Bristol Myers Squibb Submits sBLAs for Opdivo-Based Regimens in First-Line Unresectable Advanced or Metastatic Esophageal Squamous Cell Carcinoma

Esophageal cancer (Image source: medindia.net)

October 12, 2021 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) recently announced that the U.S. Food and Drug Administration (FDA) has accepted two supplemental Biologics License Applications (sBLAs) for the anti-PD-1 therapy Opdivo (nivolumab):Opdivo in combination with anti-CTLA-4 therapy Yervoy (ipilimumab), or Opdivo in combination with chemotherapy (fluorouracil plus cisplatin), for the first-line treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC).。FDAThe Prescription Drug User Fee Act (PDUFA) target date has been set for May 28, 2022. In the European Union, the two aforementioned Opdivo regimens were accepted by the European Medicines Agency (EMA) in August of this year and have entered the centralized review procedure.

Chemotherapy has long been the standard of care for ESCC. However, the prognosis for ESCC patients receiving chemotherapy alone remains poor, and there is an urgent need for additional regimens to improve treatment outcomes. Opdivo-based combination therapy has the potential to provide further clinical benefits and address this critical need.

These applications are based on the results of the pivotal Phase 3 CheckMate-648 trial. The trial evaluated the efficacy and safety of Opdivo in combination with chemotherapy (fluorouracil plus cisplatin), Opdivo in combination with Yervoy, and standard-of-care chemotherapy in adult patients with unresectable advanced or metastatic ESCC. The primary endpoints of the study included: determined by Blinded Independent Central Review (BICR) assessmentTumorOverall survival (OS) and progression-free survival (PFS) in PD-L1–expressing patients, comparing two Opdivo combination regimens with chemotherapy. Secondary endpoints include: OS and PFS in the overall randomized patient population as assessed by BICR.

It is worth mentioning that CheckMate-648 is the first global Phase 3 study to concurrently evaluate immunotherapy plus chemotherapy and dual immunotherapy for the treatment of advanced ESCC. The results of this trial were presented this June at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. The results showed that, in the prespecified interim analysis,Compared with chemotherapy, Opdivo + chemotherapy and Opdivo + Yervoy inTumorDemonstrated statistically significant and clinically meaningful improvement in OS in the patient population with tumor PD-L1 expression ≥1% and across all randomized patient populations.. It is worth noting that,Opdivo+Yervoy is the first dual immunotherapy regimen to demonstrate a superior survival benefit compared with chemotherapy in the treatment of ESCC.

CheckMate-648 is one of four positive Phase 3 trials.Clinical Trialone of them. In these trials,Opdivo or Opdivo-based combination therapy provides significant therapeutic benefits for patients with upper gastrointestinal cancers (gastric cancer, gastroesophageal junction cancer, and esophageal cancer).

The specific data from the CheckMate-648 trial are as follows: (1) inTumorIn PD-L1–expressing patients, (1) the median OS was 15.4 months in the Opdivo + chemotherapy group versus 9.1 months in the chemotherapy group (HR = 0.54; 99.5% CI: 0.37–0.80, p < 0.0001); (2) in the overall randomized patient population, the median OS was 13.2 months in the Opdivo + chemotherapy group versus 10.7 months in the chemotherapy group (HR = 0.74; 99.1% CI: 0.58–0.96, p = 0.0021).

Per BICR assessment, compared with chemotherapy, the Opdivo plus chemotherapy regimen inTumorResulted in a statistically and clinically significant improvement in PFS among PD-L1-expressing patients (median PFS: 6.9 months vs. 4.4 months; HR=0.65; 98.5% CI: 0.46-0.92; p=0.0023).

