In order to allow my country's clinical oncology workers to share world-class scientific research results faster and more conveniently, the Chinese Society of Clinical Oncology (CSCO) and Beijing Xisike Clinical Oncology Research Foundation will hold a conference from July 1, 2022 to On the 2nd, they co-hosted the "2022 China Clinical Oncology Annual Progress Symposium (BOC) and Best of ASCO®2022China" in Jinan, Shandong.
In this special session of Urinary System Tumors , Professor Chen Shouzhen from Qilu Hospital of Shandong University and Professor Yu Wei from Peking University First Hospital will share the exciting content of the ASCO annual meeting, and will be shared by Beijing Professor Yang Yong from University Cancer Hospital commented. Yimaitong is organized as follows for the readers’ convenience.
Urological Oncology Special Session 1: Prostate Cancer
SHR3680 combined with androgen deprivation therapy (ADT) in the treatment of high-burden metastatic hormone-sensitive prostate cancer (mHSPC)
There are approximately 1.4 million new cases of prostate cancer in the world every year, of which 375,000 patients die. In 2020, prostate cancer was the second most common cancer in men worldwide and the fifth leading cause of cancer death in men. The TITAN study and the ARCHES study confirmed that second-generation androgen receptor inhibitors (AIRS) combined with ADT have significant benefits compared with placebo combined with ADT. However, the advantages of second-generation ARIs over first-generation ARIs remain to be verified. The
CHART study evaluated the efficacy and safety of SHR3680, a novel oral ARI, versus bicalutamide in high-load mHSPC. The research design is shown in Figure 1.
Figure 1 Research design
The CHART study is closer to the characteristics of the Chinese people. The Chinese population accounts for more than 90%, and the proportion of people with high tumors is relatively high.
The latest data show that compared with bicalutamide, the SHR3680 group has a significant improvement in investigator-assessed (IRC) imaging progression-free survival (rPFS) and a 54% reduction in imaging and death risks (HR=0.46; 95 %CI 0.36-0.60; median time, not yet reached vs 23.5 months); patients' overall survival (OS) was significantly prolonged and the risk of death was reduced by 42% (HR=0.58; 95%CI 0.42-0.80; p=0.0009, see figure 2).
Figure 2 rPFS (top) and OS (bottom) results assessed by IRC
In addition, OS subgroup analysis results showed that patients with fewer visceral or bone metastases benefited better. Secondary research endpoints such as PSA progression time, bone-related event occurrence time, objective response rate (ORR), etc. all support the SHR3680 combined with ADT regimen as being better. Research shows that the quality of life of patients in the SHR3680 group is better than that of patients in the bicalutamide group (Figure 3). The incidence of any-grade adverse events (AE) was similar in both groups. The incidence rates of grade ≥3 treatment-related AEs in the SHR3680 group and bicalutamide group were 19.2% and 13.9%, respectively.
Figure 3 Assessment of the quality of life of prostate cancer patients
Professor Chen Shouzhen concluded that compared with bicalutamide combined with ADT, SHR3680 combined with ADT significantly improved rPFS and OS results in patients with high-burden mHSPC, and SHR3680 has a good safety profile. The CHART study is more in line with the characteristics of the Chinese population and may change the treatment landscape of mHSPC with high tumor burden in the future. SHR3680 has also been included in the 2022 CSCO prostate cancer guidelines for clinical reference. Comparison of OS between
177Lu-PSMA-617 (Lu-PSMA) and cabazitaxel after 3 years of median follow-up. The
study included patients with mCRPC who progressed after treatment with docetaxel. The flow chart is as follows (Figure 4), and the final enrollment was 200 patients.
Figure 4 TheraP research flow chart
The main research endpoint is PFS. The results of the study showed that Lu-PSMA significantly delayed progression (HR=0.62, 95%CI 0.45-0.85, p=0.0028), and the patient's risk of disease progression was reduced by 38%. There was no significant difference in OS results between the two groups (p=0.99), which may be due to cross-treatment after the patients left the group, which affected the results. In addition, patients who were unable to be enrolled due to PSMA/FDG-PET ineligibility had worse OS and PFS results than those who were enrolled.
Figure 5 PFS results of TheraP study
Professor Chen commented that this study is a prospective, randomized controlled, multi-center study with a follow-up time of 3 years. The results of the study showed that Lu-PSMA had therapeutic advantages compared with the control group. However, this study also has limitations: there is crossover between the two groups of patients, which may affect the OS results, and OS is not valid as a secondary research endpoint.Overall, the TheraP study data supports the choice of Lu-PSMA over cabazitaxel for the treatment of PSMA-positive CRPC patients who have progressed after treatment with docetaxel and ARIs. Lu-PSMA has a higher PSA response rate and greater PFS benefit. The survival benefit was similar to that of cabazitaxel with greater benefit in quality of life, higher safety profile, and a more patient-friendly dosing schedule. And the study found that patients with low PSMA expression or discordant disease had a much shorter survival time excluded by PSMA/FDG-PET.
Intermediate clinical endpoint (ICE) as a potential surrogate marker for OS in male patients with mHSCP
OS is the gold standard for clinical endpoints in oncology trials, but it takes nearly 10 years for mHSPC clinical trials with OS as the primary endpoint to obtain results. The researchers hypothesized that radiographic progression-free survival (rPFS) and clinical progression-free survival (cPFS) could be used as effective surrogate markers for OS in patients with mHSPC and were verified. The research uses a two-stage meta analysis verification model for analysis. The research design is shown in Figure 6.
Figure 6 Research design The
study ultimately included 8592 patients. The study found that the R2 of rPFS and cPFS were both 0.78, and the Kendall's Tau coefficients were 0.83 (95%CI 0.82-0.84) and 0.84 (955CI 0.83-0.85) respectively, indicating strong correlation.
Figure 7 There is a correlation between ICE and OS
Subsequently, the study verified that the treatment effect measured by rPFS/cPFS and OS was correlated. The data shows that the R2 of rPFS and cPFS are both 0.81, with good correlation.
Figure 8 The treatment effects measured by ICE and OS are correlated
Professor Chen concluded that this study has a large number of cases (more than 8500 cases), and the analysis parameters based on single case data are more accurate and can conduct subgroup analysis; however, the trials included in the study The time span is long, and other trials before the CHAARTED trial did not collect disease burden and transfer time, which has certain limitations. Overall, the study validated rPFS and cPFS as valid surrogate endpoints for OS in mHSCP.
Urological tumors special session 2: Renal cancer and urothelial cancer
Everolimus for postoperative adjuvant treatment of renal cancer
Radical surgery is the standard treatment plan for patients with localized or locally advanced renal cancer. About 1/3 of renal cancer patients experience postoperative recurrence, and simple postoperative follow-up is the standard choice for these patients. Since 2006, there have been studies exploring the clinical research of a new generation of targeted drugs for adjuvant treatment after renal cancer surgery. The SWOG S0931-EVEREST study is a phase III clinical study exploring the use of everolimus as adjuvant treatment for postoperative renal cancer. A total of 1545 patients were included in the study, with a median follow-up time of 76 months. The primary endpoint of
is recurrence-free survival (RFS), defined as the time from randomization to first official recurrence/metastasis or death from any cause. Secondary study endpoints are OS, toxicity, analysis of biobank, and the relationship between different everolimus plasma concentrations and AEs at steady state.
Figure 9 Research design
The incidence rate of any AE in the everolimus group was 96% (the incidence rate of grade 3 or above was 46%). The main AE was oral mucositis, the incidence rate was 64% (the incidence rate of grade 3 or above was 14%). .
In the overall population, the 5-year RFS rates of everolimus and placebo groups were 67% and 63% respectively (HR=0.85, 95%CI 0.72-1.00, p1-side=0.025), which did not reach the preset statistics. The scientific significance p value was 0.022, and the primary observation endpoint was not reached.
Figure 10 RFS results
Among very high-risk patients, the 5-year RFS rates in the everolimus and placebo groups were 57% and 51%, respectively (HR=0.79, 95%CI 0.65-0.97, p1-side=0.011); medium Among high-risk patients, the 5-year RFS rates of everolimus and placebo groups were 80% and 78% respectively (HR=0.99, 95%CI 0.73-1.35, p1-side=0.48), indicating that some patients can benefit from everolimus. benefit from adjuvant therapy.
Figure 11 RFS based on risk stratification
Professor Yu Wei concluded that adjuvant therapy with everolimus improved postoperative RFS in patients with renal cancer, but did not reach the significance level. Everolimus has significant therapeutic value for extremely high-risk groups, but patients taking the drug have a high discontinuation rate.
Analysis of pembrolizumab combined with axitinib first-line treatment of advanced clear cell renal cell carcinoma (ccRCC) after subsequent treatment progress
Targeted combination immunity has been widely validated as a first-line treatment for metastatic renal cancer. However, how to choose the subsequent line of treatment is a hot issue of clinical concern.The
KEYNOTE-426 study confirmed that compared with sunitinib, pembrolizumab combined with axitinib in the first-line treatment of ccRCC significantly improved patients' OS, PFS and ORR. At this ASCO meeting, researchers announced the tumor control effect of subsequent treatment. The research design is shown in Figure 12.
Figure 12 Research design
Figure 13 Follow-up treatment
Data show that in the pembrolizumab combined with axitinib group, the median PFS2 was 40.1 months (95% CI 34.9-43.8 months), and in the sunitinib group The median PFS2 was 27.7 months (95% CI 23.1-29.9 months), HR=0.63 (95% CI 0.53-0.75), and the risk was reduced by 37% (Figure 14). The PFS2 results of the two groups of patients based on IMDC stratification were similar, with HR=0.68 (95%CI 0.47-0.98) in the IMDC low-risk group and HR=0.62 (95%CI 0.51-0.76 in the IMDC intermediate- and high-risk group, Figure 15).
Figure 14 PFS in the intention-to-treat population (ITT)2
Figure 15 PFS2 based on IMDC stratification (A: low risk; B: intermediate and high risk)
Based on the above data, Professor Yu concluded that the long-term study results of Keynote-426 support Paboli Tizumab combined with axitinib is the standard treatment for patients with advanced, previously untreated clear cell renal cell carcinoma . Data show that the PFS2 of patients in the pembrolizumab combined with axitinib group was significantly increased compared with the sunitinib group, and it was not related to the IMDC risk factor stratification status.
Long-term follow-up results of Enfortumab Vedotin (EV) compared with chemotherapy in patients with previously treated advanced urothelial cancer
The primary endpoint of EV-301 is OS; the secondary endpoints are PFS, safety and tolerability.
Figure 16 EV-301 study design
After a follow-up time of 23.75 months, compared with the chemotherapy group, the median OS of the EV group was significantly longer by 3.97 months (12.91 months vs. 8.94 months; HR=0.704, 95%CI 0.581- 0.852, one-sided p=0.00015). Compared with the chemotherapy group (median PFS 3.71 months), the PFS of the EV group (median PFS 5.55 months) was also significantly improved (HR=0.632, 95%CI 0.525-0.762, one-sided p<0.00001).>
Figure 17 Analysis of OS and PFS results of the two groups
The clinical response rate data evaluated by IRC showed that the ORR in the EV group was 41.3% (6.9% was complete response) and the chemotherapy group was 18.6% (p<0.001);>
Figure 18 IRC-assessed clinical response rate
The incidence of treatment-related adverse events (TRAEs; 93.9% vs 91.8%) and serious TRAEs (22.6% vs 23.4%) was similar in the EV group and the chemotherapy group. The incidence of grade ≥3 TRAEs was 50% in both groups.
Professor Yu commented that the efficacy data obtained by comparing EV with chemotherapy confirmed that it has clinical significance and significant survival benefit (improving PFS and ORR) for advanced urothelial cancer, and EV has good safety profile.
Expert comments
After the report, Professor Yang Yong from Peking University Cancer Hospital commented on the above content. Professor Yang pointed out that the TheraP study showed that compared with cabazitaxel, Lu-PSMA has better PFS results but no significant difference in OS. In the second-line chemotherapy of prostate cancer, radionuclide treatment of may have more advantages. In addition, Professor Yang mentioned that the subgroup analysis results of the CHART study showed that patients with visceral metastasis did not benefit from OS, which was a bit regrettable. This is also a common problem of many anti-androgen drugs. Regarding the setting of efficacy indicators in clinical trials of mHSPC, Professor Yang commented that rPFS and cPFS can replace OS and solve the difficulties of clinical research to a certain extent; while the treatment of mCRPC has not yet achieved a breakthrough, OS can still be used as an efficacy evaluation indicator for mCRPC patients. .
Regarding the content of renal cancer and urothelial cancer, Professor Yang commented that in terms of results, everolimus became the third adjuvant treatment drug for renal cancer to obtain positive results. The results of subgroup analysis showed that patients with very high-risk renal cancer had greater benefit from RFS, which deserves attention. Studies related to adjuvant therapy after renal cancer surgery all show benefit in RFS. The benefit in OS needs further follow-up, and we need to look forward to the emergence of more effective drugs or combined adjuvant therapy (such as everolimus combined with pembrolizumab). In addition, regarding the relevant data of the KEYNOTE-426 study, Professor Yang pointed out that the first-line treatment option is axitinib combined with pembrolizumab (which is more effective than sunitinib). Once it progresses, no matter what subsequent treatment regimen is chosen (immune checkpoint inhibitors, other TKI drugs or others), were better than the previous sunitinib monotherapy group.Finally, Professor Yang made comments on EV-301 research. EV is currently a guideline-recommended regimen for second-line treatment of metastatic urothelial cancer. Combined with the OS and PFS results of this study, EV may be the drug of choice for second-line treatment.
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