MASLD-Related HCC—Update on Pathogenesis and Current Treatment Options
Abstract
:1. Introduction
2. Epidemiology of HCC in MASH
3. Pathogenesis of HCC in MASH
3.1. Genetic Factors
3.2. Intestinal Microbiome
4. HCC Surveillance in MASLD/MASH
5. Therapeutical Challenges in Patients with MASH-Related HCC
5.1. Treatment of Intermediate-Stage HCC
5.2. The Treatment Landscape for Advanced-Stage HCC
5.3. Immunotherapy and Targeted Therapies in Non-Viral HCC
6. Future Directions
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Trial And Treatment Arms | Etiology * | Stratification Criteria | Primary Endpoints | Secondary Endpoints |
---|---|---|---|---|
SHARP—sorafenib vs. placebo [70] | HCV 29% HBV 19% Alcohol 26% Unknown 16% Other 9% | Geographical region ECOG PS (0 vs. 1–2) Macrovascular invasion or extrahepatic spread (presence vs. absence) | OS 10.7 vs. 7.9 (HR 0.69, 95%-CI 0.55–0.87, p < 0.0019) TTSP 4.1 vs. 4.9 (HR 1.08, 95% CI 0.88–1.31, p = 0.77) | TTRP 5.5 vs. 2.8 (HR 0.58, 95% CI 0.45–0.74, p < 0.001) DCR 43% vs. 32%; p = 0.002 |
Asia-Pacific—sorafenib vs. placebo [71] | HCV 70.7% HBV 10.7% | Geographical region Macrovascular invasion and/or extrahepatic spread (presence vs. absence) ECOG PS (0–2) | OS 6.5 vs. 4.2 (HR 0.68 95% CI 0.50–0.93. p = 0.014) | TTP 2.8 vs. 1.4 (HR 0.57, 95% CI 0.42–0.79, p = 0.0005) TTSP 3.5 vs. 3.4 (HR 0.90, 95% CI 0.67–1.22, p = 0.50) DCR 35.3% vs. 15.8% (p = 0.0019) |
IMbrave150—atezolizumab + bevacizumab vs. sorafenib [76,80] | HCV 21% HBV 49% Non-viral 30% # | Geographical region (Asia excluding Japan vs. rest of the world) Macrovascular invasion or extrahepatic spread (presence vs. absence) Baseline AFP < 400 ng/mL vs. ≥400 ng/mL ECOG PS (0 vs. 1) | OS 19.2 vs. 13.4 (HR 0.66, 95% CI 0.52–0.85, p < 0.001) PFS 6.9 vs. 4.3 (HR 0.65, 95% CI 0.53–0.81, p < 0.001) | ORR 30% vs. 11% (p < 0.001) DoR 18.1 (95% CI 14.6-NE) vs. 14.9 (95% CI 4.9–17.0) |
HIMALAYA—durvalumab vs. sorafenib and durvalumab + tremelimumab vs. sorafenib [77] | HBV 31% HCV 28% Nonviral 41% | Asia (excluding Japan) 39.7% and rest of world 60.3%. ECOG PS (0 vs. 1), AFP ≥ 400 (yes vs. no)), macrovascular invasion (yes vs. no), extrahepatic disease (yes vs. no), PD-L1 status pos. vs. neg.) | OS STRIDE 16.4 vs. sorafenib 13.8 (HR 0.78, 96% CI 0.65–0.92, p = 0.0035) | ORR STRIDE 20.1% vs. sorafenib 5.1% TTP 5.4 (95% CI, 3.8 to 5.6) in STRIDE arm, 3.8 (95% CI, 3.7 to 5.4) in durvalumab arm, and 5.6 (95% CI, 5.1 to 5.8) in Sorafenib arm |
REFLECT—lenvatinib vs. sorafenib [72] | HCV 19% HBV 52.5% Alcohol 7.5% Other 7.9% Unknown 13% | Geographical region (Asia-Pacific or Western) ECOG PS (0 vs. 1) Presence or absence of macroscopic portal vein invasion and/or extrahepatic spread Body weight (<60 kg or ≥60 kg) | OS 13.6 vs. 12.3 (HR 0.92, 95% CI 0.79–1.06 | PFS 7.4 vs. 3.7 (HR 0.66, 95% CI 0.57–0.77, p < 0.0001) TTP 8.9 vs. 3.7 (HR 0.63, 95% CI 0.53–0.73, p < 0.0001) ORR 24.1% vs. 9.2% (OR 3.13, 95% CI 2.15–4.56, p < 0.0001) |
RESORCE—regorafenib vs. placebo [73] | HCV 21% HBV 38% Alcohol 24% Unknown 17% MASH 7% Other 7% | Geographical region (Asia vs. rest of world) Macrovascular invasion (yes vs. no) Extrahepatic spread (yes vs. no) Baseline AFP < 400 ng/mL vs. ≥400 ng/mL ECOG PS (0 vs. 1) | OS 10.6 vs. 7.8 (HR 0.68, 95% CI 0.50–0.79, p < 0.0001) | PFS 3.1 vs. 1.5 (HR 0.46, 95% CI 0.37–0.56, p < 0.0001) TTP 3.2 vs. 1.5 (HR 0.44, 95% CI 0.36–0.55, p < 0.0001) ORR 11% vs. 4% (p = 0.0047) DCR 65% vs. 36% (p < 0.0001) |
CELESTIAL—cabozantinib vs. placebo [74] | HCV 24% HBV 38% HBV + HCV 2% Alcohol 24% MASH 9% Other 5% Unknown 16% | Etiology (HBV with or without HCV vs. HCV without HBV, or other) Geographical region (Asia or other) Extrahepatic spread and/or macrovascular invasion (yes vs. no) | OS 10.2 vs. 8 (HR 0.76; 95% CI 0.63–0.92, p = 0.005) | PFS 5.2 vs. 1.9 (HR 0.44, 95% CI 0.36–0.52, p < 0.001) ORR 4% vs. <1% (p = 0.009) |
REACH-2—ramucirumab vs. placebo [75] | HCV 24% HBV 36% Alcohol 24% MASH 10% Cryptogenic 6% Other 9% | Geographical region (America, Europe, Australia, Israel vs. Asia, excluding Japan vs. Japan) Macrovascular invasion (yes vs. no) ECOG PS (0 vs. 1) | OS 8.5 vs. 7.3 (HR 0.710. 95% CI 0.53–0.95, p = 0.0199) | PFS 2.8 vs. 1.6 (HR 0.452, 95% CI 0.34–0.60, p < 0.0001) ORR 5% vs.1%, p = 0.1697) TTRP 3 vs. 1.6 (HR 0.427, 95% CI 0.31–0.58, p < 0.0001) |
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Leyh, C.; Coombes, J.D.; Schmidt, H.H.; Canbay, A.; Manka, P.P.; Best, J. MASLD-Related HCC—Update on Pathogenesis and Current Treatment Options. J. Pers. Med. 2024, 14, 370. https://doi.org/10.3390/jpm14040370
Leyh C, Coombes JD, Schmidt HH, Canbay A, Manka PP, Best J. MASLD-Related HCC—Update on Pathogenesis and Current Treatment Options. Journal of Personalized Medicine. 2024; 14(4):370. https://doi.org/10.3390/jpm14040370
Chicago/Turabian StyleLeyh, Catherine, Jason D. Coombes, Hartmut H. Schmidt, Ali Canbay, Paul P. Manka, and Jan Best. 2024. "MASLD-Related HCC—Update on Pathogenesis and Current Treatment Options" Journal of Personalized Medicine 14, no. 4: 370. https://doi.org/10.3390/jpm14040370