EMA Validates Bristol Myers Squibb’s Type II Variation Application for Opdivo Plus Yervoy for First-Line Treatment of Unresectable or Advanced HCC

Bristol Myers Squibb announced that the European Medicines Agency (EMA) validated its Type II variation application for Opdivo (nivolumab) plus Yervoy (ipilimumab) as a potential first-line treatment option for adult patients with unresectable or advanced hepatocellular carcinoma (HCC) who have not received prior systemic therapy. The application was based on results from the phase 3 CheckMate -9DW trial and validation of the application confirms the submission is complete and begins the EMA’s centralized procedure review.

“Approximately 62,000 cases of liver cancer are diagnosed annually in the European Union, with HCC being the predominant type. Despite recent treatment advances, the prognosis remains poor for patients in more advanced stages which highlights the need for therapies with better clinical outcomes,” said Dana Walker, M.D., M.S.C.E., vice president, global programme lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb. “We look forward to working with the EMA to advance our application for Opdivo plus Yervoy to provide a new first-line dual immunotherapy combination treatment option for adult patients with unresectable or advanced hepatocellular carcinoma in the European Union.”

In the phase 3 CheckMate -9DW trial, Opdivo plus Yervoy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) compared to investigator’s choice of lenvatinib or sorafenib, which showed the clinical benefit of the combination treatment option when provided in the first-line setting. The safety profile for the combination of Opdivo plus Yervoy remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified. Results were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Bristol Myers Squibb thanks the patients and investigators involved with the phase 3 CheckMate -9DW clinical trial.

CheckMate -9DW is a phase 3 randomized, open-label trial evaluating the combination of Opdivo plus Yervoy compared to investigator’s choice of lenvatinib or sorafenib monotherapy in patients with unresectable or advanced hepatocellular carcinoma who have not received prior systemic therapy.

Approximately 668 patients were randomized to receive Opdivo plus Yervoy (Opdivo 1mg/kg plus Yervoy 3 mg/kg Q3W for up to four doses, followed by Opdivo monotherapy 480 mg for a maximum duration of 2 years) infusion, or single agent lenvatinib or sorafenib as oral capsules in the control arm. The primary endpoint of the trial is overall survival and key secondary endpoints include objective response rate and time to symptom deterioration.

Liver cancer is the third most frequent cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and accounts for 75% - 85% of all liver cancers. HCC is often diagnosed in an advanced stage, where effective treatment options are limited and are usually associated with poor outcomes.

Up to 70% of patients experience recurrence within five years, particularly those still considered to be at high risk after surgery or ablation. While most cases of HCC are caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, metabolic syndrome and nonalcoholic steatohepatitis (NASH) are rising in prevalence and expected to contribute to increased rates of HCC.

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumour immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including phase 3, in a variety of tumour types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumour infiltrating T-effector cells. Inhibition of CTLA-4 signalling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumour immune response. On March 25, 2011, the US Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumour types.

Checkmate 227–previously untreated metastatic non-small cell lung cancer, in combination with Yervoy; Checkmate 9LA–previously untreated recurrent or metastatic non-small cell lung cancer in combination with Yervoy and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 238– adjuvant treatment of patients with completely resected Stage III or Stage IV melanoma; Checkmate 76K–adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with Yervoy; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with Yervoy; Attraction-3–esophageal squamous cell carcinoma; Checkmate 648–previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma; Checkmate 648–previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma; Checkmate 040–hepatocellular carcinoma, in combination with Yervoy; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with Yervoy; Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with Yervoy; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 901–Adult patients with unresectable or metastatic urothelial carcinoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with Yervoy; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 205/039–classical Hodgkin lymphoma.

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.