Bristol-Myers Opdivo Is Approved By The US FDA: No Matter How PD-L1 Is, It Significantly Prolongs The Survival Time!

- Jun 21, 2020-

Bristol-Myers Squibb (BMS) recently announced that the US Food and Drug Administration (FDA) has approved the anti-PD-1 therapy Opdivo (common name: nivolumab) for a new indication for the treatment of previously accepted fluoropyrimidine and platinum as Patients with unresectable, advanced, relapsed, or metastatic esophageal squamous cell carcinoma (ESCC) whose disease progresses after basic chemotherapy.

It is particularly worth mentioning that Opdivo is the first tumor immunotherapy approved for the aforementioned ESCC patient population, regardless of the level of PD-L1 expression. Prior to this indication application, the FDA granted priority review qualification. Clinical data shows that Opdivo prolongs overall survival compared with chemotherapy, and the benefit does not depend on PD-L1 expression status. Patients with advanced esophageal squamous cell carcinoma have a poor prognosis and treatment options are very limited. This approval will provide an important second-line treatment option for ESCC patients, prolonging survival and improving quality of life.

This approval is based on the results of the Phase III ATTRACTION-3 (ONO-4538-24/CA209-473; NCT02569242) study. The data shows that Opdivo showed better overall survival (OS) results compared to taxane chemotherapy (docetaxel or paclitaxel selected by the researchers) (HR=0.77; 95%CI: 0.62-0.96; p=0.0189) . The median OS in the taxane chemotherapy group was 8.4 months (95% CI: 7.2-9.9), while the median OS in the Opdivo treatment group reached 10.9 months (95% CI: 9.2-13.3), regardless of PD-L1 What is the level of expression.

Adam Lenkowsky, general manager and director of Bristol-Myers Squibb's oncology, immunology, cardiovascular, said: "Many cases of esophageal cancer are diagnosed at an advanced stage, at which time the disease may have a significant impact on the patient's health. Once the advanced esophagus Patients with squamous cell carcinoma are getting worse, and treatment options are very limited. The approval of Opdivo will provide a new treatment plan for patients with advanced esophageal squamous cell carcinoma previously treated, regardless of PD-L1 expression level. This reflects our Committed to providing new options to meet the unmet medical needs of patients and allow us to further understand the full potential of immunotherapy for gastrointestinal tumors

. "

ATTRACTION-3 is a multicenter, randomized, open-label, global study conducted in patients with unresectable advanced or relapsed ESCC who are refractory or intolerant to the combination therapy of first-line fluoropyrimidine and platinum drugs. The efficacy and safety of Opdivo compared to chemotherapy (docetaxel or paclitaxel). Patient enrollment mainly occurred in Asia, and up to 96% of patients in the two treatment groups were from Asia. In the study, patients received treatment until the disease worsened or unacceptable toxicity. The primary endpoint of the study was overall survival (OS), and secondary endpoints included investigator-assessed overall response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and safety Sex. The research was sponsored by Bristol-Myers Squibb’s Opdivo partner Ono Pharma.

The results showed that the study reached the primary endpoint of OS: Compared with the chemotherapy group, the Opdivo treatment group showed a statistically significant improvement in OS and a 23% reduction in risk of death (HR=0.77, 95%CI: 0.62-0.96, p=0.0189 ), the median OS is extended by 2.5 months (10.9 months [95%CI: 9.2-13.3] vs 8.4 months [95%CI: 7.2-9.9]). The 12-month and 18-month survival rates (OS rates) of the Opdivo treatment group were 47% (95% CI: 40-54) and 31% (95% CI: 24-37), and the chemotherapy group was 34% (95 %CI: 28-41) and 21% (95% CI: 15-27). Regardless of the tumor's PD-L1 expression level, Opdivo's survival benefit was observed. An exploratory analysis of the patient's reported results shows that patients receiving Opdivo have achieved a significant overall improvement in quality of life compared to chemotherapy.

In terms of ORR, the Opdivo treatment group and the chemotherapy group were 19% (95% CI: 14-26) and 22% (95% CI: 15-29), respectively. However, the study showed that Opdivo significantly extended the duration of median response compared to chemotherapy (DOR: 6.9 months [95%CI: 5.4-11.1] vs 3.9 months [95%CI: 2.8-4.2]). At the time of data cut-off, 7 patients in the Opdivo treatment group remained in remission, and 2 patients in the chemotherapy group. In terms of progression-free survival (PFS), there was no significant difference between the Opdivo treatment group and the chemotherapy group (HR=1.08 [95%CI: 0.87-1.34]).

In this study, the safety of Opdivo is consistent with previous studies conducted in ESCC and other solid tumors. Compared with chemotherapy, Opdivo treatment-related adverse events (TRAE) are less. The incidence of TREA at any grade in patients treated with Opdivo is 60%, and 95% in patients with chemotherapy. The incidence of grade 3 or grade 4 TREA was lower in the Opdivo treatment group than in the chemotherapy group (18% vs 63%), and the proportion of patients who experienced TREA discontinuation was the same in both groups (both 9%).

Esophageal cancer is the seventh most common cancer in the world and the sixth leading cause of cancer death. The five-year relative survival rate of patients diagnosed with metastatic disease is 8% or lower. The two most common types of esophageal cancer are squamous cell carcinoma and adenocarcinoma, accounting for about 90% and 10% of all esophageal cancers.

It is estimated that 572,000 new cases are diagnosed each year and about 500,000 people die from esophageal cancer. Most cases are diagnosed with advanced disease, which should affect the patient's daily life, including diet capacity. Asia has the highest prevalence of esophageal cancer, with 444,000 cases diagnosed each year, accounting for 80% of esophageal cancer cases worldwide.

It is worth mentioning that at the end of July 2019, Merck's PD-1 tumor immunotherapy Keytruda (Kerida, common name: pembrolizumab, pablizumab) was approved by the US FDA to treat PD-L1 positive esophageal squamous cell carcinoma (ESCC) patients, specifically: tumors expressing PD-L1 (combined positive score [CPS] ≥10) determined by an FDA approved test method, relapse of disease progression after receiving one or more systemic therapies, local Patients with advanced or metastatic ESCC. Keytruda is the first anti-PD-1 therapy approved for the treatment of patients with recurrent locally advanced or metastatic ESCC (tumor expressing PD-L1, CPS ≥ 10).

The approval is based on data from 2 clinical studies, KEYNOTE-181 (NCT02564263) and KEYNOTE-180 (NCT02559687). Data from the KEYNOTE-181 study showed that among patients with ESCC tumors expressing PD-L1 (CPS ≥ 10), Keytruda-treated patients showed improved OS (median OS: 10.3 months [95% CI :7.0-13.5] vs 6.7 months [95%CI: 4.8-8.6]; HR=0.64[95%CI: 0.46-0.90]). Data from the KEYNOTE-180 study showed that among 35 ESCC patients whose tumors express PD-L1 (CPS ≥ 10), the ORR was 20% (95% CI: 8.0, 37.0). Among the 7 patients with remission, the DOR ranged from 4.2 months to 25.1+ months. 71% of the patients (5 cases) had DOR ≥ 6 months and 57% of the patients (3 cases) had DOR ≥ 12 months.