Additionally, compared with chemotherapy, the Opdivo + Yervoy regimen also met both primary and secondary endpoints: demonstrating statistically significant and clinically meaningful improvements in OS in patients with PD-L1–expressing tumors (median OS: 13.7 months vs 9.1 months; HR = 0.64; 98.6% CI: 0.46–0.90; p = 0.001) and in the overall randomized patient population (median OS: 12.8 months vs 10.7 months; HR = 0.78; 98.2% CI: 0.62–0.98; p = 0.011). However, the Opdivo + Yervoy regimen in`Tumor`The primary endpoint of improved PFS was not met in PD-L1-expressing patients (median PFS: 4.0 months vs. 4.4 months; HR=1.02; 98.5% CI: 0.73-1.43; p=0.8958).

Duration of Response (DoR): (1) InTumorIn patients with PD-L1 expression, the median DoR was 8.4 months in the Opdivo + chemotherapy group, 11.8 months in the Opdivo + Yervoy group, and 5.7 months in the chemotherapy-alone group; (2) in the overall randomized patient population, the median DoR for the three groups was 8.2 months, 11.1 months, and 7.1 months, respectively.

In terms of objective response rate (ORR), Opdivo + chemotherapy also demonstrated a clinically meaningful improvement: (1) in# TumorAmong patients with PD-L1 expression, the ORR was 53% for the Opdivo + chemotherapy group, 35% for the Opdivo + Yervoy group, and 20% for the chemotherapy-alone group; (2) in the overall randomized patient population, the ORRs for the three groups were 47%, 28%, and 27%, respectively. In this trial, the safety profiles of Opdivo and Opdivo + Yervoy were consistent with those previously reported.

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide, with approximately 604,000 new cases and over 544,000 deaths in 2020. The two most common types are esophageal squamous cell carcinoma (ESCC) and adenocarcinoma, which account for approximately 90% and 10% of all esophageal cancers, respectively, although histological types may vary by region. The overall burden of ESCC is concentrated in Asia, accounting for approximately 80% of global cases in 2020. Most esophageal cancer cases are diagnosed at an advanced stage, affecting patients' daily lives, including their ability to eat. ESCC most frequently occurs in the upper and middle portions of the esophagus, whereas adenocarcinoma originates from the mucus-secreting glandular cells of the esophagus and is most commonly found in the lower portion.

Opdivo is a PD-(L)1 tumor immunotherapy designed to harness the body’s own immune system to fight cancer. By blocking the PD-1/PD-L1 signaling pathway, it induces cancer cell death and holds potential for treating various types of tumors. To date, Opdivo has been approved for multiple cancer indications. In October 2015, Opdivo + Yervoy became the world’s first regulatory-approved immuno-oncology combination therapy. It has since been approved for multiple tumor types in over 50 countries and regions worldwide, including lung cancer, pleural mesothelioma, melanoma, renal cell carcinoma, colorectal cancer, and hepatocellular carcinoma.

In the field of esophageal cancer, Opdivo has been approved for three therapeutic indications, specifically: (1) for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) following prior fluoropyrimidine- and platinum-based chemotherapy, regardless of PD-L1 expression level; (2) as adjuvant treatment for adult patients with esophageal or gastroesophageal junction (GEJ) cancer who have residual pathologic disease after neoadjuvant chemoradiotherapy (CRT) and complete resection; (3) in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of adult patients with advanced or metastatic gastric cancer (GC), gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma (EAC), regardless of PD-L1 expression status.

In China, Opdivo (Oudiwo) was granted marketing approval in June 2018, becoming the first approved immuno-oncology (I-O) therapeutic agent in the Chinese market. To date, Opdivo has received approval from the National Medical Products Administration (NMPA) for multiple tumor indications, including: non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma, and malignant pleural mesothelioma, among others.

In China, Opdivo + Yervoy was approved by the NMPA in June 2021 for the treatment of adult patients with unresectable, treatment-naïve nonepithelioid malignant pleural mesothelioma. This marks the first indication approved in China for a dual immunotherapy combination, signifying the official launch of Yervoy, the world's first CTLA-4 inhibitor, in China. (Bioon.com)

Original Source:U.S. Food and Drug Administration Accepts Bristol Myers Squibb’s Applications for Opdivo (nivolumab) + Yervoy (ipilimumab) and Opdivo + Chemotherapy for Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma