Safety of Nivolumab/Ipilimumab Combination Confirmed for Advanced HCC

For those with advanced hepatocellular carcinoma, the CheckMate 040 study found that the combination can be effective. Information from that study found that the combination can also yield a favorable safety profile, said Anthony B. El-Khoueiry, MD, in his presentation at the 2019 ILCA Annual Conference.

Anthony B. El-Khoueiry, MD

The combination of nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, with ipilimumab (Yervoy), a CTLA-4 checkpoint inhibitor, has shown activity in multiple tumor types. For those with advanced hepatocellular carcinoma(HCC), the CheckMate 040 study found that the combination can be effective, with the first such findings presented at the 2019 ASCO Conference. Information from that study found that the combination can also yield a favorable safety profile, said Anthony B. El-Khoueiry, MD, in his presentation at the 2019 ILCA Annual Conference in Chicago, Illinois.

Investigators focused on the primary endpoints of safety and tolerability using NCI Common Terminology Criteria for Adverse Events. They compared a total of 148 patients with advanced HCC who had previously been treated with first-line therapy sorafenib (Nexavar), were sorafenib intolerant, or whose disease had progressed after sorafenib.

Patients were randomized 1:1:1 between 3 arms with different dosing combinations and schedules until unacceptable intolerability or disease progression. Fifty patients in arm A were given 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for 4 cycles. Forty-nine patients in arm B were given 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks times 4. Both of these arms were then given nivolumab 240 mg intravenously as a flat dose every 2 weeks. Forty-nine patients in arm C only received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks.

The majority of patients, 88%, 85%, and 79% in arms A, B, and C, respectively, had discontinued sorafenib due to disease progression. Also, most patients across the treatment arms had either hepatitis B or C virus (74% to 82%).

Treatment Tolerance, Toxicity, and Response

The median follow-up across all 3 arms was 31 months. As is the nature with systemic therapies and HCC, disease progression halted treatment. It was the most common reason for treatment discontinuation in all 3 arms, with the lowest such cause in arm A at 51% versus 69% in both arms B and C.

In contrast, arm A, with the higher dose of ipilimumab, resulted in 22% of patients discontinuing treatment due to toxicity versus 6% in B and 2% in C. Despite the higher toxicity, arm A had the longest median duration of therapy, with patients lasting 5.1 months on therapy, compared with 2.3 months and 4 months for arms B and C, respectively.

“This may be associated with the efficacy seen in that arm,” said El-Khoueiry, associate professor of clinical medicine, Division of Medical Oncology and director of the phase I drug development clinical program at the University of Southern California (USC), as well as medical director of the Clinical Investigations Support Office at the USC Norris Comprehensive Cancer Center. The overall response rate (ORR) was 31% in arms B and C and was 32% in arm A. Arm A had the highest CR rate, at 8%, versus 6% in arm B and 0% in arm C. Partial responses were achieved by 24% of patients in arm A, 24% in arm B, and 31% in arm C.

“The greatest survival benefit was also observed in arm A, with a median overall survival [OS] of 22.8 months, and the highest OS rate of 44% through 30 months,” said El-Khoueiry. The median OS is arm B was 12.5 months and was 12.7 months in arm C. The median durations of response were 17.5, 22.2, and 16.6 months in arms A, B, and C, respectively.

Adverse Events

In treatment-related adverse events (TRAEs), El-Khoueiry said there were no surprises in the data. “It’s similar to what’s seen in other tumor types,” he said. The most common TRAEs involved skin and subcutaneous tissue, investigations (including liver laboratory abnormalities), general and administration site events, gastrointestinal events, and endocrine related.

“Although rates of any-grade TRAEs were higher in arm A (94%), the types of TRAEs observed were similar across treatment arms. No new safety signals were observed, and most TRAEs were manageable and reversible,” said El-Khoueiry.

Overall, the incidence of grade 3/4 TRAEs was also higher in arm A, at 53%, compared with 29% in arm B and 31% in arm C. Among hepatic investigations, the most common abnormalities were increased AST and ALT.

“There were several serious events, 4 of which were hepatic-related and required steroid therapy,” said El-Khouiery. “None of the hepatic events required anything besides corticosteroids.”

There were 5 patients with heptobilliary events, 3 in arm A, 1 in B, and 1 in C. Of these, 4 patients had to discontinue their therapy, 2 in A and 2 in B. “The patient labeled as drug-induced liver injury was labeled as such by the investigator. However, that patient did not meet the protocol prespecified, specifically the patient did not have a bilirubin above the upper limits of normal,” said El-Khoueiry.

Select hepatic events were also reported in 27% of patients in arm A versus 24% in B and 17% in C. Among all select TRAEs, systemic corticosteroids were used to treat 51% of patients in arm A, 24% in B, and 23% in C. With the exception of endocrine events, the vast majority of select TRAEs were resolved across all arms.

The study also looked at immune-mediated adverse events (IMAE), a subset of select TRAEs, where patients had to be placed on either immunosuppressive agents or other corticosteroids. These events could have happened up to 100 days after the last dose of therapy, said El-Khoueiry. The most common IMAEs were rash, hepatitis, adrenal insufficiency, diarrhea/colitis, and pneumonitis. As expected, these were more common in arm A, specifically for hepatitis, he said, which occurred in 10 patients versus 5 in B and 3 in C.

Ninety percent of IMAEs resolved. Of the 10 patients in arm A who had hepatitis, 7 received glucocorticoids for a median of 2 weeks. Of patients experiencing hepatic adverse effects, roughly 60% to 70% were re-challenged across arms. “No patients experienced a recurrence of any category of IMAEs upon re-challenge with either therapy,” said El-Khoueiry.

Across all arms and all organs—skin, endocrine, hepatitis, the median time to onset was short, between 3 and 8 weeks. “Generally, across tumor types, that’s going to happen in the first 3 to 5 months anyway,” said El-Khoueiry.

With hepatic events, the median time to onset was between 4.1 to 5.3 weeks. Resolution took between 3.1 to 12 weeks, with similar high rates of resolution among arms, 92% for arms A and B and 88% in arm C.

Given both the favorable OS and the favorable risk profile of this combination, further investigation is warranted, said El-Khoueiry. The soon to launch phase III CheckMate 9DW study will undertake this task comparing nivolumab and ipilimumab against the standard of care (NCT04039607).


El-Khoueiry AB, Hsu C, Kang YK, et al. Safety profile of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 40 study. Presented at: 2019 ILCA Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-13.