Sintilimab In Combination Research Articles

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200mg every 3 weeks) for three cycles plus FLOT (50mg/m 2 docetaxel, 80mg/m 2 oxaliplatin, 200mg/m 2 calcium levofolinate, 2600mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Anti-PD-1 Antibody Sintilimab in Combination with Anlotinib and Pegaspargase As a Highly Effective Salvage Regimen for the Treatment of Relapsed or Refractory Natural Killer /T-Cell Lymphoma

Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive neoplasm associated with Epstein-Barr virus (EBV) infection. When patients experience relapse or disease progression after initial treatment, options for salvage therapy are limited. Targeting the PD-1/PD-L1 pathway has emerged as a highly potent treatment approach for NKTCL. However, the overall response rate (ORR) and complete response (CR) rate were limited with a short median progression-free survival (PFS) of 2.7 months. Therefore, improving the efficacy of immune checkpoint inhibitors is a critical clinical concern. In this study, we reported the efficacy and safety of a novel triplet regimen called LEAP, which combines PD-1 blockade (sintilimab 200mg on day 1), pegaspargase (2500U/m2 capped at 3750U on day 1), and angiogenesis inhibitor anlotinib (8mg on day 1-14), as a salvage treatment for relapsed/refractory (R/R) NKTCL. From March 2019 to May 2020, a total of 33 patients with R/R NKTCL were included in this study. The median age of patients was 48 years (range: 18-76), with 75.8% being male. At study entry, 88% of patients had stage IV disease, while 4 patients had stage II disease, with a history of primary refractory response to radiotherapy and L-asparaginase-based combination therapy. Moreover, 69.7% of patients had refractory disease, including those who were progressive or non-responsive to L-asparaginase-based regimens. Additionally, 10 patients experienced relapse or disease progression within 6 months after prior L-asparaginase-based therapy, and 10 patients had a history of PD-1/PD-L1 blockade monotherapy. A total of 221 cycles of the LEAP regimen were administered to these patients. The median number of cycles was 8 (range: 2-8). All patients reported at least one or more adverse events (AE). Hematological toxicities were mild, with no grade 3/4 neutropenia, anemia, or thrombocytopenia observed. Non-hematological AEs were common, and the most frequent (>20%) included hypofibrinogenemia (66.7%), hyperbilirubinemia (57.5%), APTT prolongation (54.5%), ALT elevation (54.5%), AST elevation (51.5%), hypoalbuminemia (48.5%), appetite loss (60.6%), nausea (57.5%), fatigue (57.5%), weight loss (42.4%), and edema (27.3%). These adverse events were typically attributed to pegaspargase. Other adverse events such as hyponatremia (24.2%), hypertriglyceridemia (21.2%), hyperglycemia (21.2%), hypothyroidism (30.3%), hypertension (24.2%), fever (39.4%), and dysphonia (21.2%) were most likely due to sintilimab or anlotinib. Most adverse events were manageable with supportive care. Among the 33 patients, the ORR was 81.8%, and CR was 45.5. The progression-free survival (PFS) rate at 1-year was 54.6% (95% CI, 36.3% to 70.0%), and at 2 years, it was 44.2% (95% CI, 26.6% to 60.4%). The median PFS time was 21.7 months. The overall survival (OS) rate at 1-year was 66.7% (95% CI, 47.9% to 80.0%), and at 2 years, it was 51.5% (95% CI, 33.5% to 66.9%). The median OS time was not reached during the study period. In conclusion, our study demonstrates that the LEAP regimen has a favorable safety profile, and is highly effective as a salvage treatment for patients with relapsed and refractory NKTCL.

Anti-PD-1 Antibody (Sintilimab) Plus Decitabine As First Line Treatment for Patients with Higher-Risk Myelodysplastic Syndrome (MDS): Primary Results from a Single-Arm,Open-Label,Phase II Study

Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients with higher-risk Myelodysplastic Syndrome (MDS). However, the survival rate of patients after HMA treatment remains poor. Studies have shown that HMAs upregulate the expression of PD-1/PD-L1 in MDS patients, making the combination of HMAs with PD-1 antibodies a compelling approach for MDS treatment. Consequently, we conducted this single-arm, open-label clinical trial (ChiCTR2100044393) to assess the safety and efficacy of sintilimab in combination with decitabine for patients with higher-risk MDS. Methods: Adult patients with higher-risk MDS, according to the IPSS-R, were eligible for enrollment in this study. The treatment regimen consisted of daily intravenous administration of decitabine at a dose of 20mg/m 2 for 5 consecutive days, along with intravenous administration of sintilimab at 200mg on the first and 22nd day of a 42-day treatment cycle. Treatment continued until disease progression, death, unacceptable toxicity, withdrawal of consent, or other protocol-defined reasons, with a maximum of 8 cycles allowed. The primary endpoint of this study was the overall response rate (ORR). To determine the sample size, we utilized Simon's optimal two-stage design. Secondary endpoints included the assessment of safety and various survival outcomes. Additionally, we investigated the relationship between the expression levels of immune checkpoints and the efficacy of the combination therapy and other potential biomarkers through genomic profiling. Results: As of the data cut-off on June 16, 2023, 53 patients were enrolled, with a median follow-up time of 14 months, and 52 patients were eligible for response evaluation. The median age of patients was 65 years (range 19-83), other characteristics were summarized in Table 1.The ORR was 76.9%, and 15 patients achieved complete response (CR), 13 marrow complete response(mCR),7 mCR+ hematologic improvement(HI), and 5 HI. Among the 40 responders, six patients (4 with CR and 2 with mCR) underwent allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) has not reached, and the median event-free survival (EFS) was 16 months. The 24-month OS and EFS rates were 54.8% (95%CI: 39.5-76.2) and 46.2% (95%CI: 31.2-68.3), respectively. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) reported in 10% or more of the patients were febrile neutropenia (67.9%) and pulmonary infection (20.8%). A total of 17 patients (32.1%) experienced immune-related adverse events (irAEs), with the most common irAEs being rash (17.0%), thyroid dysfunction (9.4%), and pneumonia (7.5%), all resolved after glucocorticoid treatment. Regarding genetic mutations, the most frequently mutated genes were ASXL1 (34.0%), RUNX1 (30.2%), TET2 (17.0%), and U2AF1 (17.0%). Conclusion: To the best of our knowledge, this is the first study evaluating the efficacy and safety of the combination therapy with sintilimab and decitabine in previously untreated patients with higher-risk MDS. This regimen showed an encouraging anti-tumor activity with a manageable safety profile.

A Phase II Study of the Efficacy and Safety of the Srmt (Sintilimab, Rituximab, Methotrexate, and Temozolomide) Regimen in Newly Diagnosed Primary Central Nervous System Lymphoma

BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of lymphoma with poor prognosis. One potential therapeutic approach could involve targeting the programmed death-1 (PD-1) immune checkpoint pathway, as these tumors often express PD-L1. However, the efficacy of this strategy using sintilimab in combination with immunochemotherapy as frontline therapy for patients with newly diagnosed PCNSL remains uncertain. METHODS In this phase II trial with a safety run-in, we enrolled treatment-naive PCNSL patients between the ages of 18 and 70, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All patients were given sintilimab combined with rituximab, high-dose methotrexate and temozolomide (SRMT) regimen (six cycles every 21 days): sintilimab (200 mg, i.v., Day-0), rituximab (375 mg/m 2, i.v., Day-0), methotrexate (3.0 g/m 2, i.v., Day-1 or 1.0 g/m 2 for patients aged ≥65 years, and temozolamide (150 mg/m 2/d, p.o., Days 1-5). The primary outcome was overall response rate (ORR), with secondary outcomes including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and potential biomarkers. RESULTS Between 3 April 2020 and 23 August 2022, a total of 28 patients were enrolled. No dose-limiting toxicities were observed during the safety run-in period. Among 27 evaluable patients, the primary outcome was met with an impressive ORR of 96.3% (95% CI: 81-99.9%). In detail, 25 patients (92.6%) achieved a complete response and one (3.7%) exhibited a partial response. As of 7 April 2023, the median follow-up was 20.8 months. The Medians for DOR, PFS, and OS were not reached. Remarkably, 2-year PFS and 2-year OS were 65.4% (48.1-88.8%) and 88.5% (74.1-100%), respectively. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (18.5%) and aspartate aminotransferase (14.8%). Additionally, the receiver operating characteristic analysis revealed that the baseline IL10/IL6 ratio in cerebrospinal fluid exhibited promising performance in predicting PFS, achieving an area under curve of 0.91 at 2 years. CONCLUSIONS The SRMT regimen as frontline treatment for PCNSL is highly efficacious and well tolerated. (Chinese Clinical Trial Registry number: ChiCTR1900027433).

