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A few days ago, the EAU guidelines added treatment recommendations: Pembrolizumab is recommended for the adjuvant treatment of high-risk (according to the study definition) operable clear cell renal cell carcinoma (ccRCC)
.
Immune checkpoint inhibitors (ICI) treat malignant tumors, aiming to restore and enhance the body's immune response to tumor cells
.
Current research shows that immunotherapy has shown impressive efficacy in advanced renal cell carcinoma (RCC)
.
There are a number of phase III randomized trials on immune adjuvant therapy in progress, and the KEYNOTE-564 study reported the results for the first time
.
A meta-analysis of adjuvant therapy with VEGFR inhibitors showed that VEGFR inhibitors have no clear disease-free survival (DFS) and overall survival (OS) benefits
.
The EAU guidelines do not recommend, and the European Medicines Agency (EMA) has not approved VEGFR inhibitors for adjuvant treatment of renal cancer
.
Pembrolizumab adjuvant therapy for high-risk RCC Phase III KEYNOTE-564 study is the first immunoadjuvant therapy study to show a positive DFS result (primary endpoint) in the area of adjuvant therapy for renal cancer
.
The study evaluated pembrolizumab vs placebo for 999 cases of intermediate risk (pT2, grade 4 or sarcomatoid differentiation, N0 M0; or pT3, any grade, N0, M0) or high risk (pT4, any grade, N0 M0; or any pT, any grade, or N + M0) or M1 NED (primary tumor + soft tissue metastasis without evidence of lesion within 1 year)
.
The results showed that at a median follow-up of 24.
1 months, compared with placebo, pembrolizumab significantly prolonged the patient's DFS (investigator's assessment) (HR=0.
68, P=0.
001)
.
The estimated 2-year DFS rates for pembrolizumab and placebo groups are 77% and 68%, respectively
.
All subgroups showed benefit from DFS, including patients with M1 NED after surgery (n = 58 [6%])
.
The pembrolizumab group showed a non-statistically significant OS benefit trend (HR=0.
54, 95% CI 0.
30-0.
96, P=0.
0164)
.
Due to the short follow-up time, OS events were rare, and the 2-year OS rates of the pembrolizumab group and placebo group were 97% and 94%, respectively
.
32% and 18% of patients in the pembrolizumab group and placebo group had grade 3 to 5 all-cause adverse events, respectively
.
After using the modified GRADE method to assess the quality of evidence and the strength of the recommendation, the EAU RCC guideline expert group reached a consensus and recommended (weak): Pembrolizumab is recommended for the adjuvant treatment of high-risk (according to the study definition) operable ccRCC patients (at least the final OS After the data is available)
.
The EAU guidelines have not previously recommended sunitinib for adjuvant therapy (positive DFS result), but the expert group still recommends adjuvant pembrolizumab
.
The reasons are as follows: 1.
Immune checkpoint inhibitors and VEGFR tyrosine kinase inhibitors (TKI) have different mechanisms of action.
Immune checkpoint inhibitors can show 16% completeness in metastatic patients who are not selected for PD-1.
Remission rate
.
2.
Although OS data is immature (early OS trends are mainly caused by M1 population factors), the expert group cannot rule out that the research results will show OS benefits
.
This is not the case with the STRAC study on adjuvant sunitinib therapy
.
3.
Compared with sunitinib, pembrolizumab is better tolerated
.
Compared with placebo, pembrolizumab does not cause a decrease in the quality of life
.
4.
Multiple studies on adjuvant treatment of VEGFR inhibitors failed to show the DFS benefit of sunitinib or other VEGFR inhibitors, resulting in negative results in the Meta analysis
.
The expert group considered the following precautions and therefore gave weak recommendations for treatment: 1.
A large part of the patients cured by surgery may receive unnecessary or harmful treatments
.
2.
Pembrolizumab is well tolerated, but grades 3 to 5 adverse events were 14.
7% higher than the placebo group (32.
4% vs 17.
7%)
.
About 18% of patients need to stop treatment early due to adverse events
.
Endocrine-related adverse events may require life-long treatment
.
3.
The results of other immune checkpoint inhibitor studies have not yet been published and cannot be used for meta-analysis
.
4.
Biomarker analysis cannot be used to predict outcomes and adverse events
.
5.
The final OS result is still unavailable
.
Metastasis resection and subsequent systemic treatment of M1 NED patients are based on the original design.
The expert group believes that the trial needs to be evaluated, including a small number of patients undergoing complete metastasis resection (6% in the trial group and 6 in the placebo group %)
.
In the KEYNOTE-564 study, patients in the M1 NED cohort underwent metastasis resection within 1 year after initial diagnosis
.
The metachronous time interval of recurrence after curative surgery <1 year is a poor prognostic factor, and immune combined systemic therapy is better than surgery in advanced patients
.
In addition, TKI-type adjuvant therapy studies have shown that adjuvant therapy after metastasis resection does not show DFS or OS benefit
.
The results of adjuvant pembrolizumab after surgery have therefore become difficult to interpret (due to this small subgroup)
.
Although the DFS HR is 0.
29, it supports the use of pembrolizumab after resection of M1 patients to NED, and patients with subclinical lesions after resection of metastases, but patients with advanced disease can benefit from pembrolizumab adjuvant systemic therapy
.
However, based on the current data, no conclusion can be drawn: for patients with oligoprogressive disease, metastasis resection plus follow-up adjuvant pembrolizumab treatment within 1 year of initial diagnosis is better than observation and first-line dual immunotherapy after progression
.
Research data in the TKI era shows that the median time of observation of patients with recurrence of metastatic disease is up to 16 months before systemic treatment is required, and this practice is common in the real world (30%)
.
In addition, compared with systemic therapy, metastatic resection may lead to a worse prognosis, because recurrence within 12 months, while (oligo) metastatic disease can be classified as the International Metastatic Renal Cell Carcinoma Joint Database (IMDC) intermediate risk Group
.
Therefore, the expert group does not encourage this group of people to undergo metastatic resection + adjuvant therapy within 1 year after the initial surgery
.
The disease state should be carefully and carefully evaluated to exclude patients with rapid progress
.
Other research data included in M1 NED immunoadjuvant therapy (including IMmotion010) will further explain the problem
.
References: J.
Bedke, L.
Albiges, U.
Capitanio et al.
, 2021 Updated European Association of Urology Guidelines on the Use of AdjuvantPembrolizumab for Renal Cell Carcinoma, Eur Urol (2021), https://doi.
org/10.
1016 /j.
eururo.
2021.
11.
022
.
Immune checkpoint inhibitors (ICI) treat malignant tumors, aiming to restore and enhance the body's immune response to tumor cells
.
Current research shows that immunotherapy has shown impressive efficacy in advanced renal cell carcinoma (RCC)
.
There are a number of phase III randomized trials on immune adjuvant therapy in progress, and the KEYNOTE-564 study reported the results for the first time
.
A meta-analysis of adjuvant therapy with VEGFR inhibitors showed that VEGFR inhibitors have no clear disease-free survival (DFS) and overall survival (OS) benefits
.
The EAU guidelines do not recommend, and the European Medicines Agency (EMA) has not approved VEGFR inhibitors for adjuvant treatment of renal cancer
.
Pembrolizumab adjuvant therapy for high-risk RCC Phase III KEYNOTE-564 study is the first immunoadjuvant therapy study to show a positive DFS result (primary endpoint) in the area of adjuvant therapy for renal cancer
.
The study evaluated pembrolizumab vs placebo for 999 cases of intermediate risk (pT2, grade 4 or sarcomatoid differentiation, N0 M0; or pT3, any grade, N0, M0) or high risk (pT4, any grade, N0 M0; or any pT, any grade, or N + M0) or M1 NED (primary tumor + soft tissue metastasis without evidence of lesion within 1 year)
.
The results showed that at a median follow-up of 24.
1 months, compared with placebo, pembrolizumab significantly prolonged the patient's DFS (investigator's assessment) (HR=0.
68, P=0.
001)
.
The estimated 2-year DFS rates for pembrolizumab and placebo groups are 77% and 68%, respectively
.
All subgroups showed benefit from DFS, including patients with M1 NED after surgery (n = 58 [6%])
.
The pembrolizumab group showed a non-statistically significant OS benefit trend (HR=0.
54, 95% CI 0.
30-0.
96, P=0.
0164)
.
Due to the short follow-up time, OS events were rare, and the 2-year OS rates of the pembrolizumab group and placebo group were 97% and 94%, respectively
.
