Molecular therapies and precision medicine for hepatocellular carcinoma

Abstract

The global burden of hepatocellular carcinoma (HCC) is increasing and might soon surpass an annual incidence of 1 million cases. Genomic studies have established the landscape of molecular alterations in HCC; however, the most common mutations are not actionable, and only ~25% of tumours harbour potentially targetable drivers. Despite the fact that surveillance programmes lead to early diagnosis in 40-50% of patients, at a point when potentially curative treatments are applicable, almost half of all patients with HCC ultimately receive systemic therapies. Sorafenib was the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months. New drugs - lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line - have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year; thus, therapeutic breakthroughs are still needed. Immune-checkpoint inhibitors are now being incorporated into the HCC treatment armamentarium and combinations of molecularly targeted therapies with immunotherapies are emerging as tools to boost the immune response. Research on biomarkers of a response or primary resistance to immunotherapies is also advancing. Herein, we summarize the molecular targets and therapies for the management of HCC and discuss the advancements expected in the near future, including biomarker-driven treatments and immunotherapies.

Fig. 1 |. Integrative molecular and immunological classification of HCC.

a | Hepatocellular carcinomas (HCCs) can be classified into two major transcriptome-based phenotypic classes that are also associated with characteristic somatic genetic alterations, epigenetic features, biological phenotypes (activated oncogenic and immune signalling pathways), and clinical characteristics. First, the proliferation class, which is associated with a poor prognosis, chromosomal instability, and activation of classic oncogenic signalling pathways (such as the RAS–MAPK and AKT–mTOR pathways). Data from genomic profiling studies indicate that a subset of tumours within the proliferation class might have a progenitor cell phenotype (S2) characterized by high levels of α-fetoprotein (AFP), overexpression of epithelial cell adhesion molecule (EPCAM), cytokeratin 19 (CK19), and/or IGF2 and a unique hypermethylation profile (36 CpG signature). The other subset of proliferation class tumours (S1) is defined by activated WNT–TGFβ signalling and an immune exhausted tumour microenvironment. Second, the non-proliferation class tumours, which have a less aggressive course with slower disease progression and thus a better prognosis than proliferation class tumours; a subset of non-proliferation class tumours (CTNNB1) is characterized by WNT–β-catenin pathway activation, predominantly via CTNNB1 mutation. The poly7 and interferon subclasses need to be further characterized. b | Immune-based classification of HCCs according to the immune status in the tumour microenvironment is shown. This novel classification defines three tumour classes on the basis of molecular data and immune-related parameters: the immune class, the immune intermediate class and the immune excluded class, each of which might require different immunotherapy approaches tailored to the immune microenvironment. E2F1, transcription factor E2F1; HBV, hepatitis B virus; HCV, hepatitis C virus; M2, M2-like macrophages; miRNA, microRNA; NOTCH, neurogenic locus NOTCH homologue protein; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; TLS, tertiary lymphoid structures.

Fig. 2 |. Hepatocellular treatments recommended in international EASL guidelines.

Treatment recommendations from the European Association for the Study of the Liver (EASL) international guidelines are illustrated according to levels of evidence and strength of recommendation (on the basis of adaptation of the GRADE system). Treatments endorsed in the international guidelines (strong positive recommendation) are shown in green^,. Treatments for which more evidence is needed (weak positive recommendations) are shown in orange, whereas those not endorsed (strong negative recommendation) are shown in red. The Milan criteria for liver transplantation are a single tumour ≤5 cm or three nodules ≤3 cm in diameter. AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; LDLT, living donor liver transplantation; LT, orthotopic liver transplantation. *Other molecularly targeted therapies include sunitinib, linifanib, brivanib, tivantinib, erlotinib, and everolimus. Figure adapted with permission from REF., Elsevier.

Fig. 3 |. Overall survival outcomes of phase III clinical trials testing molecularly targeted therapies or radioembolization with ⁹⁰Y in patients with advanced-stage HCC.

The figure illustrates the estimated overall survival hazard ratios (HRs) and 95% confidence intervals (in parentheses) for the experimental drug (or combination) versus either sorafenib in the first-line setting (part a) or placebo in the second-line setting (part b). Green-shaded text indicates positive results from trials with a superiority design. The orange-shaded text indicates a positive result from a trial with a non-inferiority design. Black text with no shading and red-shaded text represent negative results with an HR confidence interval crossing or not crossing 1, respectively. Second-line treatment with ramucirumab did improve overall survival when tested in patients with high serum α-fetoprotein (AFP) levels (≥400 ng/ml). The blue lines and red hashed lines indicate the upper limits for superiority and non-inferiority, respectively. HCC, hepatocellular carcinoma.

Fig. 4 |. Molecularly targeted therapies for HCC and their target signalling pathways.

Green boxes indicate drugs with positive results from phase III trials (sorafenib, regorafenib, lenvatinib, cabozantinib, and ramucirumab). Red boxes indicate drugs with negative results from phase III trials (everolimus, sunitinib, linifanib, erlotinib, brivanib, and tivantinib). Drugs in yellow boxes are currently in development for hepatocellular carcinoma (HCC) in either phase I, phase II, or phase III clinical trials (TABLE 2). The dashed lines indicate indirect activities. A3AR, adenosine receptor A3; AR, androgen receptor; AURKB, Aurora kinase B; CCR4, CC-chemokine receptor 4; CDKs, cyclin-dependent kinases; CTLA-4, cytotoxic T lymphocyte protein 4; FGFR, FGF receptor; HDACs, histone deacetylases; HSP90, heat shock protein 90; IDO1, indoleamine 2,3-dioxygenase 1; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; PDGFR, PDGF receptor; SHH, sonic hedgehog protein; SK2, sphingosine kinase 2; STAT3, signal transducer and activator of transcription 3; TGFβR1, TGFβ type 1 receptor; TIE2, angiopoietin 1 receptor; VEGFR, VEGF receptor.

Fig. 5 |. Treatment strategy for advanced HCC.

Drugs in green have positive results from phase III trials with a superiority design (sorafenib in the first-line setting and regorafenib and cabozantinib in the second-line setting). Ramucirumab improved overall survival in the phase III REACH-2 trial, which involved patients with high serum α-fetoprotein (AFP) levels (≥400 ng/ml). Drugs in orange have positive results from phase III trials with a non-inferiority design (lenvatinib in the first-line setting). Drugs in red have received accelerated approval from the FDA on the basis of promising efficacy results in phase II trials (nivolumab in the second-line setting). Key details of the patient populations are provided. BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EHS, extrahepatic spread; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IHC, immunohistochemistry; mRECIST, modified Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell death 1 ligand 1.