Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations

Abstract

Despite the established efficacy of sorafenib in advanced hepatocellular carcinoma (HCC), a significant number of sorafenib-treated patients experience disease progression. Current guidelines recommend either best supportive care or clinical trial enrollment for this population. As such, there remains an unmet need for tolerable, life-prolonging strategies in the second-line setting. New information regarding the molecular pathogenesis of resistance to antiangiogenic therapy and positive post-progression experience with antiangiogenics in other tumor types has led to trials investigating the effect of continued use of sorafenib, alone or combined with other agents. Trials investigating the effect of switching from sorafenib to alternate antiangiogenic agents, phosphatidylinositol 3 kinase/AKT/mammalian target of rapamycin inhibitors, or cMet inhibitors are also underway. As these data emerge, clinicians may consider a new paradigm for managing advanced HCC. This article briefly reviews the mechanisms of disease resistance to antiangiogenic therapy as a vehicle for discussing clinical strategies to prolong survival in patients with advanced HCC that are currently employed at our institutions or are under investigation. Key ongoing trials investigating the use of molecularly targeted therapies in patients with progressive disease are also highlighted.

Refining Sorafenib Therapy: Lessons from Clinical Practice

“…Should alternative therapies with proven efficacy in the second-line setting not be available, the consensus statement recommends the continuation of sorafenib treatment after disease progression, which may be beneficial in slowing down tumor growth [60][61][62]. Evidence supporting this approach has recently come from a study measuring the size of metastatic lesions in patients with advanced HCC following their first radiologic progression of disease while receiving sorafenib [62].…”

“…Expert opinion thus concludes that sorafenib may be continued after disease progression for patients with stable performance status, although there is currently no clear evidence from large studies supporting the effectiveness of this approach [60,61]. conclusion HCC is extremely heterogeneous in its nature and in most cases develops on a background of liver cirrhosis that has its own natural history.…”

Manipulating Angiogenesis by Targeting Endothelial Metabolism: Hitting the Engine Rather than the Drivers—A New Perspective?

“…However, treatment with agents targeting VEGF signaling often fails to yield sustained responses, because the majority of patients develop resistance (Schneider and Sledge, 2007;Bergers and Hanahan, 2008;Cortes-Funes, 2009;Grothey and Galanis, 2009;Mackey et al, 2012;He and Goldenberg, 2013;Vincent et al, 2015). This, together with the failure of these treatments to extend patients' survival, highlights the need for alternative antiangiogenic therapies based on fundamentally different principles and mechanisms.…”

The c-Met receptor: Implication for targeted therapies in colorectal cancer

“…55,56 Another study revealed that HGF overexpression causes resistance to lenvatinib (a VEGFR inhibitor). This resistance is overcome by golvatinib (a c-Met inhibitor).…”