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The POLARIS-03 study is a multi-center, single-arm, open-label Phase II study (NCT 03113266) carried out by the team of Professor Guo Jun and Professor Sheng Xinan from Peking University Cancer Hospital.
Safety and efficacy of locally advanced or metastatic urothelial carcinoma (mUC) patients after tolerance or failure
.
The results of the study were published in Clinical Cancer Research a few days ago
.
Research background The prognosis of mUC patients is poor.
The median overall survival (OS) is 15 months, and the 5-year survival rate is about 18%.
Platinum-based chemotherapy is still the first-line standard treatment for mUC
.
About 50% of patients respond to platinum-containing therapy, but the response time is short, and the progression-free survival (PFS) is short (7 to 8 months), and the effective rate of second-line single-agent chemotherapy is about 10%
.
At present, there are 6 immune checkpoint inhibitors (pembrolizumab, nivolizumab, atilizumab, duvalizumab, aviruzumab and tislelizumab ) Approved for second-line treatment of mUC
.
In the unselected population, the objective response rate (ORR) of immunotherapy is 15%~21%, and in the PD-L1+ positive population, the ORR is 24%~28%
.
The phase III KEYNOTE-045 study showed that immunotherapy compared with chemotherapy can significantly prolong the overall survival (OS) of patients
.
The indications for second-line treatment of mUC were withdrawn due to the failure of phase III studies of atilizumab and duvalizumab
.
Teriprizumab is a humanized IgG4 monoclonal antibody targeting PD-1.
It was approved in 2018 and 2021 for the second-line treatment of melanoma and the third-line treatment of recurrent or metastatic nasopharyngeal carcinoma, respectively.
Listed in China
.
The phase I study showed that tereprizumab showed better safety and anti-tumor activity in treated patients with mUC
.
Research methods The study included patients with locally advanced or mUC who were pathologically confirmed by the progression of systemic chemotherapy over 18 years of age
.
The enrolled patients had at least one measurable lesion at baseline, an ECOG PS score of 0 or 1, and good organ and bone marrow function
.
Exclude patients with a history of autoimmune diseases or who have previously received PD-1/PD-L1 immunotherapy
.
The enrolled patients received teriprizumab treatment (3mg/kg Q2W) until the disease progressed or an intolerable toxic reaction occurred or the study was withdrawn
.
The primary endpoint was safety and ORR as assessed by the Independent Review Committee (IRC)
.
Main results From June 2017 to September 2019, the study included 151 patients from 15 centers
.
At the time of enrollment, 87% of patients had visceral metastases
.
In 47% and 52% of patients, the primary tumor was the upper urinary tract and lower urinary tract, respectively
.
48 patients (32%) had positive expression of PD-L1
.
All patients had previously received systemic chemotherapy, of which 143 (95%) patients had received platinum-containing chemotherapy, and 8 patients (5%) had received non-platinum therapy
.
As of September 8, 2020, the median dose of teriprizumab received by patients was 8 (range: 1 to 66 doses).
At a median follow-up of 10.
5 months, compared with other immune checkpoint inhibitors, there was no A new security incident was discovered
.
Treatment-related adverse events occurred in 85% of patients (Table 1)
.
Adverse events of particular concern include 15 (10%) cases of hypothyroidism, 12 (8%) cases of hyperthyroidism, 4 (3%) cases of liver dysfunction, 2 (1%) cases of interstitial lung disease, 2 (1%) cases of adrenal insufficiency, autoimmune hepatitis, liver injury, myositis (grade 3) and myocarditis (grade 1) each (1%)
.
Table treatment-related adverse events (TRAE) anti-tumor activity As of September 8, 2020, 54% of patients died, 9% of patients were still receiving treatment, 37% of patients had stopped treatment, and the median duration of treatment was 3.
3 months.
In the ITT population, 2 patients achieved complete remission (CR), 37 patients achieved partial remission (PR), 29 patients had stable disease (SD), confirmed ORR was 26%, and disease control rate (DCR) was 45% (Picture 1)
.
Figure 1 The largest change in target lesions from baseline.
The ORR of patients who progressed on platinum therapy was 27%.
The ORR of patients with the upper urinary tract and lower urinary tract where the tumor originated was similar, 27% and 24%, respectively.
The median response was sustained The time to remission (DOR) was 19.
7 months, and the median time to remission was 1.
8 months
.
The median PFS and median OS of the ITT population were 2.
3 months and 14.
4 months, respectively
.
The investigator's assessment is similar to the clinical efficacy assessed by the IRC (Table 2)
.
