Nivolumab for Sorafenib-Pretreated HCC Withdrawn from the US Market


The indication for nivolumab as a single agent for the treatment of hepatocellular carcinoma in patients previously treated with sorafenib has been withdrawn from the US market.

The indication for nivolumab (Opdivo) as a single agent for the treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib (Nexavar) has been withdrawn from the US market, according to a press release by Bristol Myers Squibb (BMS).

Nivolumab is a programed death-1 (PD-1) inhibitor checkpoint that is meant to elicit and anti-tumor response. It was initially granted an accelerated approval by the FDA in 2017 but did not show the benefit of the drug in a confirmatory clinical trial, as required. Nivolumab is also approved for use in metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma, and others.

“We are disappointed by the position the Advisory Committee and the FDA have taken regarding the continued approval of Opdivo monotherapy as a treatment for HCC post-sorafenib. HCC is a complex and challenging disease, and for patients who are initially treated with sorafenib and either cannot tolerate treatment or whose disease progresses, immunotherapy is an important treatment option. For the past three and a half years, Opdivo monotherapy has been an important option that physicians have relied on to address this need and is currently the most commonly used therapy in the post-sorafenib setting,” said Jonathan Cheng, senior vice president and head of oncology development, BMS, in a press release

In late April 2021, the FDA’s Oncologic Drug Advisory Committee (ODAC) voted 5 to 4 against nivolumab monotherapy’s continued approval for this patient population. The decision to overturn nivolumab’s accelerated approval was based on the results of the CheckMate-459 study (NCT02576509). The study had an actual enrollment of 743 participants and the primary end point of overall survival (OS) based on Kaplan-Meier estimates. Secondary end points included objective response rate (ORR) per BICR RECIST 1.1, progression-free survival (PFS), and efficacy based on PD-L1 expression.

The study was conducted across 134 study locations. Patients were randomized to receive either nivolumab or sorafenib.

Statistical analysis found that the initial OS benefit nivolumab had over sorafenib was not statistically significant and the study did not meet its primary end point. The OS for nivolumab was 16.4% versus 14.7% in the sorafenib group. The median 12-month OS rate was 59.7% in the nivolumab group and 55.1% in the sorafenib group. The median 24-month OS for the nivolumab group was 36.8% and 33.1% for the sorafenib group. The median PFS for the nivolumab cohort was 3.7 months and 3.8 months for the sorafenib cohort.

Response data showed that the ORR for the experiemantal nivolumab cohort was 57% and 26% for the sorafenib cohort. 

Nivolumab in combination with ipilimumab (Yervoy) remains an option for patients in this space, according to BMS. Accelerated approval for nivoluman plus ipilimumab this combination was granted in March 2020 and was based on the CheckMate-040 study (NCT01658878).

“Opdivo helped usher in an entirely new way to treat patients with this disease. We continue to support the FDA’s accelerated approval program, which has been integral to enabling people with difficult to treat cancers to gain access to certain safe and effective new therapies sooner,” Cheng added.

1.Bristol Myers Squibb statement on Opdivo® (nivolumab) monotherapy post-sorafenib hepatocellular carcinoma U.S. indication. News release. Bristol Meyers Squibb. July 23, 2021. Accessed July 26, 2021.
2.April 27-29, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. FDA website. April 29, 2021. Accessed July 26, 2021.
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