherapy (eGFR≥50 ml/min using cisplatin, eGFR 30-49ml/min) with carboplatin) or observation
    .

    The results showed that adjuvant chemotherapy significantly improved DFS and metastasis-free survival, but OS data were immature at that time [13]
    .

     This year's ASCO-GU reported updated data from the POUT trial after a median follow-up of 49.
    2 months [14]
    .

    The HR value for the comparison of DFS between the adjuvant chemotherapy group and the observation group was 0.
    51 (95% CI, 0.
    35-0.
    76; P=0.
    0006), and the HR value for the comparison of metastasis-free survival was 0.
    52 (95% CI, 0.
    36-0.
    77; P=0.
    0007)
    .

    The 3-year OS rates of the adjuvant chemotherapy group and the observation group were 79% (95% CI, 71%-86%) and 67% (95% CI, 58%-75%), respectively, and the 5-year OS rates were 65% ( 95% CI, 54%-74%) and 57% (95% CI, 46%-66%)
    .

    The risk of death in the adjuvant chemotherapy group was 30% lower than that in the observation group, but there was no statistical difference (HR, 0.
    70; 95% CI, 0.
    46-1.
    06; P=0.
    09)
    .

    This updated data maintains the results reported in 2018 that DFS and metastasis-free survival in patients with upper urinary tract cancer could benefit from postoperative adjuvant chemotherapy, but ultimately failed to benefit OS
    .

     It should be noted that, compared with the adjuvant chemotherapy group, a higher proportion (65.
    1% vs.
    45.
    0%) of patients in the observation group received systemic therapy at the time of disease recurrence
    .

    In the context of the rapid development of novel drugs, a high proportion of systemic therapy may mean better survival, which may have a greater impact on the OS results of the POUT study
    .

    However, since patients with upper urinary tract cancer have decreased renal function after unilateral nephrectomy, whether they can tolerate adjuvant chemotherapy will become an important factor affecting the choice of adjuvant therapy
    .

     3.
    After nivolumab (CheckMate-274) following neoadjuvant therapy, immunotherapy has made another breakthrough in the field of adjuvant therapy this year
    .

    At the 2021 ASCO-GU Congress, the results of the Phase 3 trial CheckMate-274 were announced for the first time [15], providing a new option for the perioperative treatment of urothelial carcinoma
    .

    The CheckMate-274 study enrolled 709 patients with high-risk muscle-invasive urothelial carcinoma (ypT2-T4a or N+ patients after neoadjuvant cisplatin chemotherapy; pT3 patients who did not receive neoadjuvant chemotherapy and were intolerant/rejected adjuvant cisplatin chemotherapy) -4a or N+ patients), randomized 1:1 to nivolumab and placebo, the trial's primary endpoint was DFS in all randomized patients and those with tumor PD-L1 expression ≥1%, a key secondary Endpoints included OS, non-urothelial recurrence-free survival (NUTRFS), and disease-specific survival
    .

     In all populations, median DFS was nearly doubled in patients treated with nivolumab (20.
    8 months) postoperatively compared with placebo (10.
    8 months)
    .

    At the same time, the risk of postoperative disease recurrence was reduced by 30%
    .

    In patients with PD-L1 expression ≥1%, nivolumab reduced the risk of disease recurrence by 45%, with median DFS not reached and 10.
    8 months in the nivolumab and placebo groups, respectively
    .

    The safety of nivolumab is basically consistent with that reported in other previous clinical studies
    .

    Treatment-related adverse events occurred in 77.
    5% and 55.
    5% of patients in the nivolumab and placebo groups, respectively, and grade 3/4 adverse events occurred in 17.
    9% and 7.
    2%, respectively
    .

    CheckMate-274 is the first study to demonstrate the efficacy of immunotherapy in the adjuvant treatment of muscle-invasive urothelial carcinoma, and has achieved positive results in all randomized populations and PD-L1 expression ≥1%
    .

    This has important clinical significance for patients with impaired renal function who cannot tolerate cisplatin-based adjuvant chemotherapy
    .

     Figure 6.
    Disease-free survival from the CheckMate-274 trial
    .

     Advanced tumor treatment For patients with advanced urothelial carcinoma intolerant to cisplatin, immunotherapy can be an alternative option, and it has been recommended by several clinical guidelines
    .

