Revisiting Antiangiogenic Multikinase Inhibitors in the Era of Immune Checkpoint Blockade: The Case of Sorafenib

Abstract

The successful development of multikinase inhibitors over the last two decades has revolutionized the management of many malignant cancers. Agents such as the antiangiogenic kinase inhibitor sorafenib have certain advantages such as a broad spectrum of activity against cancer cells, vascular endothelial cells, and pericytes, and are the mainstay of treatment in diseases such as advanced renal or liver cancer. The more recent emergence of immunotherapy—using immune checkpoint blockade—in some of the same diseases has raised important questions about the treatment interaction with antiangiogenic drugs, seven such combinations have been approved for lung, liver, kidney, and endometrial cancers, and multiple combination therapies are being aggressively pursued in the clinic. Thus, revealing mechanisms of action of antiangiogenic kinase inhibitors in combination with immune checkpoint blockade is critical to improving the treatment outcome further. This Landmark commentary on sorafenib in cancer therapy highlights these important questions.

Molecularly targeted therapies have revolutionized cancer therapy over the last two and a half decades. One by one, cancer cell–targeted drugs, antiangiogenic drugs, and immune checkpoint blockers have shown efficacy and prolonged the life of millions of patients with cancer. However, their development has not always been straightforward. The mechanisms of action of these molecularly targeted drugs have proven quite complex. A better understanding of how these drugs benefit patients may help address the critical challenges related to patient selection for therapy and treatment resistance. The case of the oncology blockbuster drug sorafenib (Nexavar) is a telling one.

Sorafenib was one of the first molecularly targeted drugs and the first anti-VEGFR tyrosine kinase inhibitor approved by the FDA. Interestingly, sorafenib (the biaryl urea compound BAY 43–9006) was discovered and initially developed as an inhibitor of the RAF kinases (including wild-type and V599E mutant BRAF) in a study by Wilhelm and colleagues (1). RAS/RAF kinases are upstream of the MAPK pathway, which is activated in many cancer types and mediates cancer cell proliferation and tumor angiogenesis. Additional characterization showed that sorafenib has inhibitory activity against several receptor tyrosine kinases involved in tumor angiogenesis and progression, including VEGFR2, VEGFR3, PDGFRβ, Flt3, and c-KIT. In subcutaneous xenograft models, once daily oral dosing of sorafenib demonstrated broad spectrum antitumor activity against colon, breast, and non–small cell lung cancers. This effect was associated with inhibition of the ERK1/2 and decreased micro-vessel density in the tumors. These data showed the potential of sorafenib as a novel dual targeted agent against cancer cell proliferation and tumor angiogenesis (1).

However, whether MAPK pathway inhibition mediates the benefits of sorafenib in patients remains unclear to this day (2). For example, sorafenib has not shown efficacy in melanoma, a disease often driven by RAF mutations and in which selective RAF and MEK inhibitors are standard of care. To date, the role of inhibiting other kinases such as RET, PDGFR, KIT, and FLT3 also remains unclear, although the latter two might be relevant for sorafenib’s efficacy in acute myeloid leukemia.

On the basis of existing evidence and clinical experience, VEGFR inhibition is widely considered the critical mechanism of benefit of sorafenib in several cancer types known to respond to VEGF inhibitors, such as advanced renal cancer, hepatocellular carcinoma, and thyroid cancer. Interestingly, sorafenib has not shown efficacy in other cancers that respond to other VEGF inhibitors, such as advanced lung or gastric cancers. In addition, while sorafenib did not show benefits in metastatic colorectal cancer, its derivative regorafenib has demonstrated efficacy and is a standard-of-care treatment after failure of several lines of chemotherapy in this disease. Compared with sorafenib, regorafenib has a fluorine atom in the central phenyl ring. This modification results in a slightly different biochemical profile when compared with sorafenib, such as a more potent inhibition of the endothelial angiopoietin receptor TIE2. Thus, a better understanding of the role of different receptor kinase targets in targeting tumor vessels remains warranted.

Given the promiscuous target activity of sorafenib and cancer heterogeneity, pinning down a mechanism of treatment resistance that operates broadly across cancer types and tumor stages has also been difficult. Indeed, dozens of such mechanisms have been reported, including, among others, changes in oncogenic and metabolic pathways, epigenetic regulation, drug delivery, pharmacokinetics and pharmacodynamics, regulated cell death, tumor fibrosis and inflammation, and epithelial-to-mesenchymal transition and stem-like phenotypes (3).

In this Landmark commentary, we will focus on the lessons from studies of sorafenib or other multikinase inhibitors with anti-VEGFR activity, the roles of treatment-induced vascular normalization versus rarefaction, and the modulation of the immune microenvironment. We will also briefly discuss potential strategies to leverage these mechanisms for improving therapy.

Initially postulated in 2001 (4), the crucial role of vascular normalization in response to antiangiogenic therapy is widely recognized today. The emergence of immune checkpoint blockade as a pillar of cancer therapy also revealed the importance of vascular normalization in reprogramming the immune microenvironment of cancer (5). Vascular normalization induced by anti-angiogenic therapy may be critical in achieving a response to concurrent immunotherapy. Indeed, seven combinations of anti-VEGF/VEGFR drugs (including five with antiangiogenic multikinase inhibitors) and anti-PD1/PD-L1 antibodies are already standard of care in renal cancer, hepatocellular carcinoma (HCC), lung cancer, and endometrial cancer (6). It is important to note that other studies have not shown a benefit, for example, cabozantinib with the anti-PD-L1 antibody atezolizumab or lenvatinib with the anti-PD-1 antibody pembrolizumab in HCC. The spectrum of activity of sorafenib is substantially different compared to cabozantinib and lenvatinib, which might be more potent antivascular drugs. A randomized phase III trial—currently being conducted in China—will reveal the efficacy of combined sorafenib/anti-PD-1 therapy in HCC (NCT04163237). In addition, more than a dozen phase II studies are testing the combination of regorafenib with anti-PD-1/PD-L1 therapy in gatsrointestinal cancers. We anticipate that drug and dose selection will be critical to achieving vascular normalization versus vessel pruning, and feasibility and synergy with immune checkpoint blockade.

Our prior work demonstrated the impact of antiangiogenic therapy dosing on vascular normalization versus vessel pruning and the impact on concurrent immunotherapy (Fig. 1; ref. 7). In terms of sorafenib, we previously demonstrated the negative impact of hypoxia in mediating treatment resistance to sorafenib alone (8) or when combined with anti-PD-1 therapy in HCC models (9). In contrast, judicious dosing of regorafenib normalized the vasculature of HCC and enhanced anti-PD-1 therapy response (10). Intriguingly, these studies also indicated a direct role of anti-PD-1 therapy in normalizing the vessels in HCC models. Anti-PD-1 therapy showed angioprotective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence—in a CD8⁺ T-cell–dependent manner—while reducing drug exposure (11). Thus, sorafenib treatment dosing and scheduling may significantly impact vascular normalization, and the feasibility and efficacy of combinations with immune checkpoint blockers.

Figure 1.

Anti-VEGFR treatment-induced vascular normalