Nivolumab Plus Ipilimumab Emerges as a Go-To Regimen for Frontline HCC

Advanced hepatocellular carcinoma (HCC) presents a clinical challenge as systemic treatment must be calibrated to preserve the function of a liver already compromised by cirrhosis. The approval of immunotherapy combinations beginning in 2020 fundamentally altered that calculus, and the April 2025 first-line approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) based on CheckMate 9DW (NCT04039607) has added a new dimension to a decision that community oncologists are now navigating in real time.

In a virtual Case-Based Roundtable event, Amit Mahipal, MD, professor of medicine and leader of the gastrointestinal (GI) oncology program at Case Western Reserve University, detailed the efficacy and safety landscape for the 3 approved immunotherapy combinations in unresectable HCC and guided participants through a case illustrating how these factors play out in practice.

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CASE SUMMARY

• A 62-year-old man presents to primary care physician with complaints of early satiety, mild discomfort in right upper quadrant, and increasing fatigue (last 2-3 months)
• Unintentional weight loss (–6 lbs) in the last 1-2 months
• Initial workup by physician:
  • Labs showed mild anemia, elevated liver enzymes: ALT 65 U/L, AST 72 U/L, AFP 850 ng/mL
  • Abdominal ultrasound revealed multiple liver lesions, referral for further workup
• Referral to GI/oncology:
  • MRI of the abdomen demonstrated 2 lesions in the right lobe (4-5 cm), mild portal hypertension, splenomegaly
  • Cirrhosis, LI-RADS 5 lesions
  • Chest CT showed multiple bilateral lung nodes, measuring 1-2 cm, ECOG performance status 1
• Diagnosis: Metastatic unresectable HCC, nonviral etiology, Child-Pugh class A, BCLC stage C

DISCUSSION QUESTIONS

• How do you assess liver function in HCC patients: Child-Pugh vs ​
  ALBI scoring?​
• How do you assess a patient’s ability to tolerate grade 3 immune-related adverse events when making treatment selection decisions?​
• ​When selecting a frontline treatment for advanced HCC, what factors drive your decision making?

EVENT RECAP

Before the data review, participants were polled on their preferred treatment approach. Mahipal noted that the vote reflected what he was observing broadly: community oncologists familiar with ipilimumab and nivolumab from kidney cancer, melanoma, and lung cancer were moving quickly to apply that experience in HCC.

Several participants weighed the clinical factors that would shape their choice. Venu Bathini, MD, a GI-focused medical oncologist in Framingham, Massachusetts, raised the ALBI score as a meaningful signal: patients with worse scores might be better served by an immunotherapy-only backbone, since anti-VEGF agents can accelerate hepatic deterioration. Tiffany George, MD, of Cleveland Clinic Florida, said she defaults to atezolizumab (Tecentriq) plus bevacizumab (Avastin) when a patient has portal vein thrombosis, given that CheckMate 9DW excluded patients with main portal vein invasion. Ram Trehan, MD, practicing in suburban Maryland, noted that the liver function question was fundamental: the trial data all derive from Child-Pugh A patients, and that inclusion criterion should anchor patient selection in community practice.

Mahipal then reviewed the trials including CheckMate 9DW, noting that patients were randomized to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab maintenance, vs investigator choice of lenvatinib (Lenvima) or sorafenib (Nexavar), with 85% of the control arm receiving lenvatinib.¹ He stressed the importance of the specific dosing sequence: the approved dose derives from the phase 2 CheckMate 040 (NCT01658878) cohort showing that ipilimumab 3 mg/kg plus nivolumab 1 mg/kg produced a median overall survival (OS) of approximately 23 months compared with roughly 12 months for the reverse dosing.² “I highly recommend using the ipilimumab 3 mg/kg, nivolumab 1 mg/kg regimen, because that’s the only proven regimen,” Mahipal told the group.

