Sintilimab Combo Shows Modest Efficacy, Safety in HER2– Gastric/GEJ Cancer

“The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced gastric/GEJ cancer, which suggested a potential therapeutic option for this population,” according to the study authors.

The neoadjuvant regimen of sintilimab (Tyvyt) plus fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) demonstrated antitumor activity and an acceptable safety profile in a small cohort of patients with HER2-negative locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to phase 2 findings from a single-arm Chinese study (NCT04341857) published in the International Journal of Surgery.

Results showed that the pathological complete response (pCR) rate with the regimen was 17.2% (95% CI, 5.8%-35.8%) in 29 evaluable patients. The rates of moderate response (TRG1), minimal response (TRG2) and poor response (TGR3) were 37.9%, 34.5%, and 10.3%, respectively. Additionally, the major pathological response (MPR) rate was 55.2% (95% CI, 35.7%-73.6%); when compared with clinical stage prior to treatment, 79.3% of patients had T downstaging, 55.2% had N downstaging, and 65.5% had TNM downstaging.

“The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced gastric/GEJ cancer, which suggested a potential therapeutic option for this population,” lead study author Ning Li, of the Department of Medical Oncology at The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital in Zhengzhou, China, and coinvestigators wrote in the paper.

Most patients with locally advanced gastric/GEJ cancer have a relapse following surgical resection, and the use of neoadjuvant chemotherapy has been adopted in a standard approach. However, there is still an unmet need to improve pathological regression and long-term survival for patients in this setting. Sintilimab is a humanized IgG4 monoclonal antibody targeting PD-1 designed to have higher binding affinity than other currently available PD-1 inhibitors.

In the investigator-initiated, single-arm, open-label, phase 2 trial, investigators sought to evaluate the efficacy and safety of neoadjuvant sintilimab and FLOT in patients with HER2-negative locally advanced gastric/GEJ adenocarcinoma. Patients were administered 200 mg of intravenous (IV) sintilimab on day 1 every 3 weeks for 3 cycles, and the investigator’s choice of FLOT chemotherapy included 1-hour 50 mg/m² of docetaxel, 2-hour 80 mg/m² of oxaliplatin, and 200 mg/m² of calcium levofolinate and 24-hour 2600 mg/m² of 5-fluorouracil on day 1. All chemotherapy agents were administrated IV every 2 weeks for 4 cycles. Surgery was scheduled within 2 to 6 weeks following neoadjuvant therapy completion, and adjuvant FLOT chemotherapy at the same dosing schedule was recommended for 4 cycles at 3 to 8 weeks following surgery.

To be eligible for enrollment, patients had to have previously untreated, histologically confirmed, cT4 and/or cN+M0 disease and be between the ages of 18 and 75 years. Disease must have been deemed resectable prior to giving neoadjuvant therapy. All patients had an ECOG performance status of 0 or 1; adequate hematopoietic, hepatic, and renal function; and tumor samples available for PD-1/PD-L1 and microsatellite instability testing.

Those who had active autoimmune disease or other primary malignancies at the time of screening were excluded from enrollment.

Follow-up continued every 2 to 3 months after postoperative treatment until death.

The primary end point was pCR, while secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival (OS), disease-free survival (DFS), event-free survival (EFS), MPR, R0 resection rate, downstaging, and safety. Pre- and post-treatment dynamics of alterations in the tumor immune microenvironment or correlative biomarkers with pathological response served as exploratory end points.

Thirty-five patients were screened between August 2019 and September 2021; 3 were excluded for use of prohibited treatment as specified on the trial; therefore, 32 patients were enrolled. Three patients did not undergo surgery due to disease progression (n = 1) and refusal of surgery (n = 2).

Of the 32 patients, the median age was 58 years (range, 43-70), and 78.1% of patients were male. Most patients had gastric primary tumors (81.3%), and all had stage III disease. cT4a was the clinical tumor stage in 59.4% of patients, and node-positive disease was found in all 32 patients. A total of 44.8% of patients had a PD-L1 combined positive score of at least 1; 81.3% of patients had microsatellite stable disease.

Twenty-nine patients underwent gastrectomy with D2 lymph node dissection at a mean time between the last neoadjuvant treatment and surgery of 26.8 days (range, 19-73). R1 resection with positive surgical margins was performed in 6.9% of patients, and the R0 resection rate was 93.1% (95% CI, 77.2%-99.2%). The mean number of lymph nodes resected was 26 (range, 14-53), while the mean operative time was 219.1 minutes (range, 166.0-272.2). Patients had a mean 12 days of postoperative hospital stay (range, 7-32). Additionally, adjuvant therapy was started in 86.2% of patients; 4 patients discontinued treatment due to the COVID-19 pandemic. Of this portion, 41.4% of patients completed 4 cycles of adjuvant therapy compared with 17.2% and 27.6% of patients who received 2 and 3 cycles, respectively.

The data cutoff date was November 1, 2023, with a median follow-up of 34.8 months (95% CI, 32.8-42.9). Eight patients in the full analysis set died, and 6 in the surgical setting relapsed. Eleven patients were followed for more than 3 years.

Further findings showed that the median EFS, DFS, and OS were not reached. The 2-year EFS rate was 75.0% (95% CI, 61.4%-91.6%), the 2-year DFS rate was 82.8% (95% CI, 70.1%-97.7%), and the 2-year OS rate was 84.4% (95% CI, 72.7%-97.9%). Three-year EFS, DFS, and OS rates 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 ORR was 84.4% (95% CI, 68.3%-93.1%), which included a 12.5% complete response rate and a 71.9% partial response rate; 4 patients (12.5%) had stable disease. The DCR was 96.9% (95% CI, 84.3%-99.5%), and the tumor shrinkage rate was also 96.9%. One patient experienced disease progression prior to surgery.

Through the biomarker analysis, investigators identified that the 2 patients with microsatellite instability–high disease did not achieve a pCR.

Regarding safety, all patients experienced at least 1 treatment-related adverse effect (TRAE) in the neoadjuvant phase; most cases were grade 1 or 2. Any-grade TRAEs included nausea (100.0%), decreased appetite (100.0%), hypodynamia (100.0%), lymphopenia (96.9%; grade ≥3, 34.4%), anemia (84.4%), leukopenia (75.0%; grade ≥3, 15.6%), and neutropenia (65.6%; grade ≥3, 28.1%). Grade 3 or higher anemia occurred in 12.5% of patients, and 18.8% of patients experienced hypothyroidism, which was deemed a potential immunologic cause. No grade 5 TRAEs occurred; however, 3 patients died due to disease progression (n = 2) and acute cerebrovascular disease following surgery (n = 1).

Of the 29 patients in the surgery set, 51.7% had grade 1/2 surgical complications, which mainly included anemia (44.8%), fever (13.8%), weight loss (10.3%), and intestinal obstruction (10.3%). There were no cases of surgical complications that led to hospital readmission within 30 days, emergency reoperation, or intensive care.

Reference

Li N, Li Z, Fu Q, et al. 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. Int J Surg. Published online February 5, 2024. doi:10.1097/JS9.0000000000001119