Table 2 Clinical efficacy PD-L1 expression analysis evaluated by IRC and investigators.
Biopsy samples were collected from all patients.
PD-L1 immunohistochemical staining showed that 32% and 64% of patients were PD-L1 positive and PD-L1 negative, respectively
.
Compared with PD-L1 negative patients, PD-L1 positive (tumor cell [TC]≥1%) patients had higher ORR (41.
7% vs 16.
7%, P=0.
002, Figure 2) and longer PFS (3.
7 months) vs 1.
8 months, P=0.
001); Compared with PD-L1 negative patients, PD-L1 positive patients had a longer median OS (35.
6 months vs 11.
2 months), but there was no statistical difference
.
Figure 2 ORR gene mutation profile and tumor mutation burden (TMB) analysis of patients with different PD-L1/TMB levels.
Whole exome sequencing shows that the most common mutations include TP53 (58%), TERT (51%), KMT2D (40%) ), CDKN2A (24%), CDKN2B (21%), KDM2A (20%), ERBB2 (17%), MTAP (17%), ARID1A (15%), CCND1 (15%), FGF19 (14%), PIK3CA (14%), FGF4 (13%), FGF3 (13%), FGFR3 (13%), CREBBP (13%), E2F3 (12%), KMT2C (12%), NOTCH1 (11%), ATM1 ( 10%) and NECTIN4 (9%)
.
The median TMB is 4.
1 mut/Mb
.
Taking 10 mut/Mb as the cutoff value, compared with patients with low TMB (22%), patients with high TMB (48%) responded better to teriprizumab (P=0.
014, Figure 2).
The median PFS (12.
9 months vs 1.
8 months, P<0.
001) (Figure 3) and the median OS (not reached and 10.
0 months, P<0.
018) were longer (Figure 4)
.
Figure 3 PFS of patients with high TMB/low TMB Figure 4 Conclusions of OS in patients with high TMB/low TMB Teriprizumab shows good anti-tumor activity and controllable safety in mUC
.
In this study, PD-L1 expression and TMB levels can be used as independent predictive biomarkers for mUC treatment
.
References: Safety, Efficacy and Biomarker Analysis of Toripalimab in Patients with Previously Treated Advanced Urothelial Carcinoma: Results from a Multicenter Phase II Trial POLARIS-03.
OnlineFirst on November 5, 2021; DOI: 10.
1158/1078-0432.
CCR-21- 2210
Safety and efficacy of locally advanced or metastatic urothelial carcinoma (mUC) patients after tolerance or failure
.
The results of the study were published in Clinical Cancer Research a few days ago
.
Research background The prognosis of mUC patients is poor.
The median overall survival (OS) is 15 months, and the 5-year survival rate is about 18%.
Platinum-based chemotherapy is still the first-line standard treatment for mUC
.
About 50% of patients respond to platinum-containing therapy, but the response time is short, and the progression-free survival (PFS) is short (7 to 8 months), and the effective rate of second-line single-agent chemotherapy is about 10%
.
At present, there are 6 immune checkpoint inhibitors (pembrolizumab, nivolizumab, atilizumab, duvalizumab, aviruzumab and tislelizumab ) Approved for second-line treatment of mUC
.
In the unselected population, the objective response rate (ORR) of immunotherapy is 15%~21%, and in the PD-L1+ positive population, the ORR is 24%~28%
.
The phase III KEYNOTE-045 study showed that immunotherapy compared with chemotherapy can significantly prolong the overall survival (OS) of patients
.
The indications for second-line treatment of mUC were withdrawn due to the failure of phase III studies of atilizumab and duvalizumab
.
Teriprizumab is a humanized IgG4 monoclonal antibody targeting PD-1.
It was approved in 2018 and 2021 for the second-line treatment of melanoma and the third-line treatment of recurrent or metastatic nasopharyngeal carcinoma, respectively.
Listed in China
.
The phase I study showed that tereprizumab showed better safety and anti-tumor activity in treated patients with mUC
.
Research methods The study included patients with locally advanced or mUC who were pathologically confirmed by the progression of systemic chemotherapy over 18 years of age
.
The enrolled patients had at least one measurable lesion at baseline, an ECOG PS score of 0 or 1, and good organ and bone marrow function
.
Exclude patients with a history of autoimmune diseases or who have previously received PD-1/PD-L1 immunotherapy
.
The enrolled patients received teriprizumab treatment (3mg/kg Q2W) until the disease progressed or an intolerable toxic reaction occurred or the study was withdrawn
.
The primary endpoint was safety and ORR as assessed by the Independent Review Committee (IRC)
.
