Molecular therapies and precision medicine for hepatocellular carcinoma (original) (raw)
Torre, L. A. et al. Global cancer statistics, 2012. CA. Cancer J. Clin.65, 87–108 (2015). PubMed Google Scholar
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim.2, 16018 (2016). PubMed Google Scholar
Zucman-Rossi, J., Villanueva, A., Nault, J. C. & Llovet, J. M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology149, 1226–1239 (2015). CASPubMed Google Scholar
Bruix, J., S. M. A. A. for the S. of L. D. Management of hepatocellular carcinoma: an update. Hepatology53, 1020–1022 (2011). PubMed Google Scholar
Llovet, J. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med.359, 378–390 (2008). CASPubMed Google Scholar
Kudo, M. et al. A randomised phase 3 trial of lenvatinib versus sorafenib in firstline treatment of patients with unresectable hepatocellular carcinoma. Lancet391, 1163–1173 (2018). CASPubMed Google Scholar
Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet389, 56–66 (2017). CASPubMed Google Scholar
Abou-Alfa, G.K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med.379, 54–63 (2018). Google Scholar
Zhu, A. X. et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafe [abstract]. J. Clin. Oncol.36, 4003 (2018). Google Scholar
El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet389, 2492–2502 (2017). CASPubMedPubMed Central Google Scholar
Llovet, J. M. & Hernandez-Gea, V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin. Cancer Res.20, 2072–2079 (2014). CASPubMed Google Scholar
Sangiovanni, A. et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology126, 1005–1014 (2004). PubMed Google Scholar
Nault, J.-C. et al. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology152, 880–894.e6 (2017). CASPubMed Google Scholar
Sia, D., Villanueva, A., Friedman, S. L. & Llovet, J. M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology152, 745–761 (2016). PubMed Google Scholar
Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet.47, 505–511 (2015). CASPubMedPubMed Central Google Scholar
Charles Nault, J. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun.4, 2218 (2013). Google Scholar
Wheeler, D. A. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell169, 1327–1341 (2017). CASPubMed Central Google Scholar
Ahn, S.-M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology60, 1972–1982 (2014). CASPubMed Google Scholar
Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet.46, 1267–1273 (2014). CASPubMed Google Scholar
Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res.68, 6779–6788 (2008). CASPubMedPubMed Central Google Scholar
Martinez-Quetglas, I. et al. IGF2 is up-regulated by epigenetic mechanisms in hepatocellular carcinomas and is an actionable oncogene product in experimental models. Gastroenterology151, 1192–1205 (2016). CASPubMed Google Scholar
Hoshida, Y. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res.69, 7385–7392 (2009). CASPubMedPubMed Central Google Scholar
Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology45, 42–52 (2007). CASPubMed Google Scholar
Lee, J.-S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med.12, 410–416 (2006). CASPubMed Google Scholar
Toffanin, S. et al. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology140, 1618–1628 (2011). CASPubMed Google Scholar
Llovet, J. M., Villanueva, A., Lachenmayer, A. & Finn, R. S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol.12, 408–424 (2015). CASPubMed Google Scholar
Hoshida, Y. et al. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin. Liver Dis.30, 35–51 (2010). CASPubMedPubMed Central Google Scholar
Wang, K. et al. Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma. Hepatology58, 706–717 (2013). PubMed Google Scholar
Villanueva, A. et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology61, 1945–1956 (2015). CASPubMed Google Scholar
Lachenmayer, A. et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin. Cancer Res.18, 4997–5007 (2012). CASPubMedPubMed Central Google Scholar
Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med.359, 1995–2004 (2008). CASPubMedPubMed Central Google Scholar
Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature431, 461–466 (2004). CASPubMed Google Scholar
Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology153, 812–826 (2017). CASPubMed Google Scholar
