FDA Approves Nivolumab/Ipilimumab for Advanced HCC


The FDA has granted an accelerated approval to the combination of nivolumab and ipilimumab for the treatment of patients with hepatocellular carcinoma who have received prior therapy with sorafenib.

The FDA has granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of patients with hepatocellular carcinoma (HCC) who have received prior therapy with sorafenib (Nexavar).1

The approval is based on cohort findings from the phase I/II CheckMate-040 study (NCT01658878), in which the combination of nivolumab and ipilimumab elicited an objective response rate (ORR) of 33% (95% CI, 20-48) in this patient population, at a median follow-up of 28 months; this included an 8% complete response (CR) rate and a 24% partial response (PR) rate.2

Moreover, the duration of response ranged from 4.6 to 30.5+ months, with 88% of responses lasting ≥6 months, 56% lasting ≥12 months, and 31% of responses lasting ≥24 months. By blinded independent central review, the ORR using modified RECIST v1.1 criteria was 35% (95% CI, 22-50), with a 12% CR rate and a 22% PR rate.

The approved doses for the combination are 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab, both given intravenously.

"HCC is an aggressive disease in need of different treatment approaches," Anthony B. El-Khoueiry, MD, lead investigator and associate professor of clinical medicine and phase I program director at the Keck School of Medicine, University of Southern California (USC) and the USC Norris Comprehensive Cancer Center, stated in a press release. "The overall response rate observed in the Opdivo plus Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients."

In a cohort of the ongoing, multicohort, phase I/II CheckMate-040 trial, investigators evaluated the safety and efficacy of nivolumab/ipilimumab in patients with previously treated advanced HCC who progressed on or were intolerant to sorafenib, had ≥1 measurable lesion by RECIST v1.1 criteria, a Child-Pugh score of A5 or A6, and an ECOG performance score of 0 or 1. Patients could have non-viral—related HCC, HCV-HCC, or HBV-HCC.

Those with known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; active brain or leptomeningeal metastases; active co-infection with both HBV and HCV; a history of hepatic encephalopathy; paracentesis for treatment of ascites within 1 year of screening; and prior liver transplant were excluded from enrollment.

Patients were randomized 1:1:1 to one of the 3 dosing schedules with the combination until unacceptable intolerability or disease progression: 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles (arm A; n = 50), 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 cycles (arm B; n = 49), and nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (arm C; n = 49). Patients in arms A and B were then given a flat dose of nivolumab 240 mg intravenously every 2 weeks.

The majority of patients—88%, 85%, and 79% in arms A, B, and C, respectively—had discontinued sorafenib due to disease progression.

The primary endpoints are safety and tolerability, as well as ORR based on investigator assessment using RECIST v1.1 criteria. Key secondary endpoints are progression-free survival, DCR, DOR, OS, time to response, and time to progression.

Initial data of this cohort were presented at the 2019 ASCO Annual Meeting.3 Here, the ORR was 32% in arm A and 31% in arms B and C, and the complete response rates were 8%, 6%, and 0%, respectively. The partial response rates were 24%, 24%, and 31% in arms A, B, and C, respectively. The median OS in arm A was 22.8 months, 12.5 months in arm B, and 12.7 months in arm C. The median DOR were 17.5 months, 22.2 months, and 16.6 months in arms A, B, and C, respectively.

For the data presented at the ILCA meeting, the median follow-up across all 3 arms was 31 months. Regarding safety, the combination was found to be well tolerated. Overall, grade 3/4 treatment-related adverse events (TRAEs) were reported in 37% of patients; grade 3/4 TRAEs that led to discontinuation occurred in 5% of patients, and all-grade serious TRAEs were reported in 18% of patients.

The most common all-grade select TRAEs were skin- (50%), hepatic- (23%), and gastrointestinal- (19%) related, comprising pruritus (35%), rash (23%), aspartate aminotransferase increased (18%), and diarrhea (18%).

Specifically, in arm A, 22% of patients discontinued treatment due to toxicity versus 6% in B and 2% in C. However, arm A had the longest median duration of therapy (5.1 months) compared with 2.3 months and 4 months for arms B and C, respectively. The incidence of grade 3/4 TRAEs was higher in arm A, at 53%, compared with 29% in arm B and 31% in C.

There were 5 cases of hepatobiliary events: 3 in arm A, 1 in B, and 1 in C. Of these, 4 patients, 2 each in A and B, had to discontinue therapy. Select hepatic events occurred in 27%, 24%, and 17% of patients on arms A, B, and C, respectively. Among all select TRAEs, systemic corticosteroids were used to treat 51% of patients in arm A, 24% in B, and 23% in C. The majority of select TRAEs were resolved across all arms, except for endocrine events.

Investigators also examined immune-mediated adverse events (imAEs), the most common of which included rash, hepatitis, adrenal insufficiency, diarrhea/colitis, and pneumonitis. imAEs were more common in arm A (n = 10), specifically for hepatitis, he said, compared with arm B (n = 5) and C (n = 3). A total 90% of imAEs resolved, and of the 10 patients in arm A with hepatitis, 7 received glucocorticoids for a median 2 weeks. Of those who had hepatic AEs, roughly 60% to 70% were rechallenged across arms.

Updated findings of another arm of nivolumab/ipillumab in HCC were presented during the 2020 Gastrointestinal Cancers Symposium.4 For patients who received prior treatment with sorafenib for ≤6 months, the combination led to a median OS of 19.2 months (95% CI, 8.3—not reached [NR]). For those who had prior sorafenib for >6 months, the median OS was 25.5 months (95%, CI, 9.4–NR). Researchers concluded that this combination could be a potential treatment option for patients, independent of prior duration of sorafenib.

The phase III CheckMate-9DW study (NCT04039607) is evaluating nivolumab plus ipilimumab compared with either sorafenib or lenvatinib (Lenvima) in the frontline setting for advanced HCC. The target enrollment is 1084 patients.

"We recognize there is a critical need to provide patients with aggressive forms of cancer, like HCC, new treatment options that may offer clinically meaningful and ultimately durable responses," Adam Lenkowsky, general manager and head, US, Oncology, Immunology, Cardiovascular, Bristol Myers Squibb, stated in the press release. “Today's announcement builds on our legacy in pioneering immunotherapy treatments and is an important step in our commitment to transforming patients' lives through science.”

The accelerated approval is contingent on the results of a confirmatory trial.


  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, NJ. Bristol-Myers Squibb. Published March 11, 2020. https://bit.ly/2TEXGBG. Accessed March 11, 2020.
  2. 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 International Liver Cancer Association Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-13. ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf.
  3. Yau T, Kang YK, Kim, TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2019;37(suppl; abstr 4012). doi: 10.1200/JCO.2019.37.15_suppl.4012
  4. He AR, Yau T, Hsu C, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): subgroup analyses from CheckMate 040. J Clin Oncol. 2020;38(suppl 512; abstr 512). doi: 10.1200/JCO.2020.38.4_suppl512
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