Main results From June 2017 to September 2019, the study included 151 patients from 15 centers
.
At the time of enrollment, 87% of patients had visceral metastases
.
In 47% and 52% of patients, the primary tumor was the upper urinary tract and lower urinary tract, respectively
.
48 patients (32%) had positive expression of PD-L1
.
All patients had previously received systemic chemotherapy, of which 143 (95%) patients had received platinum-containing chemotherapy, and 8 patients (5%) had received non-platinum therapy
.
As of September 8, 2020, the median dose of teriprizumab received by patients was 8 (range: 1 to 66 doses).
At a median follow-up of 10.
5 months, compared with other immune checkpoint inhibitors, there was no A new security incident was discovered
.
Treatment-related adverse events occurred in 85% of patients (Table 1)
.
Adverse events of particular concern include 15 (10%) cases of hypothyroidism, 12 (8%) cases of hyperthyroidism, 4 (3%) cases of liver dysfunction, 2 (1%) cases of interstitial lung disease, 2 (1%) cases of adrenal insufficiency, autoimmune hepatitis, liver injury, myositis (grade 3) and myocarditis (grade 1) each (1%)
.
Table treatment-related adverse events (TRAE) anti-tumor activity As of September 8, 2020, 54% of patients died, 9% of patients were still receiving treatment, 37% of patients had stopped treatment, and the median duration of treatment was 3.
3 months.
In the ITT population, 2 patients achieved complete remission (CR), 37 patients achieved partial remission (PR), 29 patients had stable disease (SD), confirmed ORR was 26%, and disease control rate (DCR) was 45% (Picture 1)
.
Figure 1 The largest change in target lesions from baseline.
The ORR of patients who progressed on platinum therapy was 27%.
The ORR of patients with the upper urinary tract and lower urinary tract where the tumor originated was similar, 27% and 24%, respectively.
The median response was sustained The time to remission (DOR) was 19.
7 months, and the median time to remission was 1.
8 months
.
The median PFS and median OS of the ITT population were 2.
3 months and 14.
4 months, respectively
.
The investigator's assessment is similar to the clinical efficacy assessed by the IRC (Table 2)
.
Table 2 Clinical efficacy PD-L1 expression analysis evaluated by IRC and investigators.
Biopsy samples were collected from all patients.
PD-L1 immunohistochemical staining showed that 32% and 64% of patients were PD-L1 positive and PD-L1 negative, respectively
.
Compared with PD-L1 negative patients, PD-L1 positive (tumor cell [TC]≥1%) patients had higher ORR (41.
7% vs 16.
7%, P=0.
002, Figure 2) and longer PFS (3.
7 months) vs 1.
8 months, P=0.
001); Compared with PD-L1 negative patients, PD-L1 positive patients had a longer median OS (35.
6 months vs 11.
2 months), but there was no statistical difference
.
Figure 2 ORR gene mutation profile and tumor mutation burden (TMB) analysis of patients with different PD-L1/TMB levels.
Whole exome sequencing shows that the most common mutations include TP53 (58%), TERT (51%), KMT2D (40%) ), CDKN2A (24%), CDKN2B (21%), KDM2A (20%), ERBB2 (17%), MTAP (17%), ARID1A (15%), CCND1 (15%), FGF19 (14%), PIK3CA (14%), FGF4 (13%), FGF3 (13%), FGFR3 (13%), CREBBP (13%), E2F3 (12%), KMT2C (12%), NOTCH1 (11%), ATM1 ( 10%) and NECTIN4 (9%)
.
The median TMB is 4.
1 mut/Mb
.
Taking 10 mut/Mb as the cutoff value, compared with patients with low TMB (22%), patients with high TMB (48%) responded better to teriprizumab (P=0.
014, Figure 2).
The median PFS (12.
9 months vs 1.
8 months, P<0.
001) (Figure 3) and the median OS (not reached and 10.
0 months, P<0.
018) were longer (Figure 4)
.
Figure 3 PFS of patients with high TMB/low TMB Figure 4 Conclusions of OS in patients with high TMB/low TMB Teriprizumab shows good anti-tumor activity and controllable safety in mUC
.
In this study, PD-L1 expression and TMB levels can be used as independent predictive biomarkers for mUC treatment
.
References: Safety, Efficacy and Biomarker Analysis of Toripalimab in Patients with Previously Treated Advanced Urothelial Carcinoma: Results from a Multicenter Phase II Trial POLARIS-03.
OnlineFirst on November 5, 2021; DOI: 10.
1158/1078-0432.
CCR-21- 2210
