Professor Zhisong He: Important clinical research on urinary system tumors in 2021

In 2021, many important advances have been made in the treatment of urinary tumors
.

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

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

As in the past three years, we will launch an inventory of clinical research in various important disease fields 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 treatment of renal clear cell carcinoma after nephrectomy is the standard of treatment for locally advanced renal cell carcinoma
.

Due to the late stage of the tumor at the time of diagnosis, nearly half of the patients recurred or metastasized after surgery, entering the stage of metastatic renal cell carcinoma
.

In the past, a number of adjuvant targeted therapy clinical trials have been conducted for locally advanced renal cancer with a high risk of recurrence, including targeted drugs sunitinib (ASSURE), pezopanib (PROTECT) and axitinib (ATLAS) ) And other drug adjuvant treatment tests, the results were all 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 kidney cancer with a high risk of recurrence, neither the European Association of Urology (EAU) nor the US NCCN recommends adjuvant targeted therapy
.

 The KEYNOTE-564 study is a randomized, double-blind, placebo-controlled phase 3 clinical trial [1], enrolled in renal clear cell carcinoma (postoperative pathology confirmed 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, once every three weeks) or placebo, and the primary endpoint was DFS
.

The study’s median follow-up time was 24.
1 months, and the 24-month DFS rates of the experimental group and the control group were 77.
3% and 68.
1% (HR, 0.
68; P=0.
002), which reached the primary endpoint set by the trial, which is support Pembrolizumab is used in the adjuvant treatment of renal cell carcinoma with high risk of recurrence
.

A subgroup analysis of the DFS endpoint found that benefits were observed in each subgroup, with the M1 NED subgroup benefiting the most
.

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

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

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

We look forward to more follow-up data to show the benefits of OS in patients
.

                     Figure 1.
Disease-free survival of KEYNOTE-564
.

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

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

First-line treatment of advanced renal clear cell carcinoma: Targeted immunotherapy KEYNOTE-426 study is a phase 3 randomized comparison of pembrolizumab combined with axitinib and sunitinib for the first-line treatment of advanced renal clear cell carcinoma Controlled clinical trial (RCT) [2]
.

The 2019 American Symposium on Genitourinary System Cancer (ASCO-GU) announced its research results for the first time, pushing the first-line treatment of advanced renal cancer into the era of immune-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]
.

A subgroup analysis based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score shows: Compared with sunitinib, pembrolizumab combined with axitinib has progression-free survival (PFS) in the low-risk group No significant benefit was achieved, while the medium-high-risk group benefited; the low-risk group OS did not achieve a significant benefit.
The 42-month OS rates of the two groups were 72.
3% and 73% (HR, 1.
17) respectively; while the medium-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), respectively
.

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

Figure 2.
KEYNOTE-426 trial outcome
.

In addition, the CLEAR study is also a first-line target immunocombination treatment of advanced renal clear cell carcinoma of stage 3 RCT [4], which compared lenvatinib combined with pembrolizumab, lenvatinib combined with everolimus and Shu Nitinib
.

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

 Compared with the sunitinib group, the PFS and OS of the lenvatinib combined with pembrolizumab group were significantly prolonged
.

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

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

The ORRs of the high-risk groups in the two groups were 72.
4% vs.
28.
8%, and the ORRs of the low-risk groups were 68.
2% vs.
50.
8%
.

Similar to the KEYNOTE-426 study, the treatment plan of lenvatinib combined with pembrolizumab did not improve the OS of low-risk groups, but the middle- and high-risk groups benefited significantly
.

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

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

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

The median PFS of the nivolumab combined with cabozantinib treatment group and sunitinib group were 17.
0 and 8.
3 months (HR, 0.
52; 95% CI, 0.
43~0.
64; P<0.
0001), respectively, and ORR was 54.
8% and 28.
4%
.

The median OS of the two groups of patients was unreached and 29.
5 months (HR, 0.
66; 95% CI, 0.
50 to 0.
87; P=0.
0034)
.

According to IMDC risk stratification (low, medium and high group), the number of involved organs (≥1 vs.
1), and the sum of the diameter of the target lesion (<72.
1 mm vs.
≥72.
1 mm), the researchers found that in all subgroups, Nivolumab combined with cabozantinib treatment can significantly increase PFS, but OS is not observed in IMDC middle/low risk population, 1 organ involvement population, and small tumor size (diameter and <72.
1 mm) Benefit
.

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

The existing posterior treatments for metastatic clear cell renal cell carcinoma are mainly divided into four types: mTOR inhibitors, TKIs, PD-1 antibodies, and targeted/immune combination therapy [7]
.

The representative drugs are everolimus, axitinib/cabotinib/lenvatinib, nivolumab and lenvatinib combined with everolimus
.

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

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

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

The CONCEPT study compares the use of voronib combined with everolimus, voronib single agent, and everolimus single agent for the treatment of advanced renal cell carcinoma after the failure of previous targeted drug therapy [8]
.

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

The primary endpoint is PFS, and secondary endpoints include OS, ORR, and safety
.

 A total of 399 patients were enrolled in the CONCEPT study from November 2016 to June 2019
.

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

OS data is not yet mature.
The OS of the combination therapy group, everolimus single agent group, and voronib single agent group were 30.
4, 25.
4, and 30.
5 months, respectively, and the ORR of the three groups were 24.
8%, 8.
3%, and 30.
5 months, 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 urinary tumor community
.

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

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

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

The current treatment options for advanced renal collecting duct carcinoma are very limited
.

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

The results showed that the patient’s ORR was 26%, PFS was 7.
1 months, and OS was 10.
5 months
.

 The 2021 ASCO annual meeting reported a prospective, single-center, phase 2 BONSAI trial, which explored the efficacy of cabozantinib in the first-line treatment of metastatic collecting duct carcinoma [10]
.

A total of 25 patients were enrolled in the trial and were given oral cabozantinib (60 mg once a day) until the disease progressed or became intolerable
.

The results showed that among the 23 patients who completed the treatment, the ORR was 35%, of which 6 had stable disease, 1 had a complete remission, and 7 had a partial remission
.

The median PFS was 6 months
.

The BONSAI study reached its primary endpoint, showing that cabozantinib has good efficacy and acceptable adverse reactions in patients with metastatic collecting duct carcinoma
.

Researchers are analyzing the peripheral blood mononuclear cell (PBMC) profile continuously performed during the treatment period to evaluate the activity of cabozantinib on local and systemic tumor immunomodulation
.

They will also show mature research results based on mutation profiles and gene signature analysis
.

 Figure 4.
The objective response rate of the BONSAI trial
.

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

The primary end point is ORR, and secondary end points include OS, PFS, duration of remission (DOR) and so on
.

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

The median PFS of the overall population was 4.
2 months, the low-risk subgroup was 5.
3 months, and the medium/high-risk subgroup was 4.
0 months
.

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

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

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

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

                                      It is expected that postoperative adjuvant pembrolizumab can improve the prognosis of renal cancer patients at high risk of recurrence, especially for those who have no measurable lesions after resection of metastatic lesions
.

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

People with low IMDC risk and small number of lesions/volume burden have limited benefit from targeted immunotherapy
.

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

In view of the different disease states of patients, choosing the best drug compatibility plan is the direction of future efforts
.

 Perioperative treatment of urothelial cancer.
Neoadjuvant therapy for urothelial cancer has been a research hotspot in recent years.
It has shined in major conferences in 2020.
From immune single drug, dual immune combination to immune combination chemotherapy, various new Adjuvant treatment options are emerging one after another
.

In contrast, there are relatively few research reports on neoadjuvant therapy this year
.

 1.
Avirumumab combined 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 aimed to explore the efficacy of aviruzumab combined with different chemotherapy regimens in MIBC [12]
.

 The trial is divided into cohort 1 (cisplatin tolerance) and cohort 2 (cisplatin intolerance).
The results of cohort 1 are reported this year
.

In cohort 1, patients received avirulumab combined with gemcitabine, cisplatin (GC) chemotherapy or dose-dense methotrexate, vinblastine, adriamycin, and cisplatin (dd-MVAC) chemotherapy
.

The primary end point is pathological complete remission rate (ypT0/is/aN0, pCR), and the secondary end point is pathological downgrade rate (<ypT2N0) and safety
.

 A total of 56 cisplatin-tolerant patients were included in the trial, most of whom were in stage T2
.

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

The pCR rate of the population receiving the dd-MVAC combined with aviruzumab regimen was better than that of the GC combined with aviruzumab regimen, which were 61% and 54%, respectively, but there was no statistical difference
.

 Figure 5.
AURA trial outcome
.

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

No patient required glucocorticoid therapy due to immune-related adverse reactions, and no patients affected subsequent surgical treatment due to treatment-related adverse reactions
.

Platinum-based chemotherapy combined with immunotherapy is currently a research hotspot in the field of neoadjuvant therapy at home and abroad, which can achieve a higher pathological complete remission rate and better tolerability
.

We look forward to follow-up research results that can show improvement in tumor outcomes
.

 2.
GC protocol (POUT) The POUT trial, which was first reported in 2018, opened a new chapter in adjuvant chemotherapy after upper urinary tract cancer surgery
.

The POUT trial enrolled 261 patients with upper urinary tract cancer who underwent full-length renal ureterectomy.
After the operation, they were randomized 1:1 to receive GC adjuvant chemotherapy (eGFR≥50 ml/min with cisplatin, eGFR 30~49ml/min Use carboplatin) or observe
.

The results showed that adjuvant chemotherapy significantly improved DFS and metastasis-free survival, but the OS data at that time was not yet mature [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 of the adjuvant chemotherapy group compared with the observation group DFS was 0.
51 (95% CI, 0.
35~0.
76; P=0.
0006), and the HR value of the metastasis-free survival comparison was 0.
52 (95% CI, 0.
36~0.
77; P=0.
0007)
.

The 3-year OS rate of the adjuvant chemotherapy group and the observation group were 79% (95% CI, 71%~86%) and 67% (95% CI, 58%~75%), and the 5-year OS rate was 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 patients with upper urinary tract cancer DFS and metastasis-free survival can benefit from postoperative adjuvant chemotherapy, but ultimately OS did not benefit
.

 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 treatment when the disease relapsed
.

In the context of the rapid development of new 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, because 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.
Nivolumab (CheckMate-274) following neoadjuvant therapy, immunotherapy has achieved a breakthrough in the field of adjuvant therapy this year
.

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

The CheckMate-274 study enrolled 709 high-risk muscular invasive urothelial cancer patients (ypT2-T4a or N+ patients after cisplatin neoadjuvant chemotherapy; pT3 who did not receive neoadjuvant chemotherapy and cannot tolerate/reject cisplatin adjuvant chemotherapy -4a or N+ patients), randomly assigned to the nivolumab group and placebo group at 1:1.
The primary endpoint of the trial is the DFS of all randomized patients and patients with tumor PD-L1 expression ≥1%, the key secondary Endpoints include OS, non-urothelial relapse-free survival (NUTRFS), and disease-specific survival
.

 In all populations, compared with the placebo group (10.
8 months), the median DFS of patients treated with nivolumab (20.
8 months) after surgery was nearly doubled
.

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

In patients with PD-L1 expression ≥1%, nivolumab can reduce the risk of disease recurrence by 45%.
The median DFS of the nivolumab group and placebo group were not reached and 10.
8 months, respectively
.

The safety of nivolumab is basically consistent with other previous clinical research reports
.

