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FDA Grants Priority Review for Nivolumab Plus Ipilimumab in Advanced HCC

Nichole Tucker
Published Online:7:42 PM, Mon November 11, 2019
FDA Logo in black and whiteA supplemental Biologics License Application (sBLA) for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar) has been accepted by the FDA and given Priority Review status.  The sBLA was given a Prescription Drug User Fee Act goal date of March 10, 2020, according to a press release from Bristol-Myers Squibb.1
The application was submitted based on positive data in the phase I/II, dose-escalation, open-label, non-comparative CheckMate 040 (NCT01658878) trial, which is studying the use of nivolumab plus ipilimumab at different dose levels in sorafenib-treated patients with HCC.
In results reported at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, the overall response rate (ORR) was 31% for patients in all arms, with 7 complete responses (CRs) seen. The median duration of response for these patients was 17 months.

In arm A—the group treated with nivolumab/ipilimumab every 3 weeks—there were 4 complete responses, 13 partial responses (PRs), and 9 cases of stable disease (SD). Arm B, which received nivolumab/ipilimumab every 2 weeks, had 3 CRs, 12 PRs, and 5 patients with SD. Finally, in arm C, the nivolumab/ipilimumab every 6 weeks group had 15 PRs and 9 patients with SD. No CRs were seen in arm C. There were patients in all 3 arms who had progressive disease, 20 (40%) in arm A, 24 (49%) in arm B, and 21 (43%) in arm C.2
The overall survival (OS) rate was 40% at 24 months. In arm A specifically, the median OS (mOS) was 23 months and 4 of the 50 patients had a CR.2
The combination had an acceptable safety profile overall. In arm A, the were 47 treatment-emergent adverse events (TEAEs), most of which were rash (35%), hepatitis (20%), and adrenal insufficiency (18%). There were also 21 patients who experienced grade 3 or higher TEAEs. In arm B, the most common all-grade TEAEs were consistent with arm A. Twenty-seven patients in arm B experienced TEAEs and 9 of them were high-grade. Arm C had the least occurrences of TEAEs (20), and 12% of them were grade 3 or higher.2

Immune-mediated adverse events (IMAEs) were also analyzed in the study and were occurred more frequently in arm A than the other arms. The most common IMAE was hepatitis and it occurred in 10 patients in arm A, 5 in arm B, and 3 in arm C. Reportedly, 90% of the IMAEs were resolved.3  
The FDA’s decision is important for patients with HCC. In a press release, Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, Bristol-Myers Squibb, stated, “the FDA’s acceptance of our application for Opdivo plus Yervoy represents important progress for patients with liver cancer in the United States, where hepatocellular carcinoma is the fastest rising cause of cancer-related death. Despite recent advances, hepatocellular carcinoma remains a difficult-to-treat cancer and patients are in need of additional effective treatment options.”

Patients in CheckMate 040 were randomized 1:1:1 to either 4 doses of nivolumab 1 mg/kg plus 3 mg/kg every 3 weeks ipilimumab in arm A, 4 doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks in arm B, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 6 weeks. The study evaluated primary endpoints, safety, and tolerability. The secondary endpoints were ORR, DOR, disease control rate, and OS.
Histologically confirmed patients with advanced HCC that were ineligible for surgical or locoregional therapy was a key criteria eligibility for the CheckMate 040 trial, which has since stopped recruiting. Individuals were also required to have a 1 or more intreated lesion, documented radiographic progression, Child-Pugh score of A5 or A6, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and their disease must be HBV or HCV based, or non–viral-related HCC. Individuals with fibrolamellar or sarcomatoid HCC, or cholangiocarcinoma, were ineligible to enroll. The study also excluded patients with active brain metastases, co-infection, prior liver transplant, and history hepatic encephalopathy.
Nivolumab was approved in 2017 as a single-agent treatment for patients with advanced HCC who were previously treated with sorafenib.4 This approval was also based on an earlier stage of the CheckMate 040 trial.
Nivolumab alone is mainly indicated for the treatment of unresectable or metastatic melanoma. However, it also has an indication in non–small cell lung cancer, small cell lung cancer, and for treatment of adult patients with classical Hodgkin lymphoma. The drug also has indications in combination with ipilimumab for unresectable or metastatic melanoma, and intermediate or poor risk, previously untreated advanced renal cell carcinoma.

The combination of nivolumab plus ipilimumab was previously granted a breakthrough therapy designation by the FDA for patients with previously treated HCC.
The phase I/II CheckMate 040 trial is ongoing and has a target completion date of July 2021.
  1. U.S. Food and Drug Administration Accepts for Priority Review Bristol-Myers Squibb’s Application for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combination for Patients with Previously Treated Advanced Hepatocellular Carcinoma [press release]. Princeton, New Jersey: Bristol-Myers Squibb Company; November 11, 2019. https://bwnews.pr/2qLbsa0. Accessed November 11, 2019.\
  2. Yau T, Kang Y, 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).
  3. 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.
  4. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib [press release]. Princeton, New Jersey: Bristol-Myers Squibb Company; September 22, 2017. https://bit.ly/33DpOaU. Accessed November 11, 2019.

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