Ignite Creation Date:
2024-05-06 @ 8:22 PM
Last Modification Date:
2024-10-26 @ 3:26 PM
Study NCT ID:
NCT06354140
Status:
RECRUITING
Last Update Posted:
2024-04-09
First Post:
2024-04-03
Brief Title:
PPIO-008 Tislelizumab Combined With S-1 in Patients With ypTN0 ESCC After Radical Resection With Neoadjuvant STUDY
Sponsor:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Organization:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Study Overview
Official Title:
The Efficacy of Tislelizumab Combined With S-1 in Patients With Residual Primary Lesions and Node-Negative Esophageal Squamous Cell Carcinoma After Neoadjuvant Immunochemotherapy Followed by Curative Resection A Phase II Multicenter Trial
Status:
RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To explore the safety and efficacy of Tegafur combined with tislelizumab in patients with esophageal squamous cell carcinoma with residual primary lesion and node-negative after radical resection following neoadjuvant immunotherapy combined with chemotherapy
Detailed Description:
Worldwide esophageal cancer is one of the most common malignancies According to statistics the incidence and mortality of esophageal cancer rank 9th and 6th respectively China is a country with a high incidence of esophageal cancer with the incidence ranking 6th among all malignant tumors and the mortality ranking 4th among all malignant tumors The main pathological type of esophageal cancer in China is squamous cell carcinoma accounting for about 90 Surgical treatment has always been the main means of esophageal squamous cell carcinoma but more than 50 of the patients were locally advanced when they were first diagnosed and the curative effect of simple surgical resection was not ideal In recent years the multi-disciplinary integrated treatment mode represented by preoperative induction chemoraotherapy or chemotherapy combined surgery has gradually become the mainstream and has improved the long-term survival of patients with locally advanced esophageal squamous cell carcinoma to a certain extent Perioperative comprehensive treatment has gradually become the standard treatment mode for locally advanced esophageal squamous cell carcinoma and its main comprehensive treatment modes include 1 Preoperative induction chemotherapy based on the American INT-0113 RTOG-8911 study the British OEO2 study and the Japanese JCOG9907 study 2 2 Preoperative induction chemoradiotherapy based on the European CROSS study and the Chinese NEOCRTEC5010 study 3 Postoperative adjuvant chemotherapy based on JCOG9204 study
In spite of the numerous perioperative comprehensive treatment modes there is still a higher risk of local and distant recurrence and metastasis after the operation of locally advanced esophageal squamous cell carcinoma and only patients who obtain pathological complete response pCR after the preoperative induction therapy may benefit from survival The pCR rates obtained by preoperative induction chemoradiotherapy reported by different studies were 49 CROSS study 432 NEOCRTEC5010 study and 333 FFCD9901 study respectively About 50 of the remaining patients non-PCR still have a high risk of recurrence and metastasis after surgery Due to the lack of high-level evidence-based medical evidence it is controversial whether these patients need complementary adjuvant therapy For example clinical guidelines represented by European and American countries only recommend regular follow-up and do not recommend postoperative adjuvant therapy for esophageal squamous cell carcinoma patients who achieve radical resection R0 regardless of lymph node metastasis For patients with esophageal adenocarcinoma whose postoperative pathological results indicate positive lymph nodes supplementary chemotherapy is recommended even for those undergoing radical resection The clinical guidelines of East Asian countries represented by Japan recommend postoperative adjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma with positive lymph nodes confirmed by postoperative pathology However for patients with negative lymph nodes after surgery the CSCO guidelines recommend that for patients who have received neoadjuvant chemoradiotherapy in the past drug O is recommended as grade II for patients who have received neoadjuvant chemoradiotherapy postoperative chemoradiotherapy is recommended as grade III for patients who have not received neoadjuvant chemoradiotherapy in the past radiotherapy and chemoradiotherapy are recommended as grade III At the same time the postoperative adjuvant of O drug in the NCCN guidelines also requires preoperative radiotherapy and chemotherapy Therefore the investigators can see that radiotherapy is required in most cases for postoperative adjuvant therapy of esophageal squamous cell carcinoma However for the general clinical and patient compliance considerations in China the compliance before and after radiotherapy is not high and the adverse reactions such as esophageal perforation radiation esophagitis esophageal obstruction airway reaction radiation pneumonia heart injury and systemic symptoms are likely to occur which reduces the life treatment and compliance of patients