The rates of treatment-related adverse events in the nivolumab group and placebo group were 77.
5% and 55.
5%, respectively, and the rates of grade 3/4 adverse events were 17.
9% and 7.
2%, respectively
.

CheckMate-274 is currently the first study to prove that immunotherapy is effective in adjuvant treatment of muscular invasive urothelial carcinoma, and positive results have been obtained in all random populations and those with PD-L1 expression ≥1%
.

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

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

 Advanced tumor treatment For patients with advanced urothelial cancer who are intolerant to cisplatin, immunotherapy can be used as an alternative option, and many clinical guidelines have been recommended
.

This year, two classic trials have updated their data, namely IMvigor210 and KEYNOTE-052.
These two trials have allowed atelizumab and pembrolizumab to be approved for the first-line treatment of patients with cisplatin intolerance, respectively
.

 1.
Atelizumab (IMvigor210) and Pembrolizumab (KEYNOTE-052, KEYNOTE-361) IMvigor210 is a phase 2 trial that explores the single-agent treatment of atilizumab in patients with advanced urothelial cancer [16]
.

Cohort 1 of the trial included 119 newly-treated patients with advanced urothelial cancer who were not suitable for cisplatin chemotherapy
.

This year’s ESMO annual meeting announced the 5.
8-year follow-up data update for IMvigor210 cohort 1.
The total population ORR was 23.
5%, the median duration of remission was 59.
1 months, and the median DOR of PD-L1 low-expressing tumor patients was 53.
5 months (high The median DOR of expressing patients has not been reached), and the results show that atelizumab monotherapy has brought a durable response and long-term survival
.

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

The 5-year follow-up data updated at the ASCO annual meeting this year showed that compared with patients with PD-L1 combined with a positive score of <10, patients with a combined positive score of ≥10 have a higher ORR and are persistent
.

The ORR of the two groups were 47.
3% and 20.
7%, the median DOR was unreached and 21.
2 months, and the median OS was 18.
5 and 9.
7 months
.

 KEYNOTE-361 compares the first-line immune monotherapy with standard chemotherapy for advanced urothelial carcinoma [18]
.

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

 2.
Avirumumab (JAVELIN Bladder100) In recent years, a large number of studies on the first-line treatment of advanced urothelial cancer have focused on the combined use of chemotherapy and immunotherapy, but neither the IMvigor130 nor the KEYNOTE-361 studies have achieved the expected results
.

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

 This year’s ASCO annual meeting reported the results of the genomic subgroup analysis of the JAVELIN Bladder100 study [20].
The trial explored the efficacy of avirumumab for first-line maintenance treatment of patients with advanced urothelial cancer in different genomic subgroups
.

The results showed that compared with the best supportive care (BSC) group, the first-line maintenance treatment of Aviruzumab + BSC can significantly prolong the OS and PFS of patients
.

Among the genomic subgroups, in addition to the luminal subgroup, Aviluzumab + BSC can bring significant OS benefits to all cancer and tumor gene atlas (TCGA) subgroups
.

 3.
Antibody-conjugated drug enfortumab vedotin (EV-301) in the field of first-line therapy, 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 has achieved amazing efficacy in the first-line treatment of platinum intolerant populations, with an 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% (where the CR ratio was 17.
8%, and the ORR of patients with liver metastases was 17.
8%).
57.
1%)
.

EV combined with pembrolizumab can benefit patients' 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 hair loss (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 cancer after the failure of platinum-based and PD-1 monoclonal antibody immunotherapy
.

EV-301 is a stage 3 RCT that further compares EV and conventional chemotherapy in patients with advanced urothelial cancer after failure of platinum and immunotherapy [22]
.

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

The chemotherapy group received docetaxel, paclitaxel or vinflunine treatment selected by the investigator
.

The primary endpoint is OS, and secondary endpoints include PFS, overall response rate, disease control rate, and safety assessed by the investigator
.