32% and 18% of patients in the pembrolizumab group and placebo group had grade 3 to 5 all-cause adverse events, respectively
.
After using the modified GRADE method to assess the quality of evidence and the strength of the recommendation, the EAU RCC guideline expert group reached a consensus and recommended (weak): Pembrolizumab is recommended for the adjuvant treatment of high-risk (according to the study definition) operable ccRCC patients (at least the final OS After the data is available)
.
The EAU guidelines have not previously recommended sunitinib for adjuvant therapy (positive DFS result), but the expert group still recommends adjuvant pembrolizumab
.
The reasons are as follows: 1.
Immune checkpoint inhibitors and VEGFR tyrosine kinase inhibitors (TKI) have different mechanisms of action.
Immune checkpoint inhibitors can show 16% completeness in metastatic patients who are not selected for PD-1.
Remission rate
.
2.
Although OS data is immature (early OS trends are mainly caused by M1 population factors), the expert group cannot rule out that the research results will show OS benefits
.
This is not the case with the STRAC study on adjuvant sunitinib therapy
.
3.
Compared with sunitinib, pembrolizumab is better tolerated
.
Compared with placebo, pembrolizumab does not cause a decrease in the quality of life
.
4.
Multiple studies on adjuvant treatment of VEGFR inhibitors failed to show the DFS benefit of sunitinib or other VEGFR inhibitors, resulting in negative results in the Meta analysis
.
The expert group considered the following precautions and therefore gave weak recommendations for treatment: 1.
A large part of the patients cured by surgery may receive unnecessary or harmful treatments
.
2.
Pembrolizumab is well tolerated, but grades 3 to 5 adverse events were 14.
7% higher than the placebo group (32.
4% vs 17.
7%)
.
About 18% of patients need to stop treatment early due to adverse events
.
Endocrine-related adverse events may require life-long treatment
.
3.
The results of other immune checkpoint inhibitor studies have not yet been published and cannot be used for meta-analysis
.
4.
Biomarker analysis cannot be used to predict outcomes and adverse events
.
5.
The final OS result is still unavailable
.
Metastasis resection and subsequent systemic treatment of M1 NED patients are based on the original design.
The expert group believes that the trial needs to be evaluated, including a small number of patients undergoing complete metastasis resection (6% in the trial group and 6 in the placebo group %)
.
In the KEYNOTE-564 study, patients in the M1 NED cohort underwent metastasis resection within 1 year after initial diagnosis
.
The metachronous time interval of recurrence after curative surgery <1 year is a poor prognostic factor, and immune combined systemic therapy is better than surgery in advanced patients
.
In addition, TKI-type adjuvant therapy studies have shown that adjuvant therapy after metastasis resection does not show DFS or OS benefit
.
The results of adjuvant pembrolizumab after surgery have therefore become difficult to interpret (due to this small subgroup)
.
Although the DFS HR is 0.
29, it supports the use of pembrolizumab after resection of M1 patients to NED, and patients with subclinical lesions after resection of metastases, but patients with advanced disease can benefit from pembrolizumab adjuvant systemic therapy
.
However, based on the current data, no conclusion can be drawn: for patients with oligoprogressive disease, metastasis resection plus follow-up adjuvant pembrolizumab treatment within 1 year of initial diagnosis is better than observation and first-line dual immunotherapy after progression
.
Research data in the TKI era shows that the median time of observation of patients with recurrence of metastatic disease is up to 16 months before systemic treatment is required, and this practice is common in the real world (30%)
.
In addition, compared with systemic therapy, metastatic resection may lead to a worse prognosis, because recurrence within 12 months, while (oligo) metastatic disease can be classified as the International Metastatic Renal Cell Carcinoma Joint Database (IMDC) intermediate risk Group
.
Therefore, the expert group does not encourage this group of people to undergo metastatic resection + adjuvant therapy within 1 year after the initial surgery
.
The disease state should be carefully and carefully evaluated to exclude patients with rapid progress
.
Other research data included in M1 NED immunoadjuvant therapy (including IMmotion010) will further explain the problem
.
References: J.
Bedke, L.
Albiges, U.
Capitanio et al.
, 2021 Updated European Association of Urology Guidelines on the Use of AdjuvantPembrolizumab for Renal Cell Carcinoma, Eur Urol (2021), https://doi.
org/10.
1016 /j.
eururo.
2021.
11.
022