The CheckMate 9DW overall survival results drew the most discussion. Median OS reached 23.7 months with nivolumab plus ipilimumab vs 20.6 months with lenvatinib or sorafenib (HR, 0.78; 95% CI, 0.65–0.93).¹

Mahipal directed attention away from the median and toward the landmark rates, which he described as the more meaningful story: 50% vs 39% at 2 years, 39% vs 25% at 3 years, and 31% vs 18%, respectively, at 4 years. “Before immunotherapy, patients living 4 or 5 years was rare,” he observed. “Now almost one-third of patients who got nivolumab plus ipilimumab were alive at 4 years.” The objective response rate was 36% compared with 13% for the tyrosine kinase inhibitor (TKI)arm, and the median duration of response was approximately 34 months vs 13 months.

Humberto Caldera, MD, a community oncologist in West Palm Beach, Florida, who manages 10 to 12 new HCC cases annually, said the long-term landmark data surprised him: “I wasn’t fully aware of the long-term outcomes. I don’t recall the other combinations giving such results.”

Fayez Estefan, MD, a hematologist-oncologist in Annapolis, Maryland, questioned whether the initial dip in the progression-free survival curve, where nivolumab plus ipilimumab appeared to underperform TKI early before separating at longer follow-up, should concern clinicians with high-burden patients. Mahipal attributed this to the fact that a subset of patients do not respond to immunotherapy and have early disease progression. He noted that combining a TKI with immunotherapy to address this had been tested and failed in multiple phase 3 trials, and that no baseline biomarker currently distinguishes likely responders.

Bathini added his perspective on the same concern, also noting that treatment-related deaths in the nivolumab-ipilimumab arm of CheckMate 9DW were approximately 4%, compared with less than 1% in the TKI arm, a difference he said always gives him pause. “That does not deter me,” he clarified, “because I don’t know who those people are who fall into that one-third category who benefit long term.”

Trehan reported having shifted strongly toward nivolumab plus ipilimumab from the HIMALAYA trial (NCT03298451) regimen over the prior 3 years: “Wherever I can now, I prefer ipilimumab-nivolumab, because the experience with the regimen is there, I’m very comfortable with it, and the numbers are really impressive. Unless I have a significant contraindication to [immunotherapy], that’s my go-to regimen now.”

Estefan raised a practical nuance that several participants recognized from other tumor types: ipilimumab at 3 mg/kg is meaningfully different from the 1 mg/kg dose used in combination regimens for non–small cell lung cancer. He sees more toxicity at the higher dose and was accustomed to avoiding it in some settings. Mahipal concurred: “There’s no doubt that ipilimumab 3 mg/kg is a different drug than ipilimumab 1 mg/kg.” He added that approximately 18% of patients in CheckMate 9DW discontinued treatment due to treatment-related adverse events, but that this discontinuation pattern was associated with favorable outcomes, with patients who stopped for toxicity rather than progression achieving a median OS of 27.9 months compared to 23.7 months for the overall population.³

Caldera raised a structural barrier that will shape real-world uptake: in South Florida, where managed care penetration is high, atezolizumab plus bevacizumab remains the preferred frontline agent by some payers, effectively limiting access to nivolumab plus ipilimumab without a documented contraindication. Mahipal acknowledged that coverage patterns vary significantly and that clinicians in community practice will often need to navigate prior authorization pathways before the regimen’s positioning on guidelines can translate to routine prescribing.

Whether the field will ultimately see nivolumab plus ipilimumab displace atezolizumab plus bevacizumab as the community default will depend not only on maturing OS data but on payers catching up to the updated evidence, and on oncologists’ comfort managing the immune-mediated toxicity profile that comes with CTLA-4 plus PD-1 blockade at this dosing intensity.

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_{DISCLOSURES: Mahipal previously reported honoraria from Astellas, AstraZeneca, and BeiGene.}

REFERENCES:

1. Galle PR, Sangro B, Decaens T, et al. Nivolumab plus ipilimumab vs lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC): 4-year follow-up of CheckMate 9DW. J Clin Oncol. 2026;44(suppl 2):LBA479. doi: 10.1200/JCO.2026.44.2_suppl.LBA479

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. Sangro B, Decaens T, Galle PR, et al. Overall evaluation of health-related quality of life (HRQoL) and efficacy assessment in patients (pts) who discontinued (d/c) due to treatment-related adverse events (TRAEs): Results from CheckMate 9DW. Ann Oncol. 2025;36(suppl 1):S62-S63. doi:10.1016/j.annonc.2025.05.161