497P Sintilimab in combination with anlotinib in advanced NSCLC treated with first-line PD-1 antibodies: An open, single-arm, phase II trial

497P Sintilimab in combination with anlotinib in advanced NSCLC treated with first-line PD-1 antibodies: An open, single-arm, phase II trial

P2.16-01 Sintilimab in Combination With Carboplatin/Cisplatin and Etoposide in the Treatment of Patients with Previously Untreated ES-SCLC

P2.16-01 Sintilimab in Combination With Carboplatin/Cisplatin and Etoposide in the Treatment of Patients with Previously Untreated ES-SCLC

444P Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple-negative breast cancer (SPACE): Preliminary results of a single-arm, multicenter phase II trial

444P Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple-negative breast cancer (SPACE): Preliminary results of a single-arm, multicenter phase II trial

Sintilimab Injection Combination with Concurrent Chemoradiotherapy (cCRT) in Patients with Localized Esophageal Squamous Cell Carcinoma: A Prospective, Multi-Center, Single-Arm Trial in Progress

Esophageal cancer had accounted for the sixth highest incidence and the fourth highest death rate in China. The predominant histological subtype is esophageal squamous cell carcinoma (ESCC). At initial diagnosis, more than half of patients with ESCC are unfit for surgery. An accepted alternative to surgery is concurrent chemoradiotherapy (cCRT); however, many patients experience local recurrence or distant metastasis after cCRT. Therefore, innovative therapies are needed. Sintilimab is a fully human IgG4 monoclonal antibody, exhibiting the highest affinity for human PD-1 and a lower off-rate, the PD-1 receptor occupancy of sintilimab on circulating T cells is superior. In previous studies, sintilimab, alone and in combination with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced ESCC. This prospective, single-arm study (NCT04602013) is designed to explore the efficacy of Sintilimab in combination with cCRT. Eligible patients have histologically confirmed localized ESCC for whom cCRT is suitable and surgery is unsuitable/ declined; patients couldn't have received prior chemoradiotherapy. Approximately 53 Chinese patients from 5 centers will be to receive sintilimab (body weight <60kg: 3mg/kg IV Q3W; body weight ≥60kg: 200mg IV Q3W) in combination with cisplatin (25 mg/m2 IV on Days 1-3 of each 3-week cycle) plus paclitaxel for injection (albumin bound) (180 mg/m2). and radiotherapy at a total dose of 60Gy. Duration of treatment will be up to 12 months for sintilimab, including two cycles for concurrent administration of chemotherapy and radiotherapy. Progression-free survival (PFS), assessed by a Blinded Independent Review Committee per RECIST v1.1, is the primary endpoint of the study. Secondary efficacy endpoints include overall response rate, duration of response, and overall survival. Incidence and severity of adverse events (CTCAE V5.0) and patient-reported outcomes of health-related quality of life are additional secondary endpoints. A total of 17 patients have completed sintilimab injection combination with concurrent chemoradiotherapy,17/53 (32%). Objective response rate (ORR) 62.5% and a median progression free survival (mPFS) 17 months. 1-year overall survival (OS) 88.2%. The most common AEs included granulocytopenia (43.7%), thrombo -cytopenia (56.2%), radiation esophagitis (50%), nausea and vomiting (50%), and immune pneumonia (18.7%). Of these AEs greater than grade 3 granulocytopenia (25.0%), thrombocytopenia (35.0%), radiation esophagitis (12.5%), and nausea and vomiting (31.3%), and one patient developed grade 3 immune pneumonia (6.2%), which recovered with treatment. The treatment of sintilimab with CCRT is safe and effective for localized ESCC patients, even with high-dose radiotherapy (60Gy). This study may help to address the unmet need for new therapeutic options for patients with localized ESCC.

