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MAIC Analysis Suggests PFS, OS Advantage With Nivolumab/Ipilimumab Over Other First-Line IO Regimens in HCC

Efficacy results from a MAIC suggest potential benefit with nivolumab/ipilimumab over other first-line IO-based regimens in first-line unresectable HCC.

Unresectable HCC | Image credit:  © Sebastian Kaulitzki - stock.adobe.com·

Unresectable HCC | Image credit:

© Sebastian Kaulitzki - stock.adobe.com·

First-line nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated long-term progression-free survival (PFS) and overall survival (OS) benefits for patients with unresectable hepatocellular carcinoma (HCC) compared with durvalumab plus tremelimumab across all analysis periods, or atezolizumab (Tecentriq) plus bevacizumab (Avastin) overall and after 6 months, according to findings from a matching-adjusted indirect comparison (MAIC) presented during the 2025 ESMO Gastrointestinal Cancer Congress

Across the overall trial period, patients treated with nivolumab plus ipilimumab achieved a statistically superior PFS (HR, 0.61; 95% CI, 0.51-0.73) and OS (HR, 0.79; 95% CI, 0.65-0.95), as well as a numerically higher overall response rate (ORR; HR, 2.35; 95% CI, 1.69-3.28) vs durvalumab (Imfinzi) plus tremelimumab (Imjudo). Moreover, nivolumab plus ipilimumab produced statistically superior PFS (HR, 0.81; 95% CI, 0.66-0.99) and numerically favorable OS (HR, 0.93; 95% CI, 0.74-1.18) vs atezolizumab plus bevacizumab across the overall trial period; numerically favorable ORR (HR, 1.39; 0.99-1.95) was also observed.

From 0 to 6 months, nivolumab plus ipilimumab generated statistically superior PFS (HR, 0.57; 95% CI, 0.46-0.71) and numerically favorable OS (HR, 0.90; 95% CI, 0.64-1.26) vs durvalumab plus tremelimumab; however, PFS and OS were numerically unfavorable (HR, 1.05; 95% CI, 0.81-1.35) and statistically inferior (HR, 1.67; 95% CI, 1.12-2.49), respectively, with this regimen vs atezolizumab and bevacizumab. After 6 months, PFS and OS were statistically superior with nivolumab plus ipilimumab vs both immuno-oncology (IO)–based regimens.

“In the absence of head-to-head randomized clinical trials, these MAICs provide insight into the potential benefit of nivolumab plus ipilimumab relative to other available immuno-oncology–based treatment regimens for first-line unresectable HCC,” presenting author Masatoshi Kudo, MD, PhD, and coauthors stated in a poster presentation of the data. “Efficacy results suggest the potential benefit of nivolumab plus ipilimumab vs durvalumab plus tremelimumab across all analysis periods and against atezolizumab plus bevacizumab overall and after 6 months.”

Kudo is a professor and chairman at the Department of Gastroenterology and Hepatology at Kindai University Faculty of Medicine in Japan.

Study Background and Design

Approved systemic therapies for unresectable HCC include durvalumab plus tremelimumab, atezolizumab plus bevacizumab, both of which demonstrated improved efficacy vs sorafenib (Nexavar) in the phase 3 IMbrave150 (NCT03434379) and HIMALAYA (NCT03298451) trials, respectively. As the most recent immuno-oncology regimen to be added to the unresectable HCC treatment paradigm, nivolumab plus ipilimumab recently showed a significant survival benefit vs investigator’s choice of sorafenib (Nexavar) or lenvatinib (Lenvima) in the phase 3 CheckMate 9DW trial (NCT04039607).

In the absence of head-to-head trials comparing the efficacy and safety of these 3 regimens, investigators conducted a study utilizing indirect treatment comparisons (ITCs).

Prior to conducting statistical analyses, a comprehensive assessment of ITC feasibility identified key challenges, including heterogeneity between trial patient populations and differences in control arms across the 3 studies. To address these differences, pairwise unanchored MAICs were conducted. Patient baseline characteristics and outcomes for nivolumab plus ipilimumab were obtained from individual patient data in CheckMate 9DW; aggregate patient baseline characteristics and safety outcomes for the other 2 regimens were extracted from published data from HIMALAYA and IMbrave150.

Baseline Characteristics and Follow-Up

In the durvalumab plus tremelimumab arm of HIMILAYA, the median duration of follow-up was 33.18 months (range, 31.74-34.53) for PFS, ORR, and safety, and 62.49 months (range, 59.47-64.79) for OS. In the atezolizumab plus bevacizumab arm of IMbrave150, the median duration of follow-up was 17.6 months (range, 0.1-28.6 months). In CheckMate 9DW, the median duration of follow-up was 35.20 months (range, 26.8-48.9).

Patient baseline characteristics were well balanced between trial populations in each comparison after weighting.

