Bristol Myers Squibb Withdraws Single-Agent Nivolumab Post-Sorafenib HCC Indication in the United States

Bristol Myers Squibb has decided to voluntarily withdraw the indication for nivolumab (Opdivo) as a monotherapy for patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib (Nexavar) from the US market.¹

The decision followed the regulatory agency's evaluation of accelerated approvals for checkpoint inhibitors that have not met their post-marketing requirements with regard to showcasing confirmatory benefit.²

In September 2017, the FDA granted an accelerated approval to the PD-1 inhibitor for the treatment of patients with HCC after previous sorafenib, irrespective of PD-L1 status, based on findings from the phase 1/2 CheckMate-040 trial (NCT01658878).³ Earlier data on the 154 patients enrolled to the trial showed that the immunotherapy elicited an overall response rate (ORR) of 18.2% per blinded independent central review and modified RECIST criteria; 3.2% achieved a complete response. The ORR per RECIST v1.1 was 14.3% with nivolumab. The duration of response achieved with the agent ranged from 3.2 months to 38.2+ months.

The confirmatory phase 3 CheckMate-459 trial (NCT02576509) that compared nivolumab with sorafenib in the frontline setting, did not achieve statistical significance for its primary end point of overall survival per the prespecified analysis.⁴

“We are disappointed by the position the Advisory Committee and the FDA have taken regarding the continued approval of nivolumab monotherapy as a treatment for [patients with] 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, [nivolumab] 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,” Jonathan Cheng, senior vice president and head of oncology development at Bristol Myers Squibb, stated in a press release. “[Nivolumab] 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.”

The multicenter phase 3 CheckMate-459 trial examined nivolumab vs sorafenib as a first-line treatment in 1009 patients with unresectable HCC. Treatment was administered until progressive disease or intolerable toxicity.

To be eligible for enrollment, patients had to be at least 18 years of age; have histologically confirmed advanced HCC that was ineligible for surgical and/or locoregional therapies, or progressive disease following either of those treatments; have locoregional therapy for HCC that must have been at least 4 weeks prior to baseline scan; have Child-Pugh Class A disease; and an ECOG performance status of 0 or 1. Patients with known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC, as well as those who had a prior liver transplant or autoimmune disease were excluded from the trial.

The primary end point of the trial was OS, and key secondary end points were ORR, progression-free survival, and evaluating the relationship between PD-L1 expression and efficacy.

Nivolumab is being evaluated in a number of other ongoing trials: as a single agent in the adjuvant setting in CheckMate-9DX (NCT03383458), and also in combination with ipilimumab (Yervoy) for previously treated patients with HCC (NCT01658878).

References

1. Bristol Myers Squibb statement on Opdivo (nivolumab) monotherapy post-sorafenib hepatocellular carcinoma US indication. News release. Bristol Myers Squibb. July 23, 2021. Accessed July 23, 2021. https://bit.ly/3zsC9OE
2. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. March 11, 2021. Accessed July 23, 2021. https://bit.ly/3cgG1bm
3. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. News release. FDA. September 22, 2017. Accessed July 23, 2021. https://bit.ly/3ry4P67
4. Bristol-Myers Squibb announces results from CheckMate -459 study evaluating Opdivo (nivolumab) as a first-line treatment for patients with unresectable hepatocellular carcinoma. Bristol-Myers Squibb. June 24, 2019. Accessed July 23, 2021. https://bit.ly/2x70MSX