Trial Title:
PPIO-008 Tislelizumab Combined With S-1 in Patients With ypT+N0 ESCC After Radical Resection With Neoadjuvant STUDY
NCT ID:
NCT06354140
Condition:
Esophageal Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Tislelizumab
Tegafur
Conditions: Keywords:
ypT1-4N0M0
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Masking description:
The study was a one-arm open study
Intervention:
Intervention type:
Drug
Intervention name:
Tegafur
Description:
Tegafur (S-1) 80mg/100mg/120mg Q3W (discontinued at the third week) + tislelizumab 200 mg
Q3W, treatment for 1 year. Tegafur: body surface area (BSA) < 1.25m2, use 80mg;
1.25-1.5m2, use 100mg; > 1.5m2, use 120mg. Treatment for 1 year
Arm group label:
S-1 Combined With Tislelizumab
Other name:
tislelizumab
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) , 43.2% (NEOCRTEC5010 study) and 33.3% (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 (96.4% CI) 0.69 (0.56 --
0.86); P = 0.0003]. Although the results of this study have been adopted and recommended
by NCCN guidelines as evidence immediately after publication (NCCN 2020 v5.0), 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 (77.2%) in the non-NAC group and 16 patients (80.0%) 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 = 0.500), 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 (66.3% vs. 49.9%, p < 0.001), these data were
confirmed in the matched group (3-year OS, 72.9% vs. 62.0%, p < 0.001). 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 35.8% and 41.0%, 28.7% and 32.1%, 16.8% and 21.1%,
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age 18-75 years old, gender is not limited;
2. Patients with esophageal squamous cell carcinoma with neoadjuvant immunotherapy
combined with chemotherapy (radiotherapy was not planned during the study period);
3. Thoracic esophageal squamous cell carcinoma patients with residual pathologic
primary site and lymph node positive (ypT1-4aN0M0) after surgery (8th UICC-TNM
stage);
4. The operation was radical resection;
5. Physical status ECOG 0 ~ 1 score;
6. No local recurrence or distant metastasis was found in the examination before
postoperative adjuvant treatment;
7. There were no contraindications of chemotherapy or immunotherapy in the evaluation
of various organ functions;
8. Understand and sign the informed consent.
Exclusion Criteria:
1. Had malignant tumors other than esophageal cancer within 5 years prior to admission
(cured localized tumors were not excluded, including cervical carcinoma in situ,
skin basal cell carcinoma and prostate carcinoma in situ, etc.); Prostate cancer
patients who received hormone therapy and obtained DFS for more than 5 years were
not excluded).
2. Prior history of interstitial lung disease, or pneumonia requiring steroid treatment
when enrolled;
3. Receiving systemic steroid therapy (more than 10mg of prednisone per day or
equivalent) or other immunosuppressant within 2 weeks prior to randomization;
4. People who have been severely allergic to chemotherapy drugs (fluorouracil) or any
monoclonal antibody;
5. Patients with active autoimmune diseases;
6. Patients with active hepatitis
7. According to the judgment of the researcher, there are other circumstances that are
not suitable for participation in this study.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Army Medical Center of the People's Liberation Army
Address:
City:
Chongqing
Zip:
400042
Country:
China
Status:
Recruiting
Contact:
Last name:
Guo
Phone:
+8613527323568
Email:
gyguowei@hotmail.com
Start date:
May 7, 2024
Completion date:
May 30, 2028
Lead sponsor:
Agency:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Agency class:
Other
Source:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06354140
