FDA Approves Nivolumab Plus Ipilimumab in Advanced Hepatocellular Carcinoma

The FDA has granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar), Bristol Myers Squibb announced in a press release.¹

“The approval of nivolumab and ipilimumab in the second-line treatment of advanced HCC means we will have a combination immune therapy option in patients who have progressed on frontline therapy. The overall survival (OS) of nivolumab and ipilimumab in the second-line treatment of advanced HCC as shown in CheckMate-040 was very promising, so far the longest duration of OS in the second-line setting for advanced-stage HCC, tested in clinical trials,” said Aiwu Ruth He, MD, PhD, associate professor of Medical Oncology at Georgetown University.

“We have to monitor the patients closely for immune-mediated [adverse] effects. Given the approval of nivolumab and ipilimumab in melanoma, [renal cell carcinoma], [microsatellite instability-high colorectal cancer], we have experience managing possible [adverse] effects of the regimen in patients [with cancer]. When the study was carried out, the standard frontline therapy was sorafenib. Now, the frontline therapy is sorafenib or lenvatinib (Lenvima). I believe the efficacy of the combination should be observed in patients who have had lenvatinib therapy as well.”

Nivolumab plus ipilimumab was approved based on data from a cohort of the phase I/II CheckMate-040 study that evaluated nivolumab alone or in combination with other agents in patients with advanced liver cancer. The results were originally presented in a poster at the 2019 American Society of Oncology (ASCO) Annual Meeting. In 2020, at the ASCO Gastrointestinal Cancers Symposium (ASCO GI), Dr He presented the data in poster session B.

After a minimum of 28 months follow-up, 33% of patients responded to treatment with the combination. Eight percent of patients who responded had a complete response ([CR], n = 4) and 24% had a partial response ([PR], n = 12).¹

The study included a total of 148 patients who were randomized to 1 of 3 arms. At baseline, 34% of patients had vascular invasion, 82% had extrahepatic spread, 91% had Barcelona Clinic Liver Cancer stage C, and 84% previously discontinued sorafenib due to disease progression or toxicity.²

At the data cutoff of January 19, 2019, as reported at ASCO GI, the overall response rate (ORR) was 32% in all patients (95% CI, 19.5%-46.7%), which included CRs in 12% of patients. In patients who received less than 6 months of sorafenib (n = 28), the ORR was 28.6% (95% CI, 13.2%-48.7%). Of these 28 patients, 7% had a CR (n = 2), 21% had a PR, n = 6), 14% had stable disease ([SD] n = 4), and 46% had progressive disease ([PD], n = 13). In patients who received 6 months of sorafenib or more, the ORR was 36.4% (95% CI, 17.2%-59.3%).

The newly reported DOR ranged from 4.6 to 30.5+ months, with 88% lasting at least 6 months, 56% lasting at least 12 months and 31% lasting at least 24 months. The ORR, as assessed by BICR using modified RECIST, was 35% (95% CI, 22%-50%), with a CR observed in 12% of patients (n = 6) and a PR reported in 22% (n = 11).¹

Overall the disease control rate (DCR) among patients in the study was 54.0% (95% CI, 39.3%-68.2%). The DCR observed in patients who received 6 months or less of sorafenib treatment was 46.4% (95% CI, 27.5%-66.1%) compared with 63.6% (95% CI, 40.7%-82.8%) among those who received 6 months of treatment or more.

The DCR overall for patients who had SD for 6 months or more was 40.0% (95% CI, 26.4%-54.8%). Patients in this subgroup who had treatment with sorafenib for 6 months or less the DCR was 35.7% (95% CI, 18.6%-55.9%) compared with 45.5% (95% CI, 24.4%-67.8%) in patients who had 6 months or more of sorafenib.

Only 8 patients were included in the time to response and duration of response (DOR) analyses. The median DOR was 17.5 months (range, 4.6-30.5+). In patients who received 6 months or less of sorafenib treatment, median DOR was 16.0 months (range, 4.6+-29.0+) and not reached (NR) in those who received 6 months or more (range, 4.6-30.5+).

In the overall study population, the median time to response (TTR) was 2.0 months (range, 1.1-12.8). Among patients who received sorafenib for 6 months or less, the TTR was 1.35 months (range, 1.1-2.7) versus 2.6 months (range, 1.2-12.8) in patients who received 6 months or more of treatment with sorafenib.

In the subgroup of patients who received a longer period of treatment with sorafenib, the median OS was longer at 25.5 months (95% CI, 9.4-NR) versus 19.2 (95% CI, 8.3-NR) in patients who received sorafenib for 6 months or less. The patient numbers were low in these groups, and the confidence intervals overlapped.

In terms of safety, the incidence of any-grade and grade 3/4 treatment-related adverse events (TRAEs) was similar across subgroups, as was the incidence of any-grade and grade 3/4 treatment-related hepatobiliary investigations. The most common any-grade TRAEs overall were skin and subcutaneous tissue disorders (61%), investigations (49%), general disorders and administration site conditions (39%), and gastrointestinal disorders (37%). The most common grade 3/4 TRAEs in the overall study population were investigations (33%), metabolism and nutrition disorders (14%), skin and subcutaneous tissue disorders (8%), and gastrointestinal disorders (6%). Patients who received sorafenib for 6 months or less and were evaluated for safety had more any-grade TRAEs than those who were treated with sorafenib for 6 months or more. However, there was no significant difference in grade 3/4 TRAEs between these subgroups.

Hepatic investigation and hepatobiliary TRAEs were also evaluated by duration of sorafenib treatment. Overall, the most common any-grade investigations were aspartate aminotransferase increase (20%), alanine aminotransferase increase (16%), blood bilirubin increase (6%), and blood alkaline phosphate increase (2%). The most common grade 3/4 investigations were aspartate aminotransferase increase (33%), alanine aminotransferase increase (16%), and blood bilirubin increase (8%). Any-grade hepatobiliary TRAEs, namely hepatitis and drug-induced injury, occurred in 4% and 2% of patients, respectively. Grade 3/4 hepatobiliary TRAEs also occurred in 4% and 2% of patients. Patients who received 6 months or less of sorafenib treatment had a higher incidence of investigations and hepatobiliary TRAEs than those who received sorafenib for 6 months or longer.

Based on the results of CheckMate-040, the combination of nivolumab and ipilimumab may be a new treatment option for patients with advanced HCC.

In the open-label, non-comparative study, arm A received 4 doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks followed by nivolumab 240 mg intravenously every 2 weeks. Arm B received nivolumab 4 doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 240 mg intravenously every 2 weeks. Patients in arm C received 4 doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 6 weeks.

The study included patients with a histologically confirmed advanced HCC who were not eligible for surgery and/or locoregional therapy. Patients were required to have at least 1 intreated lesion per RECIST v1.1, documented radiographic progression during or after sorafenib therapy or sorafenib intolerance, Child-Pugh score of A5 or A6, and an ECOG performance score of 0 or 1. The key exclusion criteria included known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC, active brain metastases or leptomeningeal metastases, active co-infection with both HBV and HCV, history of hepatic encephalopathy, paracentesis for treatment of ascites within 1 year of screening, and prior liver transplant.

The coprimary end points of the study were ORR and DOR and the secondary end points included DCR, progression-free survival, OS, time to progression, and TTR.

The approved dosage for the combination is 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab administered intravenously.

Nivolumab is a programmed death-1 checkpoint inhibitor, which is approved by the FDA as monotherapy for patients with HCC treated with sorafenib. The approval was based on earlier results from CheckMate-040, showing an ORR of 14% and an OS of 16 months. It also has indications in many other malignancies. Ipilimumab is a monoclonal antibody that has an indication in melanoma.³

The combination of nivolumab and ipilimumab is also under investigation as a potential treatment for indicated for the treatment of patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, unresectable or metastatic melanoma, intermediate or poor risk, previously untreated advanced renal cell carcinoma.

"In patients who have progressed on sorafenib or lenvatinib, or who cannot tolerate sorafenib or lenvatinib, the current standard therapies are regorafenib (Stivarga), cabozantinib (Cabometyx), ramucirumab (Cyramza), nivolumab, and pembrolizumab (Keytruda). The current TKIs, regorafenib, cabozantinib (Cabometyx) have shown prolongation of survival but a low response rate. The single-agent anti—PD-1 nivolumab, pembrolizumab therapies have shown a response rate around 15%, to improve survival in the responders, however, may not benefit patients who have not responded to the single-agent anti–PD-1. In comparison with the current 2nd line therapy options, the combination of nivolumab and ipilimumab may provide a better response rate (30%+), prolong disease control in patients who respond to treatment, prolong survival in patients who respond to this patient as shown in CheckMate-040 study,” said He.

Continued approval of nivolumab plus ipilimumab for this indication may be contingent upon verification and description of clinical benefit in other confirmatory trials.¹

References

1. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib [news release]. Princeton, New Jersey: Bristol Myers Squibb Company. March 11, 2020.https://bit.ly/2THE7Zx. Accessed March 11, 2020.
2. He AR, Yau T. Hsu C, et al. Nivolumab + ipilimumab combination therapy in patients with advanced hepatocellular carcinoma: subgroup analysis from CheckMate 040. Presented at: 2020 Gastrointestinal Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract B15.
3. Bristol-Myers Squibb Announces First Presentation of Results for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combination in Advanced Hepatocellular Carcinoma at ASCO 2019 [news release]. Princeton, New Jersey: Bristol Myers Squibb; June 3, 2019.https://bit.ly/38yjNOt. Accessed March 10, 2020.