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The treatment of advanced urothelial carcinoma (mUC) has achieved breakthroughs in recent years.
Immunotherapy, targeted therapy and antibody-conjugated drugs have been successful.
In particular, immune checkpoint inhibitors and antibody-conjugated drugs may change the current status of treatment.
This year's ASCO-GU conferences are still heavyweights, focusing on clinical practice and solving many clinical concerns.
This article sorts out these issues for readers.
Author: Zhou Li Sheng Xinan a Peking University Cancer Hospital, platinum-based first-line in patients who can not tolerate a second-line treatment option for advanced urothelial cancer treatment based on the traditional platinum-based chemotherapy, with the breakthrough immunotherapy, chemotherapy and immunotherapy It has become a plan for many first-line clinical researches in recent years.
However, several randomized controlled phase 3 clinical studies have not been successful, which means that the first-line treatment of advanced urothelial cancer is still platinum-based chemotherapy; and for people who cannot tolerate platinum, immunotherapy can be used as the first-line Treatment options.
IMvigor130 is a comparison of the first-line treatment efficacy of atilizumab combined with gemcitabine + platinum chemotherapy (group A), atilizumab single agent (group B) and gemcitabine + platinum chemotherapy (group C) in mUC Phase 3 clinical study.
This meeting reported the results of the stratification of atezizumab single agent (group B) and chemotherapy (group C) based on PD-L1 expression, in which PD-L1 positive is defined as the application of VENTANA SP142 immunohistochemical staining as IC2 /3, that is, tumor cell PD-L1 expression is ≥5%.
In the PD-L1 high expression group, the overall survival (OS) of atilizumab monotherapy was prolonged compared with chemotherapy, but it did not reach a significant difference (17.
8 months for comparison, HR 0.
68 [0.
43-1.
08]) ; But further limiting the population to patients who are intolerant to cisplatin can significantly improve OS (18.
6 months vs.
10.
0 months, HR 0.
53 [0.
30-0.
994]). OS based on PD-L1 expression stratification.
From the updated data of this study, it is again confirmed that for advanced urothelial cancer, compared with chemotherapy, even patients with positive PD-L1 expression, if they can tolerate platinum For similar treatments, atelizumab alone is not a routine recommendation; only patients who cannot tolerate cisplatin and have positive PD-L1 expression can benefit from first-line immunotherapy.
For those who cannot tolerate platinum, there are no standard treatment options for second-line treatment.
The meeting reported on the EV201 study cohort 2, which is a phase 2 study in patients who are intolerant to cisplatin and who have previously received immunotherapy.
The primary endpoint is the objective response rate (ORR).
Most of the patients enrolled were elderly people with renal impairment, and 12% of patients had an ECOG score of 2 points.
The results showed that the ORR of Enfortumab Vedotin (EV) treatment reached 52%, and the complete remission (CR) rate reached 20%.
Most of the different subgroups have seen curative effects, including primary upper urinary tract (ORR=61%), liver metastasis (48 %) and those who did not respond to immunotherapy in the past (48%).
The median duration of efficacy (DoR) was 10.
9 months, the median progression-free survival (PFS) was 5.
8 months (95%CI 5.
0-8.
3), and the median OS was 14.
7 months (95%CI 10.
5-18.
2) .
The adverse reactions that need attention are still skin reactions (61%, G3≥17%), peripheral neurotoxicity (54%, G3≥8%)) and hyperglycemia (10%, G3≥6%).
This study provides a potentially more effective treatment plan for platinum intolerant populations.
Changes in tumor lesions assessed by BICR 2.
The choice of third-line treatment for advanced urothelial cancer Antibody-conjugated drugs (ADC) are anti-tumor drugs with a unique mechanism of action, and have made rapid progress in the field of urothelial cancer in recent years. EV is an antibody-conjugated drug consisting of a monoclonal antibody targeting Nectin-4 and a microtubule disruptor MMAE.
At the end of 2019, based on its single-arm registration clinical study, EV201 was approved by the U.
S.
FDA for the immunization of platinum and PD-1 monoclonal antibodies.
Treatment of mUC after treatment failure.
That is to say, for most of the current mUC patients, people who have previously received platinum-based first-line chemotherapy and advanced after second-line immunotherapy can receive EV therapy.
Study design EV301 is a randomized controlled phase 3 clinical study that further validates EV compared with conventional chemotherapy for the population with advanced urothelial cancer after failure of platinum and immunotherapy.
A total of 608 patients were enrolled and randomly assigned to the EV group and the chemotherapy group.
The chemotherapy group received treatment with docetaxel, paclitaxel or vinflunine selected by the investigator, and the primary endpoint of the study was OS.
At the end of 2020, the sponsor has announced the success of the study, and this conference reported the results of the interim analysis.
The median follow-up was 11.
1 months.
Compared with conventional chemotherapy, EV can significantly improve the overall survival of these patients.
The median OS was 12.
9 months and 9.
0 months (HR 0.
7, P=0.
00142), and the median PFS was At 5.
6 months and 3.
7 months (HR 0.
62, P<0.
00001), the ORR 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 (TRAEs, 93.
9% vs 91.
8%) and severe TRAEs (22.
6% vs 23.
4%) in the EV group and the chemotherapy group were similar.
OS results With the success of this randomized controlled phase 3 clinical study, a third-line treatment pattern for advanced urothelial cancer has formed.
For advanced urothelial cancer, the standard first-line treatment is mainly platinum-based chemotherapy, and effective patients are immune maintenance therapy.
If chemotherapy is ineffective, they can receive second-line immunotherapy; for patients who have failed platinum-based and immunotherapy, that is, third-line treatment, the EV301 study has laid the foundation The third-line treatment status of antibody-conjugated drug EV. The TROP-2 antibody-conjugated drug Sacituzumab govitecan (SG) is also conducting a similar phase 3 clinical study globally for the third-line treatment population after the failure of previous platinum-based chemotherapy and immunotherapy.
3.
The treatment of advanced refractory urothelial carcinoma after failure of multi-line therapy is very low effective for late-line treatment of advanced urothelial carcinoma, and new combined treatment methods are also being tried, including immune combined anti-vascular targeted therapy .
Cabozantinib is an inhibitor of MET, AXL and VEGFR, which can improve the immune microenvironment, and combined with immune checkpoint inhibitors has shown promising clinical activity in a variety of solid tumors.
Previously combined treatments with a variety of immune checkpoint inhibitors have achieved good results, such as the COSMIC-021 study (phase 1b) reported by the ASCO conference in 2020.
Ateliizumab combined with cabotinib has failed in previous platinum-based treatments.
27% of the patients achieved ORR, and the incidence of grade 3-4 TRAEs was 57%.
Also at the 2020 ASCO conference, preliminary data on Cabotinib combined with Nivolumab (CaboNivo) ± Ipilimumab (CaboNivoIpi) was reported.
The study is a phase 1 study exploring the dose and efficacy of CaboNivo or CaboNivoIpi in a variety of refractory urinary tumors.
The preliminary data will be published in the JCO Journal in 2020.
54 patients were included in 8 treatment dose groups, the main purpose of which was to determine the recommended dose for phase 2 clinical trials.
Among them, the ORR of 29 mUC patients was 38.
5%, the median DoR was not reached, and the median PFS and OS were 12.
8 months and 25.
4 months, respectively.
The ASCO GU conference updated the final results.
The 120 patients enrolled included 33 patients with advanced urothelial carcinoma, with ORR reaching 42.
4%, CR rate 21.
2%, and median DoR 32.
1 months (95%CI: 20.
3-NE).
Such results provide new treatment ideas for refractory urothelial carcinoma, and anti-vascular combined immunity may benefit these patients.
Efficacy results 4.
Summary The above explained the latest progress in the treatment of advanced urothelial cancer at the ASCO-GU meeting in 2021.
The treatment of advanced urothelial cancer continues to achieve breakthroughs.
In fact, the above-mentioned clinical problems involved in immunization combined with antibody-conjugated drugs may bring hope.
The 2020 ASCO meeting reported that the study of pembrolizumab combined with antibody-conjugated drug EV103 has shown good efficacy in patients with advanced urothelial cancer who are intolerable to platinum.
Currently, corresponding phase 3 clinical studies are being carried out globally .
The domestic ADC drug for HER2 coupling is expected to be launched soon, which will provide new hope for this part of the population.
The clinical study of its combination with PD-1 monoclonal antibody is also underway.
It is believed that the treatment of advanced urothelial cancer in the future Continue to have breakthroughs. Reference 1.
Apolo AB, Nadal R, Girardi DM, et al: Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.
J Clin Oncol 38:3672-3684, 20202.
Galsky MD, Arija JÁA, Bamias A, et al: Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
The Lancet 395:1547-1557, 2020 Recommended reading 2021 ASCO GU | Professor Sheng Xinan's interpretation: Research progress in the posterior treatment of advanced renal cell carcinoma 2021 ASCO GU | Professor Sheng Xinan's interpretation: Non-clear cell cancer treatment exploration 2021 ASCO GU | Professor Sheng Xinan's interpretation: Upper urinary tract urothelial cancer research progress 2021 ASCO GU | Professor Sheng Xinan Interpretation: Progress in immunotherapy for prostate cancer
Immunotherapy, targeted therapy and antibody-conjugated drugs have been successful.