    Two classic trials have updated their data this year, IMvigor210 and KEYNOTE-052, which led to the approval of atezolizumab and pembrolizumab for first-line treatment of cisplatin-intolerant patients, respectively
    .

     1.
    Atezolizumab (IMvigor210) and Pembrolizumab (KEYNOTE-052, KEYNOTE-361) IMvigor210 is a phase 2 trial exploring atezolizumab monotherapy in patients with advanced urothelial carcinoma [16]
    .

    Cohort 1 of the trial included 119 treatment-naïve patients with advanced urothelial carcinoma who were not candidates for cisplatin chemotherapy
    .

    This year's ESMO annual meeting announced the 5.
    8-year follow-up data update of IMvigor210 cohort 1.
    The overall population ORR was 23.
    5%, the median duration of response was 59.
    1 months, and the median DOR for patients with tumors with low PD-L1 expression was 53.
    5 months (high The median DOR in express patients has not yet been reached), and the results showed that atezolizumab monotherapy resulted in durable responses and long-term survival
    .

     KEYNOTE-052 is a single-arm phase 2 trial of pembrolizumab in first-line treatment of patients with cisplatin-intolerant advanced urothelial carcinoma [17]
    .

    The 5-year follow-up data updated at this year's ASCO annual meeting showed that patients with a combined positive score of ≥10 had higher and durable ORR compared with patients with a combined positive PD-L1 score of <10
    .

    The ORR of patients in the two groups was 47.
    3% and 20.
    7%, respectively, the median DOR was not reached and 21.
    2 months, and the median OS was 18.
    5 and 9.
    7 months
    .

     KEYNOTE-361 compared first-line immunotherapy with standard chemotherapy in the treatment of advanced urothelial carcinoma [18]
    .

    The results of the study showed that the ORR of carboplatin combined with gemcitabine was higher than that of pembrolizumab alone, both in the general population and in patients with a combined positive score ≥10 (41.
    8% vs.
    27.
    6% in the overall population, with a combined positive score ≥10).
    population 46.
    1% vs.
    29.
    8%), which reconfirms that platinum-based chemotherapy is still the preferred first-line treatment for platinum-resistant patients
    .

     2.
    Avelumab (JAVELIN Bladder100) in the first-line treatment of advanced urothelial carcinoma in recent years has focused on the combination of chemotherapy and immunotherapy, but neither the IMvigor130 nor KEYNOTE-361 studies have achieved the expected results
    .

    On the contrary, the innovative JAVELIN Bladder 100 trial brought us encouraging results and was written into major guidelines, which are changing our clinical practice [19]
    .

     This year's ASCO Annual Meeting reported the results of a genomic subgroup analysis of the JAVELIN Bladder100 study [20], which explored the efficacy of avelumab as first-line maintenance therapy in patients with advanced urothelial carcinoma in different genomic subgroups
    .

    The results showed that avelumab + BSC first-line maintenance therapy significantly prolonged the OS and PFS of patients compared with the best supportive care (BSC) group
    .

    Among genomic subgroups, avelumab plus BSC resulted in significant OS benefit in all Cancer and Tumor Gene Atlas (TCGA) subgroups except the luminal subgroup
    .

     3.
    Antibody-conjugated drug enfortumab vedotin (EV-301) In the field of first-line treatment, in addition to the attempts of chemotherapy combined with immunotherapy, antibody-conjugated drugs have also achieved good results in recent years
    .

    The results of the EV-103 study, first published at the 2019 ESMO Annual Meeting, showed that enfortumab vedotin (EV) combined with pembrolizumab achieved amazing efficacy in the first-line treatment of platinum-intolerant people, with ORR as high as 71%
    .

     This year's ASCO annual meeting updated the long-term follow-up results and safety data of this study [21].
    The median follow-up time was 25.
    6 months, and the confirmed ORR was 73.
    3% (the CR rate was 17.
    8%, and the ORR for patients with liver metastases was 73.
    3%).
    57.
    1%)
    .

    EV combined with pembrolizumab can benefit patients with PFS, OS, and DOR
    .

    The median PFS was 12.
    3 months, the median OS was 26.
    1 months, and the OS rate at a median follow-up of 24 months was 56.
    3%
    .

