Phase III CheckMate 459 Trial in Unresectable HCC Misses Primary Endpoint

Topline results from the phase III CheckMate 459 trial revealed that the trial did not meet its primary endpoint of improved overall survival with nivolumab as compared with sorafenib for the treatment of patients with newly diagnosed, unresectable hepatocellular carcinoma. 

Bruno Sangro, MD

Topline results from the phase III CheckMate 459 trial (NCT02576509) revealed that the trial did not meet its primary endpoint of improved overall survival (OS) with nivolumab (Opdivo) as compared with sorafenib (Nexavar) for the treatment of patients with newly diagnosed, unresectable hepatocellular carcinoma (HCC).

Although it did not meet statistical significance (HR, 0.85; 95% CI, 0.72-1.02;P= .0752), Bristol-Myers Squibb, the manufacturer of the PD-1 inhibitor, stated that the findings did show a clear trend towards an OS improvement with nivolumab versus sorafenib. The company stated that the full data will be presented at an upcoming medical meeting.

“We are encouraged by the promising efficacy and safety trends seen with Opdivo in CheckMate-459, especially as HCC is a devastating and difficult-to-treat cancer, for which there have been no significant advances over sorafenib, a standard treatment, in more than a decade,” Bruno Sangro, MD, head of the Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain, stated in a press release.

The multicenter, randomized, phase III CheckMate 459 trial evaluated nivolumab compared with sorafenib as a first-line treatment in 1009 patients with unresectable HCC. Patients were treated until disease progression or unacceptable toxicity.

To be eligible for enrollment, patients had to be ≥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 ≥4 weeks prior to baseline scan; have Child-Pugh Class A disease; and an ECOG performance status of 0 or 1. Those 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 endpoint was OS, and secondary endpoints were overall response rate (ORR), progression-free survival, and the relationship between PD-L1 expression and efficacy.

Nivolumab was approved by the FDA as a treatment for patients with HCC who have been previously treated with sorafenib in September 2017. The agency granted the PD-1 inhibitor an accelerated approval based on efficacy data from the CheckMate 040 trial, in which treatment with nivolumab elicited an 18.2% ORR and a 3.2% complete response (CR) rate by blinded independent central review per mRECIST criteria. By RECIST 1.1, the ORR was 14.3% and the duration of response (DOR) ranged from 3.2 to 38.2+ months. The FDA-approved dose is 240 mg every 2 weeks.

In CheckMate 040, 262 patients with advanced HCC with or without hepatitis C virus or hepatitis B virus infection were enrolled from November 26, 2012, to August 8, 2016. Forty-eight patients were in the dose-escalation phase and 214 patients were in the dose-expansion phase. In the dose-escalation phase and dose-expansion phase, 77% and 68% of patients had prior sorafenib.

In the dose-escalation phase, patients received 0.1 to 10 mg/kg of intravenous nivolumab every 2 weeks. Patients in the expansion phase were treated with nivolumab at 3 mg/kg every 2 weeks.

The median age in the escalation phase was 62 years (range, 55-69), 75% of patients were male, 58% were white, and 40% had an ECOG performance status of 1. Additionally, 75% had surgical resection and 21% had received radiotherapy. In the dose-expansion phase, the median age was 64 years (range, 56-70), 80% of patients were male, 49% were white, 47% were Asian, and 36% had an ECOG performance status of 1. Sixty percent of patients had surgical resection and 19% received prior radiation.

Results had showed that, in the expansion phase of those in the sorafenib-experienced group (n = 145), the mRECIST ORR by BICR was 19%. There were 2 CRs (1%), 19 partial responses (PRs; 13%), and 60 patients had stable disease (SD; 41%). The disease control rate was 56%.

In the sorafenib-naïve group, across both the dose-expansion and -escalation cohorts (n = 80), the ORR by BICR was 20% by RECIST v1.1 and 24% by mRECIST. In the v1.1 analysis, there was 1 CR (1%), 15 PRs (19%), and 27 patients with SD (34%). The median DOR was 17 months.

In the treatment expansion cohort, the median OS was 15.6 months (95% CI, 13.2-18.9), and the 12-month OS rate was 60% and the 18-month OS rate was 44%. In the sorafenib-naïve group, the median OS was 28.6 months with nivolumab. The 12- and 18-month OS rates were 73% and 57%, respectively.

Moreover, 56% of sorafenib-naïve patients and 64% of sorafenib-experienced patients who responded to nivolumab did so within 3 months of initiation. Responses were also ongoing in 50% of sorafenib-naïve patients and in 39% of sorafenib-experienced patients.

Regarding safety, 23 sorafenib-naïve patients (29%) experienced grade 3/4 treatment-related adverse events (TRAEs) and 78% experienced all-grade TRAEs. The most common (>10%) all-grade TRAEs were pruritus (24%), fatigue (20%), rash (16%), and diarrhea (13%). The most common (≥5%) grade 3/4 TRAEs were aspartate aminotransferase (AST) increased (9%), lipase increased (8%), amylase increased (6%), and alanine aminotransferase (ALT) increased (5%).

Additionally, in the sorafenib-experienced group, 77% of patients experienced all-grade TRAEs and 18% had grade 3/4 TRAEs. The most common (≥10%) any-grade TRAEs were fatigue (22%), pruritus (20%), rash (18%), and diarrhea (14%). The most common grade 3/4 TRAEs were fatigue (4%), AST increased (4%), lipase increased (4%).

Investigators observed 1 dose-limiting toxicity, a grade 2 hepatic impairment in the dose-escalation phase. The maximum tolerated dose was not reached, and 1 sorafenib-experienced patient died due to treatment-related pneumonitis.

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).

“We remain confident in the important role of Opdivo for the treatment of patients with HCC and look forward to evaluating insights garnered from this trial with the goal of ensuring patients with liver cancer have the opportunity to achieve the best possible outcomes,” Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, Bristol-Myers Squibb, stated in the press release.


  1. 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. Published June 24, 2019. Accessed June 24, 2019.
  2. Crocenzi TS, El-Khoueiry AB, Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.J Clin Oncol.2017;35 (suppl; abstr 4013).