152. SINTILIMAB PLUS CISPLATIN AND PACLITAXEL INDUCTION TREATMENT FOR BORDERLINE RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A PHASE II CLINICAL TRIAL

Abstract Background An increasing number of clinical studies focus on investigating the use of immunotherapy in the treatment of esophageal cancer. This phase II trial (NEOCRTEC-2001 clinical trial) aimed to assess the safety and efficacy of sintilimab in combination with cisplatin and paclitaxel induction immunochemotherapy followed by surgery for locally advanced borderline-resectable esophageal squamous cell carcinoma (BR-ESCC). Methods Patients with primary tumor or bulky lymph nodes that might invade nearby organs were eligible. Treatment started with 2–4 cycles of induction immunochemotherapy, followed by surgery if the tumor was assessed resectable, or by radical concurrent chemoradiotherapy if unresectable. The primary endpoint was pathologically proven complete resection (R0) rate. The secondary end points included pathological complete response (pCR) rate, overall survival (OS), progression-free survival (PFS), adverse events and postoperative complication. Results From September 2020 to now, a total of 34 patients were enrolled. After immunochemotherapy, 21 patients (61.8%) received surgery and 13 (38.2%) did not. All patients underwent McKeown procedure, and median operation time was 295 minutes (range 201–489 minutes). All patients received esophageal reconstruction using gastric tube, and underwent cervical anastomosis. An average of 46.6 lymph nodes were dissected, and positive lymph nodes were observed in 5 of the 21 patients. R0 resection was confirmed in 20 patients (58.8%). One patient underwent R2 resection because of tumor invasion of the aorta. Pathologic complete response was confirmed in 6 patients (6/34, 17.6%), while 5 patients (5/34, 14.7%) had few or no regressive changes (TRG3). Conclusion The treatment strategy of induction immunochemotherapy followed by surgery is promising for patients with locally advanced borderline-resectable esophageal squamous cell carcinoma. The whole results of pathologic response and prognostic value are awaited with interest.

Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial

In this multicenter, single-arm phase 2 trial (ChiCTR1900024428), patients with locally advanced gastric/gastroesophageal junction cancers receive one cycle of sintilimab (anti-PD1) and chemotherapy (S-1 and nab-paclitaxel), followed by 5 weeks of concurrent chemoradiotherapy and sintilimab, and another cycle of sintilimab and chemotherapy thereafter. Surgery is preferably scheduled within one to three weeks, and three cycles of adjuvant sintilimab and chemotherapy are administrated. The primary endpoint is the pathological complete response. Our results meet the pre-specified primary endpoint. Thirteen of 34 (38.2%) enrolled patients achieve pathological complete response (95% CI: 22.2-56.4). The secondary objectives include disease-free survival (DFS), major pathological response, R0 resection rate, overall survival (OS), event-free survival (EFS), and safety profile. The median DFS and EFS were 17.0 (95%CI: 11.1-20.9) and 21.1 (95%CI: 14.7-26.1) months, respectively, while the median OS was not reached, and the 1-year OS rate was 92.6% (95%CI: 50.1-99.5%). Seventeen patients (50.0%) have grade ≥3 adverse events during preoperative therapy. In prespecified exploratory biomarker analysis, CD3+ T cells, CD56+ NK cells, and the M1/M1 + M2-like macrophage infiltration at baseline are associated with pathological complete response. Here, we show the promising efficacy and manageable safety profile of sintilimab in combination with concurrent chemoradiotherapy for the perioperative treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma.

