Analyzing Nivolumab and Ipilimumab as HCC Therapy

Immunotherapy has become a cornerstone of treatment for unresectable hepatocellular carcinoma (HCC). During a virtual Case-Based Roundtable event, Anthony B. El-Khoueiry, MD, an associate professor of clinical medicine in the Division of Medical Oncology and director of the phase I drug development clinical program at the Keck School of Medicine at the University of Southern California, detailed the results of the CheckMate 9DW trial (NCT04039607) for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with investigator's choice of lenvatinib (Lenvima) or sorafenib (Nexavar).

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: Can you discuss the design and outcomes of the CheckMate 9DW trial?

Anthony B. El-Khoueiry, MD: These are the most recent data. I am hearing that familiarity and use of the regimen is important to [everyone in attendance tonight], so it could be that these are the most recent data and it hasn't percolated as much; I do not know.

The trial was for patients with unresectable HCC who had no prior systemic therapy, Child-Pugh A, good ECOG performance status and no main portal vein invasion. These patients were excluded, similar to the HIMALAYA trial [NCT03298451], and the reason they were excluded is because they have poor prognosis. Randomization was 1:1 to nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab single agent. The comparator arm was investigator’s choice of lenvatinib or sorafenib Eighty-five percent of patients in the control arm received lenvatinib, which is very unique about this trial, that the control arm was a very effective therapy with lenvatinib. The primary end point was overall survival [OS].¹

There was a solid mix of patients with hepatitis B, C, and uninfected, meaning non-viral [etiology]. Patients had mostly ECOG performance status of 0 at 70%…73% were Barcelona Clinic Liver Cancer stage C—so definitely advanced disease—23% had vascular invasion, and 32% had an alpha-fetoprotein greater than 400 ng/mL.

How were the dosing levels decided for nivolumab and ipilimumab?

Remember the nivolumab 1 mg/kg, ipilimumab 3 mg/kg regimen was chosen because of the CheckMate 040 study [NCT01658878], where we compared 3 different schedules of nivolumab/ipilimumab and 3 different doses.² All of them showed a response rate of around 30%, but nivolumab 1 mg/kg, ipilimumab 3 mg/kg had the best median OS of 23 months after sorafenib, and possibly 1 more line. So patients must have progressed on sorafenib, but they could have had even another line of therapy. So with 1 or 2 prior regimens, we still got a median OS of 23 months. That's why nivolumab 1 mg/kg, ipilimumab 3 mg/kg was taken forward compared with the other regimens of nivolumab 3 mg/kg, ipilimumab 1 mg/kg [every 3 weeks or] every 6 weeks continuously.

What were the survival outcomes with nivolumab/ipilimumab for these patients with HCC?

CheckMate 9DW was a very positive trial with a median OS of 23.7 months for nivolumab/ipilimumab, and 20.6 months for lenvatinib or sorafenib.¹ This was mostly driven by lenvatinib. The HR was 0.79, so a 21% reduction in the risk of death. The Kaplan-Meier curves separated and stayed separate. We have data at 36 months with an OS rate of 38% vs 24%, respectively.

Initially, around 12 months, the curves crisscross; before, the lenvatinib or sorafenib curve is a little bit on top, and then the nivolumab/ipilimumab curve crosses over around 12 months. There is no obvious explanation for this. There were slightly more non-related adverse events and non-related death in the nivolumab/ipilimumab arm, because this trial was done during the COVID-19 period. So they had a few more COVID-19 deaths in that initial period. So whether this was adverse event–driven or that is a subset of patients who don't necessarily benefit from dual immunotherapy and benefit from lenvatinib, [we don't know]. But still, the trial was positive and met its primary end point.

The progression-free survival [PFS], which was approximately 9 months in both arms, was not unusual. When you use a dual immunotherapy regimen, you do not necessarily see an improvement in PFS, but you still get superior OS. The same was seen with durvalumab [Imfinzi]/tremelimumab [Imjudo].³

What were the results for response rates and other analyses in CheckMate 9DW?

The objective response rate was 36% with nivolumab/ipilimumab vs 13% with lenvatinib or sorafenib, and a striking 7% complete response rate with the combination.⁴ The median duration of response [showed] patients who respond do well for a long time with dual immunotherapy.¹ There was a median duration [of response] of 30.4 months vs 12.9 months with lenvatinib or sorafenib.

There was an analysis of survival based on best overall response. In both cases, whether the experimental or the TKI arm, patients who respond do better.⁵ If they have stable disease, they're in the middle, and if they have progression on their first scan, they do the poorest. This is not a surprise to anybody.

There was an interesting analysis of PFS2:PFS when patients got on second-line therapy after progression on the trial. The patients who receivednivolumab/ipilimumab in the first line had a superior PFS after progression when they got on their second-line treatment, compared with the patients who had lenvatinib or sorafenib in first line.⁴ So the hypothesis here is that maybe the dual immunotherapy, especially the CTLA-4, is modulating that immune microenvironment and potentially having a long-lasting effect.

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_{DISCLOSURES: El-Khoueiry previously reported receiving honoraria from Bayer, Bristol Myers Squibb, Roche/Genentech, Eisai, Merck, Agenus, Exelixis, AstraZeneca/MedImmune, ABL Bio, QED Therapeutics, Servier, Tallac Therapeutics, Senti Biosciences, and Qurient; and a consulting or advisory role with Bristol Myers Squibb, Bayer, Eisai, Roche, Merck, Exelixis, Pieris Pharmaceuticals, Agenus, Gilead Sciences, AstraZeneca/MedImmune, ABL Bio, QED Therapeutics, Servier, Tallac Therapeutics, Senti Biosciences, and Qurient.}

_REFERENCES

_{1. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008}

_{2. Yau T, Kang YK, Kim TY, et al. Efficacy and Safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. doi:10.1001/jamaoncol.2020.4564}

_{3. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070}

_{4. Decaens T, Yau T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC): Expanded analyses from CheckMate 9DW. Ann Oncol. 2024; 35 (suppl 2): S656-S673.doi: 10.1016/j.annonc.2024.08.1025}

_{5. Kudo M, Yau T, Decaens T, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses. J Clin Oncol. 2025;43(suppl 4):520. doi:10.1200/JCO.2025.43.4_suppl.520}