 This year’s ASCO GU conference reported the results of the interim analysis [23]
.

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

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

Subgroup analysis showed that EV has significant advantages in multiple preset subgroups
.

The incidence of treatment-related adverse events (93.
9% vs.
91.
8%) and serious treatment-related adverse events (22.
6% vs.
23.
4%) were similar in the EV group and the chemotherapy group
.

 Figure 7.
The overall survival of the EV-301 trial
.

With the success of this clinical study, a third-line treatment pattern for advanced urothelial cancer has been formed
.

For advanced urothelial carcinoma, the standard first-line treatment is platinum-based chemotherapy.
Effective patients can choose immune maintenance therapy, and second-line immunotherapy if chemotherapy fails
.

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

 4.
Antibody-conjugated drug RC48 (RC48-C009) In the field of antibody-conjugated drugs, domestic drugs have followed up very quickly.
The RC48 antibody-conjugated drugs for patients with HER2 overexpression have proven their effectiveness and safety.
The final research data of the RC48-C009 study was reported in the ASCO annual meeting [24]
.

This study aims to explore the treatment of RC48 antibody-conjugated drugs in patients with locally advanced or metastatic urothelial cancer who have progressed after previous conventional chemotherapy (including gemcitabine, platinum, and paclitaxel) and have overexpression of HER2 (IHC 3+ or 2+) Efficacy and safety
.

The results showed that the ORR of patients treated with RC48 antibody conjugated drugs reached 46.
9%
.

The median PFS of the patients was 4.
3 months, and the OS reached 14.
8 months, and each subgroup had obvious benefits
.

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

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

 RC48 is also trying to advance to the front line treatment based on the success of the back line treatment
.

The RC48-C014 study is a phase 1b/2, open-label, researcher-initiated clinical trial [25], which aims to evaluate the efficacy and safety of RC48 combined with immunotherapy in the treatment of patients with locally advanced or metastatic urothelial cancer
.

52.
6% of the enrolled patients had not received treatment before, and 47.
4% had received ≥1 line treatment before
.

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

.

 Prospects With the advent of targeted therapy, immunotherapy and antibody-conjugated drugs, systemic treatment of urothelial cancer has progressed rapidly in recent years
.

The involvement of immunotherapy in neoadjuvant therapy has become a research hotspot in recent years, but whether tumor control can ultimately translate into patient survival benefits and whether it can provide more opportunities for bladder-saving 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 future clinical practice, especially for patients who cannot tolerate cisplatin chemotherapy, immunotherapy may become the standard treatment option in the future
.

 The treatment pattern of advanced urothelial cancer is gradually taking shape.
The first-line treatment is still platinum-based chemotherapy.
Effective patients can choose immune maintenance therapy, and second-line immunotherapy can be used if chemotherapy is ineffective
.

For patients who have failed platinum and immunotherapy, antibody-conjugated drugs 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 emergence of multi-drug combination therapy, the management of patients' adverse reactions also needs to arouse our great attention
.

 Prostate Cancer Prostate Cancer Magnetic Resonance Screening (STHLM3-MRI) Those with elevated prostate-specific antigen (PSA) should first complete the MRI examination, and then receive a puncture after a positive lesion is found on MRI.
This diagnosis and treatment process is gradually becoming clinical in major centers in China Routine diagnosis and treatment
.

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

Previously, the PRECISION study (2018)[26], Trio study (2020)[27] and PRECISE study (2021)[28] were all aimed at PSA screening populations, comparing MRI targeting + system puncture with simple system puncture Multi-center Phase 3 RCT
.

 The multi-center STHLM3-MRI study from Europe [29] published this year further confirmed the role of MRI as a further screening step for people with elevated PSA
.

The trial enrolled 1,532 participants, who were randomly assigned to the standard biopsy group or the trial biopsy group according to 3:2 (click for related reading: MRI targeted biopsy reduces overdiagnosis and treatment, and can still effectively detect prostate cancer)
.

