FDA Grants Priority Review to Nivolumab/Ipilimumab in Advanced HCC

The FDA has granted a priority review designation to a supplemental biologics license application for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of patients with advanced hepatocellular carcinoma (HCC) who received prior therapy with sorafenib (Nexavar).¹

The designation is based on results of a cohort from the phase I/II CheckMate-040 study (NCT01658878), in which nivolumab and ipilimumab were evaluated in this patient population at varying doses. In an abstract presented at the 13th Annual Conference of the International Liver Cancer Association (ILCA), results showed that across 3 dosing schedules, the objective response rate (ORR) with the combination was 31%.² Additionally, the median duration of response (DOR) was 17 months, the disease control rate (DCR) was 49%, and the 2-year overall survival (OS) rate was 40%.

“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,” Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, Bristol-Myers Squibb, the manufacturer of the PD-1 and CTLA-4 inhibitors, stated in a press release. “Despite recent advances, hepatocellular carcinoma remains a difficult-to-treat cancer and patients are in need of additional effective treatment options. We look forward to working with the FDA to bring the potential of a dual immuno-oncology therapy to these patients for the first time.”

Under the Prescription Drug User Fee Act, the FDA must make a decision on the application by March 10, 2020. The FDA had also granted a breakthrough therapy designation to the combination for use in this setting.

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.

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.

In September 2017, the FDA granted an accelerated approval to nivolumab monotherapy for the treatment of patients with HCC who have been previously treated with sorafenib. The approval was based on another cohort of the CheckMate-040 trial, in which the ORR by blinded independent central review with single-agent nivolumab was 18.2% per mRECIST criteria for patients who had previously been treated with sorafenib.⁴

References

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. Bristol-Myers Squibb. Published November 11, 2019. https://bit.ly/2NCyxEE. Accessed November 11, 2019.
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. 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). doi: 10.1200/JCO.2016.34.15_suppl.4078.