Weis, S. M. & Cheresh, D. A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med.17, 1359–1370 (2011). CASPubMed Google Scholar
Khan, K. A. & Kerbel, R. S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol.15, 310–324 (2018). CASPubMed Google Scholar
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol.15, 325–340 (2018). CASPubMedPubMed Central Google Scholar
Yau, T. et al. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology146, 1691–1700.e3 (2014). PubMed Google Scholar
[No authors listed]. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology28, 751–755 (1998). Google Scholar
Sobin, L. H. & Compton, C. C. TNM seventh edition: what’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer116, 5336–5339 (2010). PubMed Google Scholar
Kudo, M., Chung, H. & Osaki, Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J. Gastroenterol.38, 207–215 (2003). PubMed Google Scholar
Llovet, J. M., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis.19, 329–338 (1999). CASPubMed Google Scholar
Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. Oncol.16, 1344–1354 (2015). CASPubMed Google Scholar
Llovet, J. M. et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet359, 1734–1739 (2002). PubMed Google Scholar
Lo, C.-M. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology35, 1164–1171 (2002). CASPubMed Google Scholar
Llovet, J. M. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology37, 429–442 (2003). CASPubMed Google Scholar
Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol.64, 1090–1098 (2016). CASPubMed Google Scholar
Meyer, T. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol.2, 565–575 (2017). PubMed Google Scholar
Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology60, 1697–1707 (2014). CASPubMed Google Scholar
Qin, S. et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J. Clin. Oncol.31, 3501–3508 (2013). CASPubMed Google Scholar
Abou-Alfa, G. K. et al. Doxorubicin plus sorafenib versus doxorubicin alone in patients with advanced hepatocellular carcinoma. JAMA304, 2154 (2010). CASPubMed Google Scholar
Yeo, W. et al. A randomized phase III study of doxorubicin versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J. Natl Cancer Inst.97, 1532–1538 (2005). CASPubMed Google Scholar
Chow, P. et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology36, 1221–1226 (2002). CASPubMed Google Scholar
Dalhoff, K. et al. A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br. J. Cancer89, 252–257 (2003). CASPubMedPubMed Central Google Scholar
Cheng, A.-L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol.10, 25–34 (2009). CASPubMed Google Scholar
Reig, M. et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J. Hepatol.61, 318–324 (2014). CASPubMed Google Scholar
Bruix, J. et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase 3 studies. J. Hepatol.67, 999–1008 (2017). CASPubMed Google Scholar
Iavarone, M. et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology54, 2055–2063 (2011). CASPubMed Google Scholar
Ganten, T. M. et al. Sorafenib in patients with hepatocellular carcinoma—results of the Observational INSIGHT Study. Clin. Cancer Res.23, 5720–5728 (2017). CASPubMed Google Scholar
Marrero, J. A. et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J. Hepatol.65, 1140–1147 (2016). CASPubMed Google Scholar
Kudo, M. et al. Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study. Liver Int.36, 1196–1205 (2016). CASPubMed Google Scholar
Wilhelm, S. M. et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther.7, 3129–3140 (2008). CASPubMed Google Scholar
Llovet, J. M. et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin. Cancer Res.18, 2290–2300 (2012). CASPubMed Google Scholar
Pinyol, R. et al. Molecular predictors of recurrence prevention with sorafenib as adjuvant therapy in hepatocellular carcinoma: biomarker study of the STORM phase III trial. J. Hepatol.66, S12–S13 (2017). Google Scholar
Llovet, J. M. et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl Cancer Inst.100, 698–711 (2008). PubMed Google Scholar
Lencioni, R. et al. Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC. J. Hepatol.66, 1166–1172 (2017). PubMed Google Scholar