 The test results show that the fusion puncture combined with the MRI results does not reduce the detection of clinically significant cancer (Gleason score ≥ 7 points) (21% in the standard biopsy group vs.
18% in the experimental biopsy group, non-inferiority design).
It can reduce the detection rate of clinically non-significant cancer (Gleason score equal to 6 points) (standard biopsy group 4% vs.
experimental biopsy group 12%)
.

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 the perspective of health economics, the author believes that the unnecessary diagnosis and follow-up treatment costs thus saved will exceed the cost of the MRI examination 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, the actual average PSA of the included population is only 4.
3 ng/ml, which is much lower than other trials 6.
2~6.
7ng/ml
.

This shows that this test 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 the Prostate Imaging Reporting and Data System (Prostate Imaging Reporting and Data System, PI-RADS) version 2.
0 and 2.
1, the prostate The area of ​​cancer is scored
.

The author believes that this method is shorter and more suitable for large-scale screening, but related standards need to be further promoted
.

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

Stockholm3 score is a prostate cancer screening tool developed in Europe in recent years, which combines the results of protein, gene and clinical data
.

One month after NEJM published the results of the trial, another analysis of the cohort was published in Lancet Oncol [30]
.

The research results show that for prostate cancer screening population, Stockholm3 score can better carry out risk stratification before MRI and targeted puncture; fusion of Stockholm3 score with MRI-guided targeted puncture can reduce over-diagnosis in screening population At the same time, the ability to diagnose clinically significant cancer is maintained
.

4.
The PRECISION, Trio, PRECISE and STHLM3-MRI studies all use different software for the fusion of B-ultrasound images and MRI images
.

Although this makes methodological heterogeneity between trials, as a multi-center trial, the heterogeneity within each trial is 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
.

 A new combination and new weapon for the treatment of 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 treatment methods have become more abundant after the failure of traditional endocrine therapy
.

 1.
Apataan and abiraterone mixture (ACIS) Apataan 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 can inhibit the androgen pathway to the maximum extent.
Is the effect better than that of abiraterone as a single agent? Can the indications of apatanol make another success and approach the field of mCRPC? These are all questions we look forward to answering from ACIS research [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 significant differences in imaging-based progression-free survival (rPFS) (24 months vs.
16.
6 cases) Months), but there was no significant difference in OS between the two groups (36.
2 months vs.
33.
7 months)
.

There was no significant difference in the safety results of the two groups
.

 The researchers believe that this trial is similar to the AllianceA031201 study [32] (mCRPC patients receiving enzalutamide + abiraterone or abiraterone monotherapy before chemotherapy) have similar rPFS results, but the overall safety is higher than the latter
.

Although limited by the complexity of follow-up treatment, no positive results were obtained in the final OS, but the 50% reduction rate of PSA and short-term indicators such as rPFS in the combined treatment group achieved better results
.

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

 2.
PARP inhibitor talazopril (TALAPRO-1) PARP inhibitor is the forerunner of precise treatment of prostate cancer
.

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

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

 The trial included patients with end-line mCRPC and DDR-HRR gene mutation (11 gene) positive
.

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

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

The researchers are quite optimistic about the results, believing that these results support the further phase 3 trial of talazoparib, and it can also include patients who do not carry BRCA gene mutations
.

 PARP inhibitors are the first practitioners to achieve basket trials
.

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

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

 It is worth noting that PARP inhibitors are usually accompanied by severe hematological toxicity, and the better the efficacy, the greater the toxicity
.

The use time of end-line treatment is still short, not enough to observe hematological 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 genetic mutation rate of about 10% of the HRR pathway in metastatic prostate cancer [37] makes PARP inhibitors widely available, but finding the right treatment for the right patient is a common goal pursued by 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 paid attention to
.

With the continuous exploration of the indications of PARP inhibitors, the use of HRR testing in metastatic hormone-sensitive prostate cancer and newly diagnosed prostate cancer has gradually entered the field 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 deficiency, and the prognosis is poor
.

Theoretically, in patients with mCRPC lacking PTEN, inhibiting the androgen pathway and the AKT pathway at the same time can effectively control the disease progression
.

 IPATential150 is a multi-center, randomized, double-blind, phase 3 controlled trial [38], which included 1101 patients and explored the efficacy of ipatasertib+abiraterone versus abiraterone as a single agent in mCRPC (without considering PTEN status)
.

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

In the intention-to-treat population, the median PFS of the two groups were 19.
2 months and 16.
6 months, respectively (HR, 0.
84; 95% CI, 0.
71 to 0.
99; P=0.
043; no statistical significance at the level of α=0.
01)
.

 Compared with HRR mutations, PTEN deletion is more common and there are many patients
.

This study is the first large-sample Phase 3 RCT
.

Although the test failed to obtain a statistically significant positive result, the rPFS benefit of the test group in the PTEN-deficient population was still observed
.

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

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

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

Previously, neither everolimus single agent [39] nor the combination 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
.

The similar drug capivasertib is also undergoing a similar study of CAPItello-281
.

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 treatment
.

 4.
Lutetium 177-PSMA radioligand therapy (VISION) In the past two years, radioligand therapy has sprung up 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 mCRPC patients who were screened by Gallium 68-PSMA-11PET/CT and randomly grouped according to 2:1.
The experimental group received β-particle-emitting lutetium 177-PSMA-617+ standard treatment for 4 to 6 cycles , The control group only received standard treatment (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, the PFS (8.
7 months vs.
3.
4 months) and OS (15.
3 months vs.
11.
3 months) of the experimental group were significantly prolonged
.

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

The 3VISION study provides new treatment options for patients who are ineffective with androgen pathway inhibitors and chemotherapy
.

There are still a number of clinical trials on lutetium 177-PSMA are still in progress
.

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

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

These trials will ultimately provide an accurate positioning of lutetium 177-PSMA in the treatment of metastatic prostate cancer
.

 With the advancement of technology, the radioisotopes in radioligands have also evolved from the traditional strontium 89 and radium 223 [43] to lutetium 177.
The efficacy and safety of the recently developed actinium 225-PSMA that emits alpha particles is more worthy of us.
Looking forward to [44]
.

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

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

Academic part-time jobs include the vice chairman of the third committee of the Chinese Medical Doctor Association Urology Branch, a member of the CSCO Council, the chairman of the CSCO urothelial cancer committee, the vice chairman of the CSCO prostate cancer committee, and the Chinese Anti-Cancer Association ( CACA) genitourinary oncology department Standing Committee, CACA genitourinary oncology department precise medical school committee deputy director of the Chinese Medical Association of Urology Oncology Branch members and other groups
.

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

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

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 Charlotte Hospital in Berlin, Germany
.

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

Participated in a number of global multi-center phase 2 and phase 3 prospective randomized controlled clinical studies of UC, RCC, PCa, published more than ten domestic core journal articles and SCI papers, participated in the writing of 3 urology monographs, and translated urology monographs 6 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 courses of clinical genetics and genetic counseling at the University of Manchester in the United Kingdom
.

The sixth batch of "group->
.

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

Good at diagnosis and comprehensive treatment of urinary system tumors
.

Committed to urinary system tumor-related research, he has published more than ten SCI and Chinese papers, and has repeatedly reported research results at AUA, EAU and CUA annual meetings
.

Fan Yu, Ph.
D.
, deputy chief physician of the 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 the Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong
.

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

He has repeatedly spoken in the EAU and AUA posters
.

FrontierOncology Magazine Peer reviewer
.

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

Participated in 8 national, provincial and ministerial-level projects
.

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

Participated in the compilation of 1 national-level textbook on urology, participated in the writing of 5 monographs, and participated in the translation of 7 urology monographs
.

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