In 2020 immunotherapy represented by anti-PD-1 has been established globally in the field of first-line treatment and adjuvant therapy for advanced esophageal cancer and esophagogastric junction cancer Among them the results of the CheckMate 649 study showed that first-line treatment with nalizumab combined with chemotherapy oxaliplatin fluorouracil regimen could significantly improve the overall survival OS of advanced esophagogastric junction adenocarcinoma patients with PD-L1 comprehensive positive score CPS 5 Similar findings of Attract-4 also suggested that first-line treatment with chemotherapy could improve progression-free survival PFS in patients with advanced esophagogastric junction adenocarcinoma but the benefit of OS was not significant Keykeynote 590 study results demonstrated that first-line treatment of pabolizumab combined with chemotherapy cisplatin fluorouracil regimen significantly prolonged the survival of advanced esophageal squamous cell carcinoma patients with CPS 10 although this advantage was not shown in non-selective populations The results of the CheckMate 577 study are a proof of concept concept level confirmed that postoperative adjuvant sodium umab can significantly improve the disease-free survival DFS of patients with locally advanced esophageal cancer and esophagogastric junction cancer with high risk of recurrence as assessed by pathology after neoadjuvant chemoradiotherapy combined with radical surgery
According to the results of CheckMate 577 for patients with locally advanced esophageal cancer at or above ypT1 or ypN1 stage after preoperative induction chemoradiotherapy adjuvant sodium umab therapy could significantly prolong DFS HR 964 CI 069 056 -- 086 P 00003 Although the results of this study have been adopted and recommended by NCCN guidelines as evidence immediately after publication NCCN 2020 v50 the proportion of esophageal squamous cell carcinoma patients is less than 30 and the patients with postoperative negative lymph nodes have not reached statistical difference so whether it is consistent with the patient population in China needs further verification Given the lack of effective adjuvant therapy after surgery for locally advanced esophageal squamous cell carcinoma and the promising preliminary results of PD-1 inhibitors in advanced esophageal squamous cell carcinoma adjuvant immunotherapy after surgery for esophageal squamous cell carcinoma seems feasible
As an oral chemotherapy drug Teggio is more convenient for patients to take In the study of esophageal cancer Chen et al found that CCRT combined with S-1 was tolerable in elderly patients with esophageal cancer and OS benefited significantly compared with radiotherapy alone Oral administration of S-1 improves patient compliance and this regimen is expected to become the preferred regimen for elderly patients with esophageal cancer Hirahara N et al studied 20 patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy NAC and 22 patients who did not receive neoadjuvant chemotherapy during 2011-2020 and took S-1 a one-week rest regimen after 2-week administration as the tolerance of postoperative adjuvant therapy One year after surgery 17 patients 772 in the non-NAC group and 16 patients 800 in the NAC group were still treated with S-1 as planned and there was no statistically significant difference in the S-1 continuation rate p 0500 indicating that S-1 can be used as a safe and sustainable adjuvant chemotherapy regimen for esophageal cancer patients with or without NAC Fu et al included 400 patients treated with postoperative chemotherapy and 582 patients treated with surgery alone In the chemotherapy group 69 patients were treated with S-1 68 with Tegafur tablets and the rest were treated with intravenous chemotherapy In the entire study cohort 3-year OS in the S CT group was significantly higher than that in the S group 663 vs 499 p lt 0001 these data were confirmed in the matched group 3-year OS 729 vs 620 p 0001 Multivariate Cox regression analysis showed that adjuvant chemotherapy was an independent prognostic factor for ESCC and patients receiving oral chemotherapy had similar OS as those receiving intravenous chemotherapy It was also confirmed that adjuvant chemotherapy can significantly improve the OS of pN ESCC patients Compared with intravenous chemotherapy oral chemotherapy S-1 has similar efficacy and fewer side effects which may be a better choice
For patients with pN0 Wang et al retrospectively analyzed pT3N0M0 thoracic segment ESCC patients who underwent esophagectomy from January 2008 to December 2012 and used multivariate proportional risk Cox model to determine the factors associated with total recurrence TR local recurrence LR and distant metastasis DM In 692 patients TR LR and DM were found to be 358 and 410 287 and 321 168 and 211 respectively at 3 and 5 years and LR was found to be the main cause of treatment failure in pT3N0M0 thoracic ESCC patients after two fields of dissection Liu Zhu et al 24 25 all found that the DFS and OS in patients with pN0 treated with postoperative radiotherapy or chemoradiotherapy were significantly higher than those in the group treated with chemotherapy alone reflecting the effectiveness of adjuvant therapy for pN0 patients
In summary the investigators can see that postoperative use of oral oral chemotherapy can bring similar efficacy and better safety to intravenous chemotherapy in patients with pN esophageal squamous cell carcinoma Meanwhile checkmate577 confirmed that postoperative use of nabriliumab in patients with neoadjuvant chemoratherapy can bring longer DFS in patients with pN The adjuvant therapy of postoperative radiotherapy for pN0 patients can also improve the DFS and OS of patients However for esophageal squamous cell carcinoma patients who have not received preoperative radiotherapy the postoperative treatment still needs to be discussed
Therefore this project intends to explore the efficacy of postoperative chemtiggio combined with tirellizumab in ESCC patients with esophageal squamous cell carcinoma who have not received neoadjuvant radiotherapy before surgery in patients with radical resection and negative pathological lymph nodes after surgery
In spite of the numerous perioperative comprehensive treatment modes there is still a higher risk of local and distant recurrence and metastasis after the operation of locally advanced esophageal squamous cell carcinoma and only patients who obtain pathological complete response pCR after the preoperative induction therapy may benefit from survival The pCR rates obtained by preoperative induction chemoradiotherapy reported by different studies were 49 CROSS study 432 NEOCRTEC5010 study and 333 FFCD9901 study respectively About 50 of the remaining patients non-PCR still have a high risk of recurrence and metastasis after surgery Due to the lack of high-level evidence-based medical evidence it is controversial whether these patients need complementary adjuvant therapy For example clinical guidelines represented by European and American countries only recommend regular follow-up and do not recommend postoperative adjuvant therapy for esophageal squamous cell carcinoma patients who achieve radical resection R0 regardless of lymph node metastasis For patients with esophageal adenocarcinoma whose postoperative pathological results indicate positive lymph nodes supplementary chemotherapy is recommended even for those undergoing radical resection The clinical guidelines of East Asian countries represented by Japan recommend postoperative adjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma with positive lymph nodes confirmed by postoperative pathology However for patients with negative lymph nodes after surgery the CSCO guidelines recommend that for patients who have received neoadjuvant chemoradiotherapy in the past drug O is recommended as grade II for patients who have received neoadjuvant chemoradiotherapy postoperative chemoradiotherapy is recommended as grade III for patients who have not received neoadjuvant chemoradiotherapy in the past radiotherapy and chemoradiotherapy are recommended as grade III At the same time the postoperative adjuvant of O drug in the NCCN guidelines also requires preoperative radiotherapy and chemotherapy Therefore the investigators can see that radiotherapy is required in most cases for postoperative adjuvant therapy of esophageal squamous cell carcinoma However for the general clinical and patient compliance considerations in China the compliance before and after radiotherapy is not high and the adverse reactions such as esophageal perforation radiation esophagitis esophageal obstruction airway reaction radiation pneumonia heart injury and systemic symptoms are likely to occur which reduces the life treatment and compliance of patients
In 2020 immunotherapy represented by anti-PD-1 has been established globally in the field of first-line treatment and adjuvant therapy for advanced esophageal cancer and esophagogastric junction cancer Among them the results of the CheckMate 649 study showed that first-line treatment with nalizumab combined with chemotherapy oxaliplatin fluorouracil regimen could significantly improve the overall survival OS of advanced esophagogastric junction adenocarcinoma patients with PD-L1 comprehensive positive score CPS 5 Similar findings of Attract-4 also suggested that first-line treatment with chemotherapy could improve progression-free survival PFS in patients with advanced esophagogastric junction adenocarcinoma but the benefit of OS was not significant Keykeynote 590 study results demonstrated that first-line treatment of pabolizumab combined with chemotherapy cisplatin fluorouracil regimen significantly prolonged the survival of advanced esophageal squamous cell carcinoma patients with CPS 10 although this advantage was not shown in non-selective populations The results of the CheckMate 577 study are a proof of concept concept level confirmed that postoperative adjuvant sodium umab can significantly improve the disease-free survival DFS of patients with locally advanced esophageal cancer and esophagogastric junction cancer with high risk of recurrence as assessed by pathology after neoadjuvant chemoradiotherapy combined with radical surgery
According to the results of CheckMate 577 for patients with locally advanced esophageal cancer at or above ypT1 or ypN1 stage after preoperative induction chemoradiotherapy adjuvant sodium umab therapy could significantly prolong DFS HR 964 CI 069 056 -- 086 P 00003 Although the results of this study have been adopted and recommended by NCCN guidelines as evidence immediately after publication NCCN 2020 v50 the proportion of esophageal squamous cell carcinoma patients is less than 30 and the patients with postoperative negative lymph nodes have not reached statistical difference so whether it is consistent with the patient population in China needs further verification Given the lack of effective adjuvant therapy after surgery for locally advanced esophageal squamous cell carcinoma and the promising preliminary results of PD-1 inhibitors in advanced esophageal squamous cell carcinoma adjuvant immunotherapy after surgery for esophageal squamous cell carcinoma seems feasible
As an oral chemotherapy drug Teggio is more convenient for patients to take In the study of esophageal cancer Chen et al found that CCRT combined with S-1 was tolerable in elderly patients with esophageal cancer and OS benefited significantly compared with radiotherapy alone Oral administration of S-1 improves patient compliance and this regimen is expected to become the preferred regimen for elderly patients with esophageal cancer Hirahara N et al studied 20 patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy NAC and 22 patients who did not receive neoadjuvant chemotherapy during 2011-2020 and took S-1 a one-week rest regimen after 2-week administration as the tolerance of postoperative adjuvant therapy One year after surgery 17 patients 772 in the non-NAC group and 16 patients 800 in the NAC group were still treated with S-1 as planned and there was no statistically significant difference in the S-1 continuation rate p 0500 indicating that S-1 can be used as a safe and sustainable adjuvant chemotherapy regimen for esophageal cancer patients with or without NAC Fu et al included 400 patients treated with postoperative chemotherapy and 582 patients treated with surgery alone In the chemotherapy group 69 patients were treated with S-1 68 with Tegafur tablets and the rest were treated with intravenous chemotherapy In the entire study cohort 3-year OS in the S CT group was significantly higher than that in the S group 663 vs 499 p lt 0001 these data were confirmed in the matched group 3-year OS 729 vs 620 p 0001 Multivariate Cox regression analysis showed that adjuvant chemotherapy was an independent prognostic factor for ESCC and patients receiving oral chemotherapy had similar OS as those receiving intravenous chemotherapy It was also confirmed that adjuvant chemotherapy can significantly improve the OS of pN ESCC patients Compared with intravenous chemotherapy oral chemotherapy S-1 has similar efficacy and fewer side effects which may be a better choice
For patients with pN0 Wang et al retrospectively analyzed pT3N0M0 thoracic segment ESCC patients who underwent esophagectomy from January 2008 to December 2012 and used multivariate proportional risk Cox model to determine the factors associated with total recurrence TR local recurrence LR and distant metastasis DM In 692 patients TR LR and DM were found to be 358 and 410 287 and 321 168 and 211 respectively at 3 and 5 years and LR was found to be the main cause of treatment failure in pT3N0M0 thoracic ESCC patients after two fields of dissection Liu Zhu et al 24 25 all found that the DFS and OS in patients with pN0 treated with postoperative radiotherapy or chemoradiotherapy were significantly higher than those in the group treated with chemotherapy alone reflecting the effectiveness of adjuvant therapy for pN0 patients
In summary the investigators can see that postoperative use of oral oral chemotherapy can bring similar efficacy and better safety to intravenous chemotherapy in patients with pN esophageal squamous cell carcinoma Meanwhile checkmate577 confirmed that postoperative use of nabriliumab in patients with neoadjuvant chemoratherapy can bring longer DFS in patients with pN The adjuvant therapy of postoperative radiotherapy for pN0 patients can also improve the DFS and OS of patients However for esophageal squamous cell carcinoma patients who have not received preoperative radiotherapy the postoperative treatment still needs to be discussed
Therefore this project intends to explore the efficacy of postoperative chemtiggio combined with tirellizumab in ESCC patients with esophageal squamous cell carcinoma who have not received neoadjuvant radiotherapy before surgery in patients with radical resection and negative pathological lymph nodes after surgery
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None