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial)

BackgroundBiliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients.MethodsThe NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China.DiscussionThe NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research.Trial registrationChinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study

BackgroundRat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8–9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy.MethodsThis is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate.DiscussionThis study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set.Trial registrationThis study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.

Artificial intelligence model for predicting the efficacy of sintilimab plus chemotherapy in treating patients with esophageal squamous cell carcinoma.

e16030 Background: Blockade of programmed cell death 1 (PD-1) could induce tumor regression in patients with advanced esophageal squamous cell carcinoma (ESCC), although little is known about the biomarker to guide immunochemotherapy. In this study, we sought to evaluate the efficacy and discover biomarkers and establish an artificial intelligence (AI) model to predict the efficacy of the combination of sintilimab and chemotherapy in the treatment of patients with ESCC. Methods: Fifty-nine (59) patients enrolled in our study received chemotherapy with sintilimab and follow-up data were available. Treatment outcomes were assessed using the Response Evaluation Criteria in Solid Tumors (v1.1). Eleven (11) clinicopathologic characteristics including age, albumin, HLA-1 evolutionary divergence (HED), TMB, body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelets, hemoglobin, stage, sex, leukocyte, lymphocyte and therapy were collected. Results: Thirty-four (34) patients with ESCC who received sintilimab as first-line chemotherapy had a median follow-up of 13.7 (range, 0.53-35.57) months. At the time of analysis, six (6, 17.6%) patients were still receiving treatment, 24 patients achieved PR, and the confirmed ORR was 67.65%. Four (4) patients had SD and the DCR was 79.41%. Median PFS (mPFS) was 10.06 months. Median overall survival (mOS) was 23.27 months. The mPFS of the PD-L1 positive population was significantly better than that of the PD-L1 negative population (19.23 months vs. 6.57 months, p = 0.046). There was no significant difference in mPFS and mOS between the high and low TMB groups. Patients were divided into response (CR or PR) and non-response (SD or PD) groups according to their response to combined immunotherapy. The response rate of patients with wild-type MET was higher than that of patients with MET mutation (75% vs. 25%, p=0.0889). Compared to patients with wild-type BRCA2, patients with mutant BRCA2 had a significantly shorter mPFS (4.2 months vs. 13.3 months, p=0.027). Based on the efficacy data and 11 additional clinicopathologic characteristics of the 59 patients who received sintilimab in combination with chemotherapy, a random forest AI model was constructed to predict response to immunochemotherapy. Patients were randomly divided into a training set and a test set in a 6:4 ratio. In the test set, the top three predictive biomarkers were HED, age, and BMI. The area under the curve of the predictive model in the test set was 0.82. Conclusions: Sintilimab combined with chemotherapy could be an effective treatment for advanced ESCC, and an AI model based on multiple clinical features at baseline could predict the efficacy of immunochemotherapy. Further studies with larger sample size are needed to validate our findings.

Sintilimab plus gemcitabine and cisplatin as a first-line treatment for patients with advanced biliary tract cancer: A biomolecular exploratory, phase II clinical trial.