The mean age was 63 years in the weighted comparison of nivolumab plus ipilimumab vs durvalumab plus tremelimumab (n = 393), and 62.9 years in the weighted comparison of nivolumab plus ipilimumab and atezolizumab plus bevacizumab (n = 336). The majority of patients were male (83.2%; 82.4%), EHS (53.2%; 63.1%); had an ECOG performance status of 0 (62.1%; 62.2%), Barcelona Clinical Liver Cancer stage C disease (80.4%; 82.1%) and a Child-Pugh score of 5 (75.1%; 71.1%). Patients were also Asian (49.6%; 56.0%), had microvascular invasion (26.2%; 38.4%), had an alpha fetoprotein tumor marker level of 400 ng/mL or above (36.9%; 37.5%), and had an albumin-bilirubin level of 2 or higher (44.5%; not applicable). Regarding etiology, more patients had hepatitis B (31.0%; 48.8%) than hepatitis C (28.0%; 21.4%).

Additional Sensitivity Analyses, Safety Data, and Study Limitations

In the non-Vp4 sensitivity analyses, nivolumab plus ipilimumab demonstrated numerically favorable PFS (HR, 0.82; 95% CI, 0.66-1.02), OS (HR, 0.98; 95% CI, 0.76-1.26) and ORR (odds ratio, 1.25; 95% CI, 0.86-1.70) vs atezolizumab plus bevacizumab in the overall trial period. From 0 to 6 months, PFS remained numerically unfavorable (HR, 1.09; 95% CI, 0.83-1.43) and OS was statistically inferior (HR, 2.05; 95% CI, 1.30-3.22). After 6 months, the nivolumab regimen produced a statistically superior PFS (HR, 0.51; 0.36-0.73) and OS (HR, 0.68; 95% CI, 0.50-0.92) vs atezolizumab plus bevacizumab.

Regarding safety, the incidence of all-cause, any-grade adverse effects (AEs) in the comparison of nivolumab plus ipilimumab vs durvalumab plus tremelimumab was 99.73% with the weighted nivolumab regimen (n = 332) and 97.42% with the durvalumab regimen (n = 388). Grade 3 or higher all-cause AEs were presented in 69.97% and 50.52% of patients treated with these respective regimens. Any-grade treatment-related AEs (TRAEs) occurred in 83.16% of patients in the nivolumab/ipilimumab arm, 41.42% of which were grade 3 or higher. The respective rates were 75.77% and 25.77% in the durvalumab/tremelimumab arm. Treatment-related deaths occurred in 3.18% and 2.32% of patients in the nivolumab/ipilimumab and durvalumab/tremelimumab arms, respectively.

In the comparison of nivolumab plus ipilimumab vs atezolizumab plus bevacizumab, the incidence of all-cause, any-grade AEs was 99.68% with the weighted nivolumab regimen (n = 332) and 97.87% with the atezolizumab regimen (n = 329). Grade 3 or higher all-cause AEs were presented in 68.28% and 62.92% of patients treated with these respective regimens. Any-grade TRAEs occurred in 81.67% of patients in the nivolumab/ipilimumab arm, 39.70% of which were grade 3 or higher. The respective rates were 86.32% and 43.47% in the atezolizumab/bevacizumab arm. Treatment-related deaths occurred in 3.63% and 1.82% of patients in the nivolumab/ipilimumab and atezolizumab/bevacizumab arms, respectively.

Investigators noted several important study limitations, including several patient factors that could not be adjusted for due to data availability; the difficulty of identifying and adjusting for all possible effect modifiers and patient factors, allowing for residual bias; a lack of consideration for temporal trends and differences in trial dosing, which could have affected safety comparisons; higher steroid use with the nivolumab- and durvalumab-based regimens vs atezolizumab/bevacizumab in their respective clinical trials; and difficulties ensuring a homogenous subgroup despite excluding patients without Vp4 and conducting non-VP4 analyses.

Future research should therefore seek to explore the potential affect of higher steroid use with a higher rate of immune-related AEs with the nivolumab- plus durvalumab-based regimens vs atezolizumab plus bevacizumab, as well as outcomes across populations with other classifications of portal vein thrombosis.

“The present findings may help inform decision-making when selecting first-line IO-based treatment options for unresectable HCC,” Kudo and colleagues concluded.

Disclosures: Kudo disclosed receiving honoraria from AstraZeneca, Bayer, Chugai/Roche, Eisai, Lilly Japan, and Takeda; serving in a consulting or advisory role for AstraZeneca, Chugai/Roche, Eisai; and receiving institutional research funding from AbbVie, Chugai/Roche, Eisai, GE Healthcare, and Otsuka Pharmaceutical.

Reference

Kudo M, Galle P, Lee A, et al. Matching-adjusted indirect comparisons (MAICs) of nivolumab + ipilimumab (N + I) vs durvalumab + tremelimumab (D + T) and atezolizumab + bevacizumab (A + B) for first-line (1L) unresectable hepatocellular carcinoma (uHCC). Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 151P.


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