In particular, immune checkpoint inhibitors and antibody-conjugated drugs may change the current status of treatment.
This year's ASCO-GU conferences are still heavyweights, focusing on clinical practice and solving many clinical concerns.
This article sorts out these issues for readers.
Author: Zhou Li Sheng Xinan a Peking University Cancer Hospital, platinum-based first-line in patients who can not tolerate a second-line treatment option for advanced urothelial cancer treatment based on the traditional platinum-based chemotherapy, with the breakthrough immunotherapy, chemotherapy and immunotherapy It has become a plan for many first-line clinical researches in recent years.
However, several randomized controlled phase 3 clinical studies have not been successful, which means that the first-line treatment of advanced urothelial cancer is still platinum-based chemotherapy; and for people who cannot tolerate platinum, immunotherapy can be used as the first-line Treatment options.
IMvigor130 is a comparison of the first-line treatment efficacy of atilizumab combined with gemcitabine + platinum chemotherapy (group A), atilizumab single agent (group B) and gemcitabine + platinum chemotherapy (group C) in mUC Phase 3 clinical study.
This meeting reported the results of the stratification of atezizumab single agent (group B) and chemotherapy (group C) based on PD-L1 expression, in which PD-L1 positive is defined as the application of VENTANA SP142 immunohistochemical staining as IC2 /3, that is, tumor cell PD-L1 expression is ≥5%.
In the PD-L1 high expression group, the overall survival (OS) of atilizumab monotherapy was prolonged compared with chemotherapy, but it did not reach a significant difference (17.
8 months for comparison, HR 0.
68 [0.
43-1.
08]) ; But further limiting the population to patients who are intolerant to cisplatin can significantly improve OS (18.
6 months vs.
10.
0 months, HR 0.
53 [0.
30-0.
994]). OS based on PD-L1 expression stratification.
From the updated data of this study, it is again confirmed that for advanced urothelial cancer, compared with chemotherapy, even patients with positive PD-L1 expression, if they can tolerate platinum For similar treatments, atelizumab alone is not a routine recommendation; only patients who cannot tolerate cisplatin and have positive PD-L1 expression can benefit from first-line immunotherapy.
For those who cannot tolerate platinum, there are no standard treatment options for second-line treatment.
The meeting reported on the EV201 study cohort 2, which is a phase 2 study in patients who are intolerant to cisplatin and who have previously received immunotherapy.
The primary endpoint is the objective response rate (ORR).
Most of the patients enrolled were elderly people with renal impairment, and 12% of patients had an ECOG score of 2 points.
The results showed that the ORR of Enfortumab Vedotin (EV) treatment reached 52%, and the complete remission (CR) rate reached 20%.
Most of the different subgroups have seen curative effects, including primary upper urinary tract (ORR=61%), liver metastasis (48 %) and those who did not respond to immunotherapy in the past (48%).
The median duration of efficacy (DoR) was 10.
9 months, the median progression-free survival (PFS) was 5.
8 months (95%CI 5.
0-8.
3), and the median OS was 14.
7 months (95%CI 10.
5-18.
2) .
The adverse reactions that need attention are still skin reactions (61%, G3≥17%), peripheral neurotoxicity (54%, G3≥8%)) and hyperglycemia (10%, G3≥6%).
This study provides a potentially more effective treatment plan for platinum intolerant populations.
Changes in tumor lesions assessed by BICR 2.
The choice of third-line treatment for advanced urothelial cancer Antibody-conjugated drugs (ADC) are anti-tumor drugs with a unique mechanism of action, and have made rapid progress in the field of urothelial cancer in recent years. EV is an antibody-conjugated drug consisting of a monoclonal antibody targeting Nectin-4 and a microtubule disruptor MMAE.
At the end of 2019, based on its single-arm registration clinical study, EV201 was approved by the U.
S.
FDA for the immunization of platinum and PD-1 monoclonal antibodies.
Treatment of mUC after treatment failure.
That is to say, for most of the current mUC patients, people who have previously received platinum-based first-line chemotherapy and advanced after second-line immunotherapy can receive EV therapy.
Study design EV301 is a randomized controlled phase 3 clinical study that further validates EV compared with conventional chemotherapy for the population with advanced urothelial cancer after failure of platinum and immunotherapy.
A total of 608 patients were enrolled and randomly assigned to the EV group and the chemotherapy group.
The chemotherapy group received treatment with docetaxel, paclitaxel or vinflunine selected by the investigator, and the primary endpoint of the study was OS.