    The most common treatment-related adverse reactions were peripheral sensory neuropathy (56%; 4% grade ≥ 3), fatigue (51%; 11% ≥ grade 3), and alopecia (49%)
    .

     As early as 2019, based on the results of the EV-201 study, EV has been approved by the U.
    S.
    Food and Drug Administration for the treatment of metastatic urothelial carcinoma after failure of platinum-based and PD-1 monoclonal antibody immunotherapy
    .

    EV-301 is a phase 3 RCT to further compare EV with conventional chemotherapy in advanced urothelial carcinoma population after failure of platinum and immunotherapy [22]
    .

    A total of 608 patients were enrolled in this trial and randomly assigned to EV group and chemotherapy group
    .

    The chemotherapy group received docetaxel, paclitaxel, or vinflunine of the investigator's choice
    .

    The primary endpoint was OS, and secondary endpoints included investigator-assessed PFS, overall response rate, disease control rate, and safety
    .

     The results of the interim analysis were reported at this year's ASCO GU meeting [23]
    .

    With a median follow-up of 11.
    1 months, EV could prolong the survival of such patients by 3.
    9 months compared with conventional chemotherapy, and the median OS was 12.
    9 and 9.
    0 months, respectively (HR, 0.
    7; P=0.
    00142)
    .

    The median PFS was 5.
    6 and 3.
    7 months in the EV group and chemotherapy group, respectively (HR, 0.
    62; P<0.
    00001), and the overall response rates were 40.
    6% and 17.
    9%, respectively (P<0.
    001)
    .

    Subgroup analysis showed a significant advantage of EV across multiple prespecified subgroups
    .

    The incidence of treatment-related adverse events (93.
    9% vs.
    91.
    8%) and serious treatment-related adverse events (22.
    6% vs.
    23.
    4%) was comparable between the EV and chemotherapy groups
    .

     Figure 7.
    Overall survival in the EV-301 trial
    .

    With the success of this clinical study, a third-line treatment landscape for advanced urothelial carcinoma has emerged
    .

    For advanced urothelial carcinoma, the standard first-line treatment is platinum-based chemotherapy.
    Patients who are effective can choose immune maintenance therapy, and those who fail to receive chemotherapy can receive second-line immunotherapy
    .

    For patients who failed platinum and immunotherapy, that is, third-line treatment, the EV-301 study established the third-line treatment status of antibody-conjugated drug EV
    .

     4.
    Antibody-drug conjugate RC48 (RC48-C009) In the field of antibody-drug conjugates, domestic drugs have followed up very quickly.
    The RC48 antibody-drug conjugate for patients with HER2 overexpression has proven its effectiveness and safety.
    The final study data from the RC48-C009 study was reported at the ASCO Annual Meeting [24]
    .

    The purpose of this study was to explore the efficacy of RC48 antibody-drug conjugates in patients with locally advanced or metastatic urothelial carcinoma with HER2 overexpression (IHC 3+ or 2+) that progressed after prior conventional chemotherapy (including gemcitabine, platinum, and paclitaxel).
    Efficacy and Safety
    .

    The results showed that the ORR of patients treated with RC48 antibody-drug conjugates was 46.
    9%
    .

    The median PFS was 4.
    3 months, and the OS was 14.
    8 months, and all subgroups had significant benefits
    .

    The most common grade ≥3 treatment-related adverse events were neutropenia (9.
    4%) and dysesthesia (6.
    3%)
    .

    Under the premise that most of the patients are third-line treatment, it is not easy to obtain such a curative effect
    .

     RC48 is also trying to move forward with front-line therapy based on the success of late-line therapy
    .

    The RC48-C014 study is a Phase 1b/2, open-label, investigator-initiated clinical trial [25] to evaluate the efficacy and safety of RC48 in combination with immunotherapy in patients with locally advanced or metastatic urothelial carcinoma
    .

    Of the enrolled patients, 52.
    6% had no prior treatment, and 47.
    4% had received ≥1 line of prior treatment
    .

    RC48 combined with immunotherapy achieved amazing efficacy in a total of 19 patients, with an overall ORR of 94.
    1%, of which the ORR of previously untreated patients was 100%, and the anti-tumor efficacy was independent of previous lines of treatment, HER2 status and PD-L1 status
    .

     Outlook With the successive advent of targeted therapy, immunotherapy and antibody-drug conjugates, the systemic treatment of urothelial carcinoma has progressed rapidly in recent years
    .