Montal, R., Lencioni, R. & Llovet, J. M. Reply to: mRECIST for systemic therapies: more evidence is required before recommendations could be made. J. Hepatol.67, 196–197 (2017). PubMed Google Scholar
Johnson, P. J. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J. Clin. Oncol.31, 3517–3524 (2013). CASPubMed Google Scholar
Cheng, A.-L. et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J. Clin. Oncol.31, 4067–4075 (2013). CASPubMed Google Scholar
Cainap, C. et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J. Clin. Oncol.33, 172–179 (2015). CASPubMed Google Scholar
Zhu, aX. et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol.33, 559–566 (2014). PubMed Google Scholar
Vilgrain, V. et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol.18, 1624–1636 (2017). CASPubMed Google Scholar
Chow, P. K. H. et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J. Clin. Oncol.36, 1913–1921 (2018). PubMed Google Scholar
Ricke, J. et al. The impact of combining Selective Internal Radiation Therapy (SIRT) with sorafenib on overall survival in patients with advanced hepatocellular carcinoma: the SORAMIC trial palliative cohort. J. Hepatol.68, S102 (2018). Google Scholar
Matsui, J. et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin. Cancer Res.14, 5459–5465 (2008). CASPubMed Google Scholar
Ikeda, K. et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J. Gastroenterol.52, 512–519 (2017). CASPubMed Google Scholar
Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA312, 57–67 (2014). PubMed Google Scholar
Zhu, A. X. et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol.16, 859–870 (2015). CASPubMed Google Scholar
Llovet, J. M. et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J. Clin. Oncol.31, 3509–3516 (2013). CASPubMed Google Scholar
Rimassa, L. et al. Second-line tivantinib (ARQ 197) versus placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): results of the METIV-HCC phase III trial. J. Clin. Oncol.35 (Suppl. 15), 4000 (2017). Google Scholar
Zhu, A. X. et al. KEYNOTE-224: Phase II study of pembrolizumab in patients with previously treated advanced hepatocellular carcinoma. J. Clin. Oncol.35 (Suppl. 4), TPS504 (2017). Google Scholar
Wilhelm, S. M. et al. Regorafenib (BAY 73–4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer129, 245–255 (2011). CASPubMed Google Scholar
Bruix, J. et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study. Eur. J. Cancer49, 3412–3419 (2013). CASPubMed Google Scholar
Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther.10, 2298–2308 (2011). CASPubMed Google Scholar
Kelley, R. K. et al. Cabozantinib in hepatocellular carcinoma: Results of a phase 2 placebo-controlled randomized discontinuation study. Ann. Oncol.28, 528–534 (2017). CASPubMedPubMed Central Google Scholar
Goyal, L., Muzumdar, M. D. & Zhu, A. X. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin. Cancer Res.19, 2310–2318 (2013). CASPubMedPubMed Central Google Scholar
Zhu, A. X. et al. A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin. Cancer Res.19, 6614–6623 (2013). CASPubMedPubMed Central Google Scholar
Terentiev, A. A. & Moldogazieva, N. T. Alpha-fetoprotein: a renaissance. Tumor Biol.34, 2075–2091 (2013). CAS Google Scholar
Shan, Y. F. et al. Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and α-fetoprotein expression status. Med. Oncol.28, 1012–1016 (2011). CASPubMed Google Scholar
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell27, 451–461 (2015). Google Scholar
Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol.13, 473–486 (2016). CASPubMed Google Scholar
Ribas, A. Releasing the brakes on cancer immunotherapy. N. Engl. J. Med.373, 1490–1492 (2015). PubMed Google Scholar
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell168, 707–723 (2017). CASPubMedPubMed Central Google Scholar
Iñarrairaegui, M., Melero, I. & Sangro, B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin. Cancer Res.24, 1518–1524 (2017). PubMed Google Scholar
Sangro, B. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol.59, 81–88 (2013). CASPubMed Google Scholar
El-Khoueiry, A. B. et al. Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): subanalyses of CheckMate-040. J. Clin. Oncol.36 (Suppl. 4), 475 (2018). Google Scholar
US Food & Drug Administration. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib (FDA, 2017).
