ODAC Opposes Ongoing FDA Approval of Nivolumab for HCC in Patients Pretreated With Sorafenib


The FDA’s Oncologic Drug Advisory Committee voted 5 to 4 against the continued accelerated approval of nivolumab for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.

The FDA’s Oncologic Drug Advisory Committee voted 5 to 4 against the continued accelerated approval of nivolumab for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.1

“The data is not there and it does not sound like there is a trial planned that will yield more data… While I believe there may be individuals [who] benefit, I don’t think the data is there for the population as a whole” said Anthony D. Sung, MD, a voting ODAC member, and assistant professor of Medicine at Duke University School of Medicine.

In September of 2017, the FDA granted accelerated approval to nivolumab as a monotherapy for the treatment of HCC in patients who have been previously treated with sorafenib. Approval was based on a 154-patient subgroup of CHECKMATE-040 (NCT01658878) study, which evaluated nivolumab as a monotherapy for patients who HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib. The overall response rate to the age was 14.3%, which included 3 complete responses and 19 partial responses. Duration of response (DOR) ranged from 3.2 months to 38.2 months and longer. Of those who responded, 91% had a response lasting 6 months or longer and 55% had a response lasting 12 months or longer.2

“For the less fit patients who are unable to tolerate combination therapy, a PD-1 inhibitor is the treatment of choice. In my practice, this represents a quarter of patients eligible for second-line therapy. As such, Nivolumab represents an important part of the therapeutic arm,” said Thomas A. Abrams MD, a medical oncologist at the Dana-Farber Cancer Institute, during the ODAC meeting.

Adverse events (AEs) occurred in 20% of patients. AEs included fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, and decreased appetite.

Continued approval of the agent was based on CheckMate-459 (NCT02576509). The phase 3, randomized study enrolled 743 participants. The primary outcome of the study was OS. Primary outcomes included objective response rate (ORR), progression-free survival (PFS), and efficacy based on PD-L1 expression.

During the study, patients were randomized to either receive nivolumab or sorafenib.

In order to participate, patients must have been18 years old or older with histologically confirmed advanced HCC and are not eligible for surgical and/or locoregional therapies. Patients must also have Child-Pugh class A and an ECOG performance status of 0 or 1. Patients with known fibrolamellar HCC, sarcomatous HCC, or mixed cholangiocarcinoma and HCC are not eligible to participate. Patients with prior liver transplant or an active, known, or suspected autoimmune disease were excluded.

Results of the study found that the overall survival benefit nivolumab had over sorafenib was not statistically significant. The median OS for the nivolumab group was 16.4% and 14.7% for the sorafenib group. For nivolumab, the 12-month OS rate was 59.7 months and the 24-month OS were 36.8 months. For sorafenib, the 12-month OS rate was 55.1 months and the 24-month OS rate were 22.1 months. The median PFS was 3.7 months for nivolumab and 3.8 months for sorafenib. The ORR was 57% for nivolumab and 26% for sorafenib. The study did not meet its primary endpoint.3

“The benefit of nivolumab vs. sorafenib was also shown by measuring health-related quality of life…Overall nivolumab showed a better quality of life compared to sorafenib, with nivolumab allowing for maintaining quality of life while sorafenib lead to worsening,” said Ashwin Sama, MD, MS, the lead of clinical development of hepatobiliary and pancreatic cancer at Bristol-Myers Squibb.

Regarding the deliberation of the continued accelerated approval, Mark Lewis, MD, an ODAC temporary voting member, stated:“…This was an extremely nuanced and difficult decision. When I am trying to perform a risk benefit calculous, I need both a numerator and a denominator and both of the quantities were not clear to me here.”


1. April 27-29, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. FDA website. April 29, 2021. Accessed April 29, 2021. https://bit.ly/2PyhdV1

2. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. News release. FDA. September 22, 2017. Accessed April 29, 2021. https://bit.ly/3aOKRgg

3. Yau T, Park J, Finn R, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann. Of Onc. VOLUME 30, SUPPLEMENT 5, V874-V875, OCTOBER 01, 2019. DOI:https://doi.org/10.1093/annonc/mdz394.029

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