A groundbreaking advancement in the treatment of advanced hepatocellular carcinoma (HCC), the most common form of liver cancer, has emerged from the collaborative efforts of researchers at the University of Hong Kong’s School of Clinical Medicine. Since 2016, a dedicated team led by Dr. Thomas Yau Chung-cheung has pioneered an innovative dual immunotherapy approach that combines two immune checkpoint inhibitors, nivolumab and ipilimumab, to revolutionize first-line treatment for patients with unresectable liver cancer. This novel therapeutic regimen has now received global regulatory approval, a landmark achievement that promises to reshape prognosis and treatment standards for liver cancer patients worldwide.
Liver cancer continues to represent a formidable global health challenge, ranking as the sixth most frequently diagnosed cancer and the third leading cause of cancer-related mortality. Hepatocellular carcinoma accounts for the vast majority of primary liver cancer cases, with approximately 90 percent of diagnoses attributed to this aggressive malignancy. The prognosis for advanced HCC has traditionally been bleak, in large part due to late-stage diagnosis, robust tumor heterogeneity, intrinsic drug resistance, and the scarcity of actionable molecular targets. Historically, the median survival for untreated advanced HCC patients seldom surpasses twelve months, underscoring the critical need for more effective therapeutic strategies.
The dual immunotherapy strategy harnesses the mechanisms of two distinct immune checkpoint inhibitors: nivolumab, a PD-1 (programmed death-1) receptor blocker, and ipilimumab, a CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitor. Both agents function by releasing the brakes on the immune system’s ability to recognize and destroy malignant cells, albeit through complementary pathways. Nivolumab intervenes in the PD-1/PD-L1 axis, preventing cancer cells from evading immune surveillance, while ipilimumab enhances T-cell activation by disrupting the CTLA-4 mediated inhibition of early immune signaling. The synergistic effect of this combination therapy leverages the immune system’s intrinsic capacity to combat tumor cells more robustly than either agent alone.
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Between 2020 and 2021, an extensive Phase 3 clinical trial known as CheckMate 9DW was conducted across 25 countries and regions, enrolling 668 patients diagnosed with previously untreated advanced HCC. This multinational, open-label, randomized study was meticulously designed to evaluate the efficacy and safety of nivolumab combined with ipilimumab compared to established first-line therapies, namely lenvatinib and sorafenib, both multikinase inhibitors and previous standards of care. The patient cohort represented a diverse population in terms of ethnicity, disease burden, and underlying liver function, providing broad applicability of the findings.
Outcomes from the CheckMate 9DW trial have been nothing short of transformative. Patients receiving the dual immunotherapy exhibited a median overall survival of 23.7 months, surpassing the 20.6 months observed in those treated with conventional agents. This approximately 15% increase in median survival represents a meaningful extension of life expectancy in a disease context where gains in survival are traditionally measured in mere months. Moreover, the durability of response was significantly enhanced, with tumor control lasting an average of 30.4 months, doubling the 12.9-month duration seen with lenvatinib or sorafenib therapies.
Perhaps most strikingly, the three-year survival rate reflected a notable improvement, with 38% of patients on nivolumab plus ipilimumab remaining alive compared to only 24% in the control arm. This differential underscores the sustained benefit offered by immune checkpoint blockade in this population. In addition, the objective response rate—a measure of the proportion of patients experiencing a significant reduction or complete disappearance of tumors—reached 36% for the dual immunotherapy group. This rate is nearly triple that of the traditional treatment cohort, which achieved a modest 13%. These robust responses not only translate to prolonged survival but also hold promise for meaningful improvements in patients’ quality of life.
The immunologic basis of these outcomes lies in the distinct yet complementary mechanisms of action of the two checkpoint inhibitors. By simultaneously targeting PD-1 and CTLA-4 pathways, the combination therapy facilitates a more comprehensive reinvigoration of antitumor T-cell responses. Nivolumab’s disruption of PD-1 signaling prevents tumors from exploiting this immune escape route, while ipilimumab’s blockade of CTLA-4 enhances T-cell priming and proliferation early in the immune activation cascade. This dual blockade amplifies the immune response while maintaining an acceptable safety profile, a critical consideration in patients often burdened with compromised liver function and comorbidities.
Dr. Thomas Yau emphasizes the translational significance of this study, stating, “Our results provide unprecedented potential for survival benefit, durable tumor control, and improved quality of life for patients with advanced hepatocellular carcinoma. This treatment paradigm shifts the therapeutic landscape and offers hope to many who previously faced grim prognoses.” The regulatory endorsement of the nivolumab plus ipilimumab combination by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and China’s National Medical Products Administration (NMPA) heralds a new era in global liver cancer therapy.
This breakthrough also sets a precedent for the broader application of combination immunotherapy in tumors characterized by inherent resistance and biological complexity. The success of CheckMate 9DW verifies the feasibility and effectiveness of harnessing dual checkpoint inhibitors in solid tumors beyond melanoma and lung cancer, where these agents have already demonstrated efficacy. It encourages ongoing investigations into optimizing immunotherapeutic regimens, addressing mechanisms of resistance, and identifying predictive biomarkers to tailor therapies more precisely.
The clinical trial’s rigorous methodology, spanning multiple continents and carefully stratified patient populations, lends robustness and credibility to its findings. This comprehensive research effort was supported by Bristol-Myers Squibb, underscoring the collaborative synergy between academia, clinical investigators, and industry partners in advancing cancer care. Future directions will focus on exploring combination strategies with other therapeutic modalities such as targeted agents, chemotherapy, or loco-regional treatments to further enhance outcomes.
In summary, the dual checkpoint inhibition approach combining nivolumab and ipilimumab marks a paradigm shift in the management of advanced hepatocellular carcinoma. Through precise modulation of the immune system, it delivers durable tumor control and significantly prolongs survival in a disease historically associated with dismal outcomes. Approved across major global regulatory bodies, this therapy offers renewed hope to patients worldwide and exemplifies the power of immunotherapy to transform the landscape of oncology.
Subject of Research: Not applicable
Article Title: Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial
News Publication Date: 8-May-2025
Web References:
The Lancet Publication Link
DOI: 10.1016/S0140-6736(25)00403-9
Image Credits: The University of Hong Kong
Keywords: Health and medicine; Clinical medicine
Tags: Dr. Thomas Yau Chung-cheung research contributionsdual immunotherapy for hepatocellular carcinomaglobal health challenges in liver cancerHKUMed liver cancer researchImmune checkpoint inhibitors in cancer therapyinnovative treatments for unresectable liver cancerinternational approval for cancer therapiesliver cancer treatment advancementsnovel therapeutic regimens for cancerovercoming drug resistance in liver cancer treatmentprognosis improvement in liver cancer patientssurvival rates for advanced hepatocellular carcinoma