Zhu, A. X. et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J. Clin. Oncol.36 (Suppl. 4), 209 (2018). Google Scholar
Finn, R. S. et al. KEYNOTE-240: Randomized phase III study of pembrolizumab versus best supportive care for second-line advanced hepatocellular carcinoma. J. Clin. Oncol.35 (Suppl. 4), TPS503 (2017). Google Scholar
Wainberg, Z. A. et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J. Clin. Oncol.35 (Suppl. 4), 4071 (2017). Google Scholar
Patel, S. P. & Kurzrock, R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther.14, 847–856 (2015). CASPubMed Google Scholar
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science348, 124–129 (2016). Google Scholar
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature515, 568–571 (2014). CASPubMedPubMed Central Google Scholar
Crocenzi, T. S. et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. J. Clin. Oncol.35 (Suppl. 15), 4013 (2017). Google Scholar
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science357, 409–413 (2017). CASPubMedPubMed Central Google Scholar
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med.377, 1345–1356 (2017). CASPubMedPubMed Central Google Scholar
Kelley, R. K. et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J. Clin. Oncol.35 (Suppl. 15), 4073 (2017). Google Scholar
Lee, C.-H. et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Ann. Oncol.28 (Suppl. 5), 295–329 (2017). Google Scholar
Collins, D. C., Sundar, R., Lim, J. S. J. & Yap, T. A. Towards precision medicine in the clinic: from biomarker discovery to novel therapeutics. Trends Pharmacol. Sci.38, 25–40 (2017). CASPubMed Google Scholar
Santoro, A. et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol.14, 55–63 (2013). CASPubMed Google Scholar
Basilico, C. et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin. Cancer Res.19, 2381–2392 (2013). CASPubMed Google Scholar
Babina, I. S. & Turner, N. C. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer17, 318–332 (2017). CASPubMed Google Scholar
Javle, M. et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J. Clin. Oncol.36, 276–282 (2017). PubMedPubMed Central Google Scholar
Konecny, G. E. et al. Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study. Lancet Oncol.16, 686–694 (2015). CASPubMed Google Scholar
Jeong Lee, H. et al. Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma. Clin. Mol. Hepatol.21, 60–70 (2015). Google Scholar
Wu, X. et al. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J. Biol. Chem.285, 5165–5170 (2010). CASPubMed Google Scholar
Gao, L. et al. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J. Exp. Clin. Cancer Res.36, 1–10 (2017). Google Scholar
Sawey, E. T. et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell19, 347–358 (2011). CASPubMedPubMed Central Google Scholar
Finn, R. S. et al. Gains in FGF19 are predictive of response to the fibroblast growth factor receptor (FGFR) small molecule tyrosine kinase inhibitor BGJ 398 in vitro [abstract 3858]. Cancer Res.72 (Suppl. 8), 3858 (2012). Google Scholar
Guagnano, V. et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective Pan-FGFR inhibitor. Cancer Discov.2, 1118–1133 (2012). CASPubMed Google Scholar
Hagel, M. et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov.5, 424–437 (2015). CASPubMed Google Scholar
Joshi, J. J. et al. H3B-6527is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res.77, 6999–7013 (2017). CASPubMed Google Scholar
Matter, M. S., Decaens, T., Andersen, J. B. & Thorgeirsson, S. S. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J. Hepatol.60, 855–865 (2014). CASPubMed Google Scholar
Villanueva, A. et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology135, 1972–1983 (2008). CASPubMed Google Scholar
Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol.15, 273–291 (2018). CASPubMed Google Scholar
Lim, H. Y. et al. A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86–9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin. Cancer Res.20, 5976–5985 (2014). CASPubMed Google Scholar
Sia, D. & Llovet, J. M. Liver cancer: Translating ‘–omics’ results into precision medicine for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol.14, 571–572 (2017). PubMed Google Scholar
de Gramont, A. et al. Pragmatic issues in biomarker evaluation for targeted therapies in cancer. Nat. Rev. Clin. Oncol.12, 197–212 (2014). PubMed Google Scholar
Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol.14, 531–548 (2017). CASPubMed Google Scholar
Xu, R. et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat. Mater.16, 1155–1162 (2017). CASPubMed Google Scholar
Mullard, A. Reining in the supersized Phase I cancer trial. Nat. Rev. Drug Discov.15, 371–373 (2016). CASPubMed Google Scholar
Torrecilla, S. et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J. Hepatol.67, 1222–1231 (2017). PubMed Google Scholar
Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. L. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol.13, 143–158 (2016). CASPubMed Google Scholar
Weber, J. S., Yang, J. C., Atkins, M. B. & Disis, M. L. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol.33, 2092–2099 (2015). CASPubMedPubMed Central Google Scholar
Masucci, G. V. et al. Validation of biomarkers to predict response to immunotherapy in cancer: Volume I — pre-analytical and analytical validation. J. Immunother. Cancer4, 1–25 (2016). PubMed Central Google Scholar
Poh, A. First tissue-agnostic drug approval issued. Cancer Discov.7, 656 (2017). Google Scholar
Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med.22, 851–860 (2016). CASPubMedPubMed Central Google Scholar
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature523, 231–235 (2015). CASPubMed Google Scholar