FDA Committee Does Not Support Maintaining Accelerated Approval of Nivolumab for Advanced HCC


By a close decision, the FDA’s Oncologic Drugs Advisory Committee voted against upholding the accelerated approval of nivolumab monotherapy to treat patients with hepatocellular carcinoma following sorafenib.

In a 5-to-4 vote, the FDA’s Oncologic Drugs Advisory Committee has decided against maintaining the acerated approval of single-agent nivolumab (Opdivo) as therapy for patients with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Nexavar).1

The indication was original granted back in 2017 based on response data from a phase 1/2 trial. Since then, data from a randomized phase 3 trial did not support the use of the single-agent nivolumab versus standard-of-care sorafenib therapy in the frontline disease setting.

“Immunotherapy is an important next treatment option for patients who have progressed on sorafenib or were unable to tolerate it. We are disappointed with today’s outcome for patients, and we will work closely with the FDA as it completes its review,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, said in a press release. “Immunotherapies have changed the way we treat many forms of advanced cancer. We’re proud of the role Opdivo has played in helping to evolve the HCC treatment landscape, and we remain focused on delivering innovative therapies for HCC patients in need.”

The accelerated approval was based on data from the CheckMate 040 trial, in which the overall response rate (ORR) per mRECIST in patients who had been previously treated with sorafenib was 18.2% by blinded independent central review (BICR), with 3.2% of patients having a complete response the therapy. The ORR by RECIST 1.1 was 14.3% with nivolumab, with a response duration ranging from 3.2 to 38.2+ months.2

The efficacy population was comprised of 262 patients with advanced HCC with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, with 48 and 214 patients in the dose-escalation and -expansion portions of the trial. Most patients in the dose-escalation phase (77%) and the expansion phase (68%) had prior sorafenib.

In 2019, topline results from the confirmatory phase 3 CheckMate 459 trial did not indicate an overall survival (OS) benefit of nivolumab versus sorafenib in the frontline setting of HCC (HR, 0.85; 95% CI, 0.72-1.02; P = .0752). Despite the data failing to show a statistically significant benefit, the investigators reported a trend towards OS benefit with nivolumab at a median of 16.4 months versus 14.7 months with sorafenib. The ORRs were 15% versus 7%, respectively.3

Investigators had also noted the favorable safety profile of nivolumab versus sorafenib in this setting as a reason to consider using the therapy. Grade 3/4 treatment-related adverse events were reported in 22% of nivolumab-treated patients versus 49% receiving sorafenib. These events led to discontinuation in 4% of patients being treated with nivolumab and 8% of patients on sorafenib.

The ODAC meeting was a part of an industry-wide review of 6 accelerated approvals that have undergone confirmatory trials with unmet primary end points and have not been given full approval.


1. Bristol Myers Squibb Statement on FDA Advisory Committee Meeting on Opdivo® Post-Sorafenib Hepatocellular Carcinoma U.S. Indication. News release. Bristol Myers Squibb. April 30, 2021. Accessed April 30, 2021. https://bit.ly/2QBEfuY

2. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. September 22, 2017. Accessed April 30, 2021. https://bit.ly/3eNpygp

3. LBA38_PR Checkmate 459: A randomized, multi-center phase 3 study of nivolumab (nivo) vs sorafenib (sor) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (AHCC). Ann Oncol. 2019;30(suppl 5):V874-V875. doi: 10.1093/annonc/mdz394.029

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