4086 Background: The prognosis of biliary tract cancer (BTC) remains unsatisfactory. Thus, this study aimed to determine the efficacy, safety, and predictive biomarkers of the immune checkpoint inhibitor sintilimab in combination with gemcitabine and cisplatin (GemCis) in advanced BTCs. Methods: In this single-arm, phase II study (Trial registration number: ChiCTR2000036652), gemcitabine (1000 mg/m²) plus cisplatin (25 mg/m²) were administered on days 1 and 8, respectively, while 200 mg sintilimab was administered on day 1 of each 21-day cycle for 6–8 weeks, followed by sintilimab alone up to 2 years. The primary endpoint was overall survival (OS). The second endpoints were objective response rate (ORR), progression-free survival (PFS), and disease control rate, assessed using RECIST V.1.1. Multiomics biomarkers associated with clinical response were assessed as exploratory objectives. Results: Thirty patients were enrolled between August 2020 and May 2022. The median follow-up duration, OS, and PFS were 12.3 months (95% confidence interval [CI]: 9.1–16.0), 15.9 months (95% CI: 8.6–not reached), and 5.1 months (95% CI: 4.3–8.7), respectively. Here, 36.7% of patients were found to achieve an objective response. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations (median, PFS: 9.8 vs. 4.5 months, p = 0.023; OS: NR vs. 9.0 months, p = 0.014; ORR: 77.8% vs. 19%, p = 0.004) or loss-of-function mutations in chromatin remodeling genes (median, PFS: 8.7 vs. 4.2 months, p = 0.021; ORR: 63.6% vs. 21.1%, p = 0.046) presented better tumor response and survival outcomes. Furthermore, transcriptome analysis of the tumor immune microenvironment revealed a markedly longer PFS, and tumor response were associated with higher expression of 3-gene effector T cell signature (median, PFS: 7.8 vs. 4.3 months, p = 0.02; ORR: 64.2% vs. 7.1%, p = 0.004) and 18-gene inflamed T cell signature (median, PFS: 8.6 vs. 4.3 months, p = 0.01; ORR: 64.2% vs. 7.1%, p = 0.004). Moreover, our findings highlighted the adverse predictive value of mast cells in immuno-chemotherapy for BTCs for the first time. Conclusions: Sintilimab plus GemCis displayed a promising antitumor activity and acceptable safety profile as a first-line treatment in patients with advanced BTC. Multiomics potential predictive biomarkers are identified and warrant further verification. Clinical trial information: ChiCTR2000036652 .

Efficacy and safety of pembrolizumab versus sintilimab treatment in patients with advanced squamous lung cancer: A real-world study in China.

Both pembrolizumab and sintilimab have been approved by the Chinese State Drug Administration (NMPA) for the first-line treatment of patients with advanced squamous lung cancer. The differences of the two drugs in efficacy and safety are unclear. To compare the real-world efficacy and safety of first-line treatments in patients with advanced squamous lung cancer. This was a retrospective review of patients with advanced squamous carcinoma who received sintilimab or pembrolizumab in combination with chemotherapy as first-line therapy between June 2018 and April 2022 in the Chinese PLA Hospital. The primary objective was to compare the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between the two groups. Secondary objectives were to compare the disease control rate (DCR) and to analyze adverse events (AEs) between the two groups. A total of 164 patients were enrolled, including 63 patients (38.4%) in the sintilimab-combined chemotherapy group and 101 patients (61.6%) in the pembrolizumab-combined chemotherapy group. The ORR was 65.10% in the sintilimab group and 61.40% in the pembrolizumab group (P=0.634). The DCR was 92.10% and 92.10% in the sintilimab and pembrolizumab groups, respectively (P=0.991). The median PFS was 22.2 months for patients treated with sintilimab group compared with 16.5 months for patients treated with pembrolizumab group[hazard ratio (HR) = 0.743; 95% confidence interval (CI): 0.479-1.152; P = 0.599]. Patients treated with pembrolizumab did not achieve a median OS, and patients treated with sintilimab had a median OS of 30.7 months. In the sintilimab group, the incidence of all treatment-related adverse events (TRAEs) was 92.1% (58/63), and the incidence of grade 3-4 TRAEs of 42.9% (27/63). In the pembrolizumab group, the incidence of all TRAEs was 90.1% (91/101), and the incidence of grade 3-4 TRAEs was 37.6% (38/101). In the clinical treatment of Chinese patients with advanced squamous lung cancer, first-line treatment with sintilimab in combination with chemotherapy provided similar efficacy to pembrolizumab in combination with chemotherapy, and the treatment-related adverse effect profiles were comparable between the two groups, including similar rates of grade 3-4 and all adverse events.