    The participation of immunotherapy in neoadjuvant therapy has become a research hotspot in recent years, but whether tumor control can ultimately translate into survival benefits for patients and whether it can provide more opportunities for bladder-preserving therapy still needs further research to confirm
    .

     The field of adjuvant therapy has ushered in a major breakthrough this year.
    The success of immunotherapy in the field of adjuvant therapy may change the clinical practice in the future.
    Especially for patients who cannot tolerate cisplatin chemotherapy, immunotherapy may become the standard treatment option in the future.

    .

     The treatment pattern of advanced urothelial carcinoma is gradually formed.
    The first-line treatment is still platinum-based chemotherapy.
    The effective patients can choose immune maintenance therapy
    .

    For patients who have failed platinum and immunotherapy, antibody-drug conjugates have established their status
    .

    For patients with platinum intolerance, the study of immune and antibody conjugated drug combination therapy is worth looking forward to, and may become an important treatment option in addition to chemotherapy in the future
    .

    With the rise of the multi-drug combination therapy model, the management of patients' adverse reactions also needs to be paid great attention
    .

     Prostate Cancer Prostate Cancer Magnetic Resonance Screening (STHLM3-MRI) Patients with elevated prostate specific antigen (PSA) should complete the MRI examination first, and MRI finds positive lesions before undergoing puncture.
    This diagnosis and treatment process is gradually becoming a clinical practice in major centers in China.
    Routine diagnosis and treatment
    .

    However, internationally, there is no definite conclusion in the academic community as to whether MRI should be used as a further screening test before puncture in patients with elevated PSA
    .

    Previously, the PRECISION study (2018) [26], the Trio study (2020) [27], and the PRECISE study (2021) [28] were all targeted at the PSA screening population and compared MRI-targeted + systematic puncture versus only systematic puncture Multicenter Phase 3 RCT
    .

     The multicenter STHLM3-MRI [29] study from Europe published this year further identified the role of MRI as a further screening step in people with elevated PSA
    .

    The trial included 1532 participants who were randomly assigned 3:2 to standard biopsy or experimental biopsy (see related reading: MRI-targeted biopsy reduces overdiagnosis and still effectively detects prostate cancer)
    .

     The trial results showed that fusion aspiration combined with MRI results did not reduce the detection of clinically significant cancer (Gleason score ≥7) (21% in the standard biopsy group vs.
    18% in the experimental biopsy group, non-inferiority design).
    Can reduce the detection rate of clinically insignificant cancer (Gleason score equal to 6) (4% in the standard biopsy group vs.
    12% in the experimental biopsy group)
    .

    This is consistent with the results of the PRECISE study, which support MRI as a tool for further screening of prostate lesions in patients with elevated PSA
    .

    From a health economics standpoint, the authors argue, the resulting savings in unnecessary diagnosis and follow-up care will outweigh the cost of the MRI exam itself
    .

    2 Compared with the previous three studies, this study has the following unique features: 1.
    The included population of this study is PSA 3 ng/ml or more, and the average PSA of the actual included population is only 4.
    3 ng/ml, which is much lower than other trials.
    6.
    2~6.
    7ng/ml
    .

    This indicates that this trial is more suitable for the early diagnosis of prostate cancer in Western clinical practice
    .

    2.
    This study only used dual-parameter (T2 and DWI) MRI, and did not use enhanced MRI.
    According to Prostate Imaging Reporting and Data System (PI-RADS) version 2.
    0 and 2.
    1, the prompt prostate The area of ​​cancer is scored
    .

    The authors believe that this method has a shorter time and is more suitable for large-scale screening, but the relevant standards need to be further promoted
    .

    3.
    In the trial, for patients with no significant lesions found by MRI, if the Stockholm3 score is greater than 25%, further puncture examination is also recommended
    .

    The Stockholm3 score is a prostate cancer screening tool developed in Europe in recent years that combines results from protein, genetic and clinical data
    .

    Another analysis of this cohort was published in Lancet Oncol a month after the NEJM published the results of the trial [30]
    .

    The results of the study show that for prostate cancer screening population, Stockholm3 score can better perform risk stratification before MRI and targeted aspiration; the fusion of Stockholm3 score with MRI-guided targeted aspiration can reduce overdiagnosis in screening population.
    while maintaining diagnostic capabilities for clinically significant cancers
    .