At the end of 2020, the sponsor has announced the success of the study, and this conference reported the results of the interim analysis.
The median follow-up was 11.
1 months.
Compared with conventional chemotherapy, EV can significantly improve the overall survival of these patients.
The median OS was 12.
9 months and 9.
0 months (HR 0.
7, P=0.
00142), and the median PFS was At 5.
6 months and 3.
7 months (HR 0.
62, P<0.
00001), the ORR 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 (TRAEs, 93.
9% vs 91.
8%) and severe TRAEs (22.
6% vs 23.
4%) in the EV group and the chemotherapy group were similar.
OS results With the success of this randomized controlled phase 3 clinical study, a third-line treatment pattern for advanced urothelial cancer has formed.
For advanced urothelial cancer, the standard first-line treatment is mainly platinum-based chemotherapy, and effective patients are immune maintenance therapy.
If chemotherapy is ineffective, they can receive second-line immunotherapy; for patients who have failed platinum-based and immunotherapy, that is, third-line treatment, the EV301 study has laid the foundation The third-line treatment status of antibody-conjugated drug EV. The TROP-2 antibody-conjugated drug Sacituzumab govitecan (SG) is also conducting a similar phase 3 clinical study globally for the third-line treatment population after the failure of previous platinum-based chemotherapy and immunotherapy.
3.
The treatment of advanced refractory urothelial carcinoma after failure of multi-line therapy is very low effective for late-line treatment of advanced urothelial carcinoma, and new combined treatment methods are also being tried, including immune combined anti-vascular targeted therapy .
Cabozantinib is an inhibitor of MET, AXL and VEGFR, which can improve the immune microenvironment, and combined with immune checkpoint inhibitors has shown promising clinical activity in a variety of solid tumors.
Previously combined treatments with a variety of immune checkpoint inhibitors have achieved good results, such as the COSMIC-021 study (phase 1b) reported by the ASCO conference in 2020.
Ateliizumab combined with cabotinib has failed in previous platinum-based treatments.
27% of the patients achieved ORR, and the incidence of grade 3-4 TRAEs was 57%.
Also at the 2020 ASCO conference, preliminary data on Cabotinib combined with Nivolumab (CaboNivo) ± Ipilimumab (CaboNivoIpi) was reported.
The study is a phase 1 study exploring the dose and efficacy of CaboNivo or CaboNivoIpi in a variety of refractory urinary tumors.
The preliminary data will be published in the JCO Journal in 2020.
54 patients were included in 8 treatment dose groups, the main purpose of which was to determine the recommended dose for phase 2 clinical trials.
Among them, the ORR of 29 mUC patients was 38.
5%, the median DoR was not reached, and the median PFS and OS were 12.
8 months and 25.
4 months, respectively.
The ASCO GU conference updated the final results.
The 120 patients enrolled included 33 patients with advanced urothelial carcinoma, with ORR reaching 42.
4%, CR rate 21.
2%, and median DoR 32.
1 months (95%CI: 20.
3-NE).
Such results provide new treatment ideas for refractory urothelial carcinoma, and anti-vascular combined immunity may benefit these patients.
Efficacy results 4.
Summary The above explained the latest progress in the treatment of advanced urothelial cancer at the ASCO-GU meeting in 2021.
The treatment of advanced urothelial cancer continues to achieve breakthroughs.
In fact, the above-mentioned clinical problems involved in immunization combined with antibody-conjugated drugs may bring hope.
The 2020 ASCO meeting reported that the study of pembrolizumab combined with antibody-conjugated drug EV103 has shown good efficacy in patients with advanced urothelial cancer who are intolerable to platinum.
Currently, corresponding phase 3 clinical studies are being carried out globally .
The domestic ADC drug for HER2 coupling is expected to be launched soon, which will provide new hope for this part of the population.
The clinical study of its combination with PD-1 monoclonal antibody is also underway.
It is believed that the treatment of advanced urothelial cancer in the future Continue to have breakthroughs. Reference 1.
Apolo AB, Nadal R, Girardi DM, et al: Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.
J Clin Oncol 38:3672-3684, 20202.
Galsky MD, Arija JÁA, Bamias A, et al: Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
The Lancet 395:1547-1557, 2020 Recommended reading 2021 ASCO GU | Professor Sheng Xinan's interpretation: Research progress in the posterior treatment of advanced renal cell carcinoma 2021 ASCO GU | Professor Sheng Xinan's interpretation: Non-clear cell cancer treatment exploration 2021 ASCO GU | Professor Sheng Xinan's interpretation: Upper urinary tract urothelial cancer research progress 2021 ASCO GU | Professor Sheng Xinan Interpretation: Progress in immunotherapy for prostate cancer