PD24-09 PHASE II, MULTI-CENTER STUDY OF SINTILIMAB IN COMBINATION WITH AXITINIB IN PATIENTS WITH ADVANCED FUMARATE HYDRATASE-DEFICIENT RENAL CELL CARCINOMA

PD24-09 PHASE II, MULTI-CENTER STUDY OF SINTILIMAB IN COMBINATION WITH AXITINIB IN PATIENTS WITH ADVANCED FUMARATE HYDRATASE-DEFICIENT RENAL CELL CARCINOMA

Cost-effectiveness analysis of sorafenib, lenvatinib, atezolizumab plus bevacizumab and sintilimab plus bevacizumab for the treatment of advanced hepatocellular carcinoma in China

Background and ObjectiveHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, especially in China. According to the 2021 Chinese Society of Clinical Oncology guidelines, sorafenib, lenvatinib, atezolizumab combined with bevacizumab, and sintilimab combined with bevacizumab are recommended as first-line treatment options for advanced HCC. This study provides a cost-effectiveness analysis of these treatments from the patient perspective.MethodsA partitioned survival model was established using the TreeAge 2019 software to evaluate the cost-effectiveness. The model includes three states, namely progression-free survival, progressive disease, and death. Clinical data were derived from three randomized controlled studies involving patients with advanced HCC who received the following treatment: sorafenib and lenvatinib (NCT01761266); atezolizumab in combination with bevacizumab (NCT03434379); and sintilimab in combination with bevacizumab (NCT03794440). Cost and clinical preference data were obtained from the literature and interviews with clinicians.ResultsAll compared with sorafenib therapy, lenvatinib had an incremental cost-effectiveness ratio (ICER) of US$188,625.25 per quality-adjusted life year (QALY) gained; sintilimab plus bevacizumab had an ICER of US$75,150.32 per QALY gained; and atezolizumab plus bevacizumab had an ICER of US$144,513.71 per QALY gained. The probabilistic sensitivity analysis indicated that treatment with sorafenib achieved a 100% probability of cost-effectiveness at a threshold of US$36,600/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the medical insurance reimbursement ratio and drug prices.ConclusionsIn this economic evaluation, therapy with lenvatinib, sintilimab plus bevacizumab, and atezolizumab plus bevacizumab generated incremental QALYs compared with sorafenib; however, these regimens were not cost-effective at a willingness-to-pay threshold of US$36,600 per QALY. Therefore, some patients may achieve preferred economic outcomes from these three therapies by tailoring the regimen based on individual patient factors.

Abstract OT1-05-02: Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial

Abstract Background: Anti-PD-1 antibody combined with antiangiogenic drugs have demonstrated antitumor activity in advanced triple negative breast cancer (TNBC). Anlotinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has synergistic effect with anti-PD-1 antibody. Preclinical studies showed that metronomic chemotherapy inhibited angiogenesis and enhanced immunotherapy efficacy in TNBC via modulation of tumor immune microenvironment. We hereby conducted a single-arm, multicenter, phase II trial to investigate the efficacy and safety of sintilimab (anti-PD-1 antibody) in combination with anlotinib plus metronomic chemotherapy as a potential novel therapeutic strategy in advanced TNBC and explore potential biomarkers. Methods: Forty-three cases were planning to be included in this trial. The eligible patients who had received no more than two lines of chemotherapy for metastatic disease were enrolled and received sintilimab (200 mg iv q3w) in combination with anlotinib (12 mg po d1-14 q3w) plus capecitabine (500 mg po, tid) or vinorelbine (40 mg po, tiw) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR) and secondary endpoints are disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Blood samples collected at different time points of the baseline, first and second cycle post-treatment, and disease progression were used for next-generation sequencing of ctDNA containing 654 tumor-related genes. Results: As of July 2022, a total of 32 patients were enrolled, and 29 patients were evaluable for efficacy. 2 patients (6.9%) achieved complete response (CR). 6 patients (20.7%) achieved partial response (PR). The ORR is 27.6% (8/29) and DCR is 79.3% (23/29). The median PFS was not reached. The most common grade 1 or 2 adverse events (AEs) include elevated thyroid stimulating hormone (37.0%, 10/27), hand-foot syndrome (18.5%, 5/27), elevated aspartate aminotransferase (14.8%, 4/27), elevated bilirubin (11.1%, 3/27) and hypertension (11.1%, 3/27). Grade 3 AEs include elevated bilirubin (3.7%, 1/27) and hypertension (3.7%, 1/27). No grade 4 or 5 AEs occurred. By analyzing ctDNA mutations of blood samples in 10 patients at baseline, we found that genes with high mutation frequency were HLA-DRB5 (8/10, 80%), TP53 (7/10, 70%), HLA-DRB1 (5/10, 50%) and PIK3CA (4/10, 40%). Among these 10 patients, 2, 3 and 5 patients achieved PR, SD and PD, respectively. The number of gene mutations in patients with PD was higher than that in patients with PR or SD at baseline. This indicate that mutations in ctDNA may be associated with poor efficacy in advanced TNBC. But this still needs further verification. Dynamic analysis of gene mutations at different time points showed that the amplification of HLA-DRB5 or the elimination of KMT2D, RELN and TP53 occurred in patients with PR and SD, but not in patients with PD. Conclusions: Sintilimab in combination with anlotinib plus metronomic chemotherapy has shown favorable efficacy and acceptable safety profile in patients with advanced TNBC. The clinical significance of ctDNA dynamic monitoring needs further validation. Clinical trial information: ChiCTR2100044725 Citation Format: Huihui Li, Qiaorui Tan, Shujuan Sun, Dongdong Zhou, Bo Yu, Mu Su, Baojiang Li, Shu Fang, Ling Qiang, Guohua Ren, Bing Bu, Sha Yin, Xiaochu Man, Pengfei Qiu, Xinzhao Wang, Chao Li, Fangli Cao, Qian Shao, Dali Han, Lihua Song, Bingjie Fan, Baoxuan Zhang, Liang Xu, Xianguang Zhao, Yuqian Liao, Xuemei Xie, Lanping Liu. Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-05-02.

Phase II multi-center study of sintilimab in combination with axitinib in patients with advanced fumarate hydratase-deficient renal cell carcinoma.

685 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly aggressive cancer mainly caused by germline or somatic aberrant of FH gene. Unfortunately, there are no standard treatment. Here we report the preliminary results of a phase II study investigating the efficacy and safety of sintilimab in combination with axitinib in patients with FH-RCC. Methods: Patients were treated at mutli-center in hospitals of the republic of China. Eligibility criteria included age ≥ 18 years and newly diagnosed as FH-RCC by FH immunohistochemistry and next-generation sequencing or multiplex ligation-dependent probe amplification. Patients received sintilimab (intravenous injection, every 3 week) in combination with axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary end point was objective response rate (ORR; RECIST v1.1). This study is registered with ClinicalTrials.gov, NCT04387500. Results: Between July 2021 and October 2022, 21 patients were enrolled. At this preliminary analysis (data cutoff, October, 2022), median follow-up was 9 months (0.9-15.2 months). Nineteen patients were available for efficacy assessment. Confirmed complete response rate was 15.8% (3/19), ORR was 63.1% (12/19). Disease-controlled rate (DCR) was 89.4% (17/19). The median of progression-free survival (PFS) was not reached, with a high 12-month PFS rate of 72.3%. All grade and ≥ 3 treatment-emergent adverse events occurred in 95% (20/21) and 23.8% (5/21), respectively. Conclusions: Sintilimab in combination with Axitinib had a manageable safety profile and achieved a promising tumor response rate in patients with advanced FH-RCC. The trial is an ongoing study, with a total of planned 41 patients from 8 sites. The study start date was June 2, 2021. Clinical trial information: NCT04387500 .

EP08.01-032 Sintilimab in Combination with Anlotinib in NSCLC Patients with Uncommon EGFR Mutations: A Phase II, Single-arm, Prospective Study

Compared with classic epidermal growth factor receptor (EGFR) mutations, uncommon EGFR alterations showed poorer outcomes in non-small-cell lung cancer (NSCLC) patients. This study aimed to investigate the efficacy and safety of PD-1/PD-L1 blockade and anti-angiogenesis treatments in NSCLC patients with uncommon EGFR mutations.