    4.
    PRECISION, Trio, PRECISE and STHLM3-MRI studies all used different software to fuse B-ultrasound and MRI images
    .

    Although this allowed methodological heterogeneity between trials, as a multicentre trial, within-trial heterogeneity was well controlled
    .

    However, the consistency between the results of these software fusions and the commonly used clinical consciousness fusion still needs to be further verified by daily clinicians
    .

     New Combinations, New Weapons for Metastatic Castration-Resistant Prostate Cancer In the era of traditional treatment, metastatic castration-resistant prostate cancer (mCRPC) is the terminal stage of prostate cancer
    .

    However, in recent years, various new drugs have emerged one after another, and the treatment methods after the failure of traditional endocrine therapy have become increasingly abundant
    .

     1.
    Apataxan and Abiraterone Combination (ACIS) Apataxan is a new type of androgen receptor blocker, and abiraterone is a new type of androgen production blocker
    .

    In the mCRPC stage, the combination of the two to maximize the inhibition of the androgen pathway is more effective than abiraterone alone? Can the indications of apataan go further and come closer to the mCRPC field? These are all questions we expect ACIS research to answer [31]
    .

     The study included mCRPC patients who had not received systemic therapy.
    After a median follow-up of 54.
    8 months, the final analysis showed that the combination therapy group only achieved a significant difference in imaging-based progression-free survival (rPFS) (24 months vs.
    16.
    6 months) months), but there was no significant difference in OS between the two groups (36.
    2 months vs.
    33.
    7 months)
    .

    There were also no significant differences in safety outcomes between the two groups
    .

     The investigators concluded that this trial had similar rPFS results to the AllianceA031201 study [32] (mCRPC patients treated with enzalutamide plus abiraterone or abiraterone monotherapy before chemotherapy), but with a higher overall safety profile
    .

    Although limited by the complexity of follow-up treatment, the final OS did not achieve positive results, but the combination therapy group achieved better results in the rate of 50% reduction in PSA and short-term indicators such as rPFS
    .

    In addition to further exploring the population that can benefit from OS at the molecular level, the efficacy of combined maximal anti-androgen therapy in metastatic hormone-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer will be an expected result in the future
    .

     2.
    PARP inhibitor talazoparib (TALAPRO-1) PARP inhibitor is a pioneer in the precision treatment of prostate cancer
    .

    In June of this year, the China National Medical Products Administration has conditionally approved olaparib (based on the PROfound test results) [33] in patients with systemic or germline BRCA mutations who have progressed on previous therapy (including a new endocrine drug).
    Indications for mCRPC patients
    .

    In 2021, the results of a phase 2 trial of another PARP inhibitor, talazoparib, as a monotherapy in mCRPC, will be published in Lancet Oncol [34]
    .

     The trial included patients with end-line mCRPC who were positive for a DDR-HRR mutation (gene 11)
    .

    After 16.
    4 months of follow-up, ORR reached 29.
    8% 
    .

    The most common grade 3-4 treatment-related adverse events included anemia (31%), thrombocytopenia (9%), and neutropenia (8%)
    .

    The researchers are optimistic about the results and believe they support further phase 3 trials of tarazoparib, which can also include patients without BRCA mutations
    .

     PARP inhibitors are the first practitioners to implement basket trials
    .

    For mCRPC patients with BRCA1 or BRCA2 mutations, in addition to olaparib (PROfound test, ORR, 33.
    3%) and tarazoparib (ORR, 29.
    8%), the TRITON2 trial of rucaparib [35 ] and the GALAHAD trial of niraparib [36] also reported ORRs of 43.
    5% and 41.
    4%, respectively
    .

    The four drugs seem to have similar effects, but the effects may be different for different gene mutations in the HRR genome
    .

     It is worth noting that PARP inhibitors are often associated with severe hematologic toxicity, and the better the efficacy, the greater the toxicity
    .

    The duration of last-line therapy was short enough to observe hematologic toxicity
    .

    If it is advanced to the treatment of metastatic hormone-sensitive prostate cancer, the safety management of long-term use will be a major problem in clinical work
    .

