At present, the main treatment option for advanced esophageal squamous cell carcinoma (ESCC) is standard chemotherapy, but the median SURVIVAL of patients is only about 10 months. Recently, the European Medicines Agency's Committee on Human Medicines (CHMP) recommended the approval of Opdivo (nivolumab) and Yervoy (ipilimumab) for the first-line treatment of non-resectable advanced, recurrent or metastatic ESCC adult patients with PD-L1 expression of 1% or more.
Introduction to O+Y dual immunotherapy
Both Opdivo and Yervoy are immunotherapies that use the body's own immune system to fight tumors by targeting different regulatory elements in the immune system. Among them, Opdivo targets and blocks the PD-1/PD-L1 pathway, while Yervoy targets and blocks CTLA-4. Opdivo+Yervoy is the only dual immunotherapy approved by the US FDA. The therapy has a potential synergistic mechanism, targeting 2 different immune checkpoints (PD-1 and CTLA-4) and acting in a complementary manner. In the United States, the combination has been approved by the FDA for the treatment of 4 types of cancer (melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma).
In September 2021, the FDA accepted the license application for Opdivo+Yervoy and Opdivo+ fluoropyrimidine and platinum-containing chemotherapy complementary biological agents for the first-line treatment of patients with non-resectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma, which is based on the survey results of CheckMate-648.
Latest treatment data of O+Y dual immunotherapy
This recommendation is based on the results of the phase 3 CheckMate-648 trial (NCT03143153). This global, open-label phase 3 CheckMate-648 trial enrolled patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma who had measurable disease and an ECOG performance status of 0 or 1. Notably, patients were not permitted to have previously received systemic therapy for advanced disease. The primary endpoints of the trial included overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 expression levels of 1% or higher. Key secondary endpoints included OS and PFS in all randomized populations, and objective response rate (ORR) in all randomized populations and a subset of patients with PD-L1-positive disease.
A total of 970 participants received 1:1:1 randomized treatment, receiving 240 mg of Opdivo every 2 weeks and chemotherapy every 4 weeks (n =321), 3 mg/kg of Opdivo every 2 weeks and 1 mg/kg of Yervoy (Yervoy) every 6 weeks (n = 325), or chemotherapy alone every 4 weeks (n = 324). The chemotherapy regimen consists of fluorouracil 800 mg/m2, days 1 to 5, cisplatin 80 mg/m2, and 4 weeks as a cycle. The course of treatment for Opdivo is up to 24 months, or until the disease progresses, unbearable toxicity, or consent is withdrawn.
Patients were stratified based on PD-L1 expression (≥1% vs <1%), region (East Asia vs other parts of Asia vs other parts of the world), ECOG performance status (0 vs 1), and number of metastatic organs (≤1 vs ≥2). In the dual immunotherapy group, the median age was 63 years (range 28–81 years), 83% were male, 70% were Asian, 54% had an ECOG performance of 1, and 99% had ESCC. Among these patients, 51% had PD-L1 expression levels of less than 1% on tumor cells, and 49% had expression levels of 1% or higher.
60% of patients have new metastatic diseases, 22% have recurrent distant diseases, 10% have non-resectable advanced diseases, and 8% have recurrent local diseases. In addition, 51% of patients had metastases of 2 or more organs, and 49% had metastases of 0 or 1 organ. 82% of patients in this group are current or former smokers.
With January 18, 2021 as the data cutoff date, the minimum follow-up time was 12.9 months. It was noted that baseline characteristics were balanced across the three treatment groups; researchers also noted that these characteristics were consistent with those of individuals with PD-L1 expression levels of 1% or higher. In the Opdivo/Yervoy group of 322 patients, the median duration of treatment was 2.8 months (range 0.0–24.0). Of these patients, 93% discontinued treatment, with 54% due to disease progression, 18% due to treatment-related toxicities, 6% due to treatment-independent adverse events (AEs), 4% at patient request, and 11% for other unstated reasons.
The trial showed that in the subset of patients with PD-L1 expression levels of 1% or higher, the median overall survival (OS) for dual immunotherapy (n = 158) was 13.7 months (95% CI, 11.2–17.0), while that for chemotherapy (n = 157) was 9.1 months (95% CI, 7.7–10.0) (HR, 0.64; 98.6% CI, 0.46–0.90; P = .0010). The 12-month OS rates in the study group and the control group were 57% and 37%, respectively.
The progress-free survival period (PFS) of dual immunotherapy compared with chemotherapy was 4.0 months (95% CI, 2.4-4.9) and 4.4 months (95% CI, 2.9-5.8) (HR, 1.02; 98.5% CI, 0.73-1.43; P= . 8958), did not reach this main end point. The 12-month PFS rates of the survey group and the control group were 26% and 10%, respectively.
Other data presented at the 2021 ASCO Annual Meeting showed that in all randomized populations, the median overall survival (OS) was 12.8 months (95% CI, 11.3–15.5) with Opdivo/Yervoy (n = 325), compared to 5.6 months (n = 324; HR, 0.78; 98.2% CI, 0.62–0.98; P = 0.78). The 12-month OS rates in the survey and control groups were 54% and 44%, respectively. In this population, PFS per BICR was not graded, but the median PFS for dual immunotherapy was 2.9 months (95% CI, 2.7–4.2), compared to 5.6 months (95% CI, 4.3–5.9) with chemotherapy (HR, 1.26; 95% CI, 1.05–1.52).
In the randomized population, the objective response rate (ORR) of Opdivo + Yervoy was 28% (95% CI, 23%–33%), compared to 27% (95% CI, 22%–32%) for chemotherapy. The median duration of response (DOR) for PD-L1-positive disease patients receiving immunotherapy was 11.8 months (95% CI, 7.1–27.4), compared to 5.7 months (95% CI, 4.4–8.7) for chemotherapy. In the randomized population, the median DOR was 11.1 months (95% CI, 8.3–14.0) in the study group and 7.1 months (95% CI, 5.7–8.2) in the control group.
80% of patients receiving the immunotherapy combination developed any level of treatment-related AEs (TRAEs), and 32% of patients developed grade 3 or 4 toxic reactions. 32% of patients developed severe TRAEs; 23% of patients reported severe effects of level 3 or 4. 18% of patients had TRAE that led to withdrawal; 13% of patients had TRAE of level 3 or 4 that led to withdrawal. There were 5 treatment-related deaths.
Reminder: Opdivo+Yervoy dual immunotherapy is expected to inject new vitality into the treatment of advanced esophageal squamous cell carcinoma.
