Nivolumab-Ipilimumab Combo Receives FDA Breakthrough Designation for Advanced Hepatocellular Carcinoma


FDA breakthrough designation is based on data for nivolumab plus ipilimumab in a study evaluating the immuno-oncology combination in patients with advanced hepatocellular carcinoma previously treated with sorafenib.

The FDA has accepted a supplemental Biologics License Application (sBLA) and granted Breakthrough Therapy Designation for nivolumab (Opdivo, Bristol-Myers Squibb Company) in combination with ipilimumab (Yervoy, Bristol-Myers Squibb Company) for the treatment of patients with advanced hepatocellular carcinoma (HCC) who were previously treated with sorafenib.

The FDA granted the application Priority Review with a Prescription Drug User Fee Act (PDUFA) goal date of March 10, 2020.

“The FDA’s acceptance of our application for [nivolumab plus ipilimumab] represents important progress for patients with liver cancer in the United States, where hepatocellular carcinoma is the fastest rising cause of cancer-related death. Despite recent advances, hepatocellular carcinoma remains a difficult-to-treat cancer and patients are in need of additional effective treatment options. We look forward to working with the FDA to bring the potential of a dual immuno-oncology therapy to these patients for the first time,” said Ian M. Waxman, MD, development lead of Gastrointestinal Cancers at Bristol-Myers Squibb.

The sBLA is based on data from the nivolumab plus ipilimumab cohort of the phase 1/2 CheckMate-040 study evaluating the immuno-oncology combination in patients with advanced HCC previously treated with sorafenib. Data from this study were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

CheckMate-040 is an ongoing phase 1/2, open-label, multi-cohort study investigating nivolumab or nivolumab-based combinations in patients with advanced HCC with and without chronic viral hepatitis who are naïve, intolerant to, or who have progressed during sorafenib therapy. The nivolumab plus ipilimumab cohort of CheckMate-040 evaluated the safety and efficacy of the combination in patients with previously treated advanced HCC.

Also presented at the ASCO meeting was a study on nivolumab and ipilimumab which, in combination, showed suitable survival outcomes in patients with advanced melanoma. The combination once again showed suitable survival outcomes once a patient stopped treatment, regardless of BRAF gene or lactate dehydrogenase status, according to the study authors.

In this trial, the study authors wanted to determine overall survival (OS) after 5 years of analysis. It was reported that patients with advanced melanoma who participated in the previous study had a 3-year OS rate of 63% with nivolumab and ipilimumab concurrent therapy in the initial phase 1 dose-escalation study for the combination.

The results indicated that 4/4.5 year survival was approximately 57% in all cohorts. Additionally, the following OS 4-year rates were found:

  • 62% for patients with normal rates
  • 49% for patients with elevated LDH rates
  • 54% for patients with wild-type
  • 61% for patients with mutant BRAF tumors

According to the study, following the last dose of study drug, overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively. In patients who discontinued due to drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively. Finally, in patients who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively.

Specialty Pharmacy Times® also interviewed Michael Atkins, MD, director of the Georgetown Lombardi Cancer Center at Georgetown University, who discussed the results of this trial that examined the long-term benefits of the nivolumab and ipilimumab combination therapy.

According to Atkins, this analysis presented at ASCO demonstrated favorable survival outcomes with nivolumab and ipilimumab, regardless of BRAF or LDH status, and provided evidence of long-term survival after patients with advanced melanoma stopped treatment.

Related Content

  • Combination Therapy Shows Favorable Overall Survival for Patients with Advanced Melanoma
  • Specific Patient Populations Benefit from Nivolumab/Ipilimumab Combo Therapy

Atkins also discussed key considerations for pharmacists regarding the trial results, which includes identifying specific patient populations who may require nivolumab/ipilimumab combination therapy to achieve maximum benefit.

Nivolumab 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-tumor immune response. By harnessing the body’s own immune system to fight cancer, nivolumab has become an important treatment option across multiple cancers.

In July 2014, nivolumab was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Nivolumab is currently approved in more than 65 countries.

The FDA’s Breakthrough Therapy Designation is a process intended to enable timely patient access by expediting the development and review of medicines for serious conditions where preliminary clinical evidence indicates a substantial improvement over available therapies on one or more clinically significant endpoints.


  • U.S. Food and Drug Administration Accepts for Priority Review Bristol-Myers Squibb’s Application for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combination for Patients with Previously Treated Advanced Hepatocellular Carcinoma [press release]. Princeton, NJ. Bristol-Myers Squibb website. Published November 11, 2019. Accessed November 11, 2019.

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