    It is true that the gene mutation rate of about 10% in the HRR pathway in metastatic prostate cancer [37] makes PARP inhibitors widely available, but finding the right drug for the right patient is the common goal of both doctors and patients
    .

     In clinical work, HRR gene detection has become a key link in the use of PARP inhibitors and other precision targeted drugs
    .

    In addition to guiding treatment, the role of genetic testing in judging prognosis and genetic counseling should also be valued
    .

    With the continuous exploration of the indications of PARP inhibitors in the front line, the use of HRR detection in metastatic hormone-sensitive prostate cancer and newly diagnosed prostate cancer has gradually entered the field of vision of clinicians
    .

     3.
    AKT inhibitor (IPATential150) AKT is an important molecule in the PI3K-AKT-TSC-mTOR pathway
    .

    About 40% of mCRPC patients have PTEN deletion and have a poor prognosis
    .

    Theoretically, in PTEN-deficient mCRPC patients, simultaneous inhibition of the androgen pathway and AKT pathway could effectively control disease progression
    .

     IPATential150 is a multicenter, randomized, double-blind, phase 3 controlled trial [38] that included 1101 patients and explored the efficacy of ipatasertib + abiraterone versus abiraterone alone in mCRPC (regardless of PTEN status)
    .

    After a median follow-up of 19 months, the results showed that in patients with PTEN deficiency, the median rPFS in the combination group and abiraterone monotherapy group was 18.
    5 months and 16.
    5 months, respectively (HR, 0.
    77; 95% CI).
    , 0.
    61~0.
    98; P=0.
    034; statistically significant at the α=0.
    04 level)
    .

    In the intention-to-treat population, the median PFS was 19.
    2 months versus 16.
    6 months, respectively (HR, 0.
    84; 95% CI, 0.
    71-0.
    99; P=0.
    043; not statistically significant at the α=0.
    01 level)
    .

     Compared with HRR mutations, PTEN deletions are more common and have a large number of patients
    .

    This study is the first large phase 3 RCT
    .

    Although the trial failed to achieve statistically significant positive results, an rPFS benefit in the PTEN-deficient population was observed in the trial arm
    .

    The researchers believe that the results not only provide a treatment reference for patients with poor prognosis confirmed by immunohistochemistry with PTEN deletion, but may also provide certain treatment options for patients with PI3KCA/AKT1/PTEN mutations in next-generation sequencing
    .

     The PI3K-AKT-TSC-mTOR pathway is no stranger to urologists
    .

    Everolimus, an inhibitor of mTOR1, is a commonly used drug for advanced renal cancer and tuberous sclerosis
    .

    Previously, neither everolimus monotherapy [39] nor the combined application of everolimus and second-generation androgen receptor inhibitors have obtained clear positive results
    .

    ipatasertib has taken the first step in the field of AKT inhibitors
    .

    A similar study of CAPItello-281 is underway for a similar drug, capivasertib
    .

    In addition, the ProCAID study showed that the combination of capivasertib and docetaxel chemotherapy failed to significantly improve the composite progression-free survival (cPFS) of mCPRC [40]
    .

    PI3K/AKT/mTOR pathway inhibitors still have a long way to go in mCRPC therapy
    .

     4.
    Lutetium 177-PSMA radioligand therapy (VISION) In the past two years, radioligand therapy has emerged in prostate cancer and has become a new hot spot, playing an increasingly important role in the diagnosis and treatment of mCRPC
    .

     The VISION trial [41] included 831 patients with mCRPC.
    After screening with gallium 68-PSMA-11 PET/CT, they were randomly divided into 2:1 groups.
    The experimental group received β-particle-emitting lutetium 177-PSMA-617 + standard therapy for 4 to 6 cycles , the control group received only standard care (click for related reading: Breakthrough in phenotypic precision medicine: Radioligand therapy improves overall survival in metastatic castration-resistant prostate cancer)
    .

    After a median follow-up of 20.
    9 months, PFS (8.
    7 months vs.
    3.
    4 months) and OS (15.
    3 months vs.
    11.
    3 months) were significantly prolonged in the experimental group
    .

    Although there were significantly more adverse reactions of grade 3 or above in the experimental group than in the control group, there was no significant difference in the quality of life between the two groups
    .

    The 3VISION study provides a new treatment option for patients who have failed both androgen pathway inhibitors and chemotherapy
    .

    There are still several clinical trials on lutetium 177-PSMA in progress
    .

    The PSMAdition study (NCT04720157) is to explore the value of lutetium 177-PSMA + standard therapy in hormone-sensitive metastatic prostate cancer
    .

    Another phase 2 TheraP trial [42] was exploring the effect of lutetium 177 combined with chemotherapy on disease control
    .

    These trials will ultimately lead to accurate localization of lutetium 177-PSMA in the treatment of metastatic prostate cancer
    .

     With the advancement of technology, the radioisotopes in radioligands have also developed from traditional strontium 89, radium 223 [43] to lutetium 177, and the efficacy and safety of the recently developed alpha particle-emitting actinium 225-PSMA are more worthy of our attention.
    Looking forward to [44]
    .

    Note: The pictures in this article, except those marked with the NEJM logo, are all from the website
    .

    The author introduces He Zhisong, director of the Department of Urology of Peking University First Hospital and deputy director of the Institute of Urology of Peking University
    .

    Academic part-time jobs include the vice chairman of the third committee of the Urology Branch of the Chinese Medical Doctor Association, the director of the CSCO Council, the chairman of the CSCO Urothelial Cancer Special Committee, the vice chairman of the CSCO Prostate Cancer Special Committee, the Chinese Anti-Cancer Association ( CACA) Standing Committee Member of Urogenital Oncology Professional Committee, Deputy Head of Precision Medicine Group of CACA Urogenital Oncology Professional Committee, Member of Oncology Group of Urology Branch of Chinese Medical Association,
    etc.

    Served as the editorial board member of "Chinese Journal of Urology" and "Modern Urology Journal"
    .

    He has long been committed to the clinical treatment and research exploration of urinary system tumors, and has presided over or participated in more than 30 Chinese and international multi-center clinical studies of urinary system tumors
    .

    Mi Yue is an attending physician in the Department of Urology, Peking University First Hospital
    .

    Visiting Scholar at Keck School of Medicine, University of Southern California, and Charlottesburg Hospital, Berlin, Germany
    .

    Member of the Urinary Oncology Sub-Committee of Beijing Cancer Prevention and Research Association, member of the Professional Committee of Oncology Clinical Research Innovation and Development of the Chinese Medical Education Association, member of the Chinese Society of Clinical Oncology, and member of the Beijing Gonadal Axis Disease Prevention and Research Association
    .

    Participated in a number of global multi-center Phase 2 and Phase 3 prospective randomized controlled clinical studies in UC, RCC, PCa, published more than ten domestic core journal papers and SCI papers, participated in the writing of 3 urology monographs, and translated 6 urology monographs Department
    .

    Tang Qi is an attending physician in the Department of Urology, Peking University First Hospital
    .

    Doctor of clinical medicine from Peking University, completed the course of clinical genetics and genetic counseling at the University of Manchester, UK
    .

    The sixth batch of "group->
    .

    Champion of the 3rd "CARS Almighty Doctor" China Kidney Cancer Comprehensive Treatment Challenge National Finals, and runner-up in the national finals of the 2019 "Who Fights" Prostate Cancer Diagnosis and Treatment Forum
    .

    Specializes in the diagnosis and comprehensive treatment of urinary system tumors
    .

    He is committed to the related research on urological tumors.
    He has published more than ten papers in SCI and Chinese, and has reported his research results at the AUA, EAU and CUA annual conferences for many times
    .

    Fan Yu, Ph.
    D.
    , Deputy Chief Physician of Department of Urology, Peking University First Hospital
    .

    Secretary of the Department of Urology, Peking University School of Medicine, Secretary of the Ethics Committee of Peking University First Hospital
    .

    Visiting Scholar at Cancer Centre, Prince of Wales Hospital, Chinese University of Hong Kong
    .

    Participated in a number of phase 2, 3, and 4 clinical studies of prostate cancer, kidney cancer, and urothelial cancer
    .

    He has made many speeches in EAU and AUA posters
    .

    FrontierOncology Journal Peer reviewer
    .

    He has published more than 30 SCI papers and several domestic core journals
    .

    Participated in 8 national, provincial and ministerial projects
    .

    Won 1 national utility model patent and 1 national software copyright
    .

    Participated in the compilation of 1 national urology textbook, 5 monographs, and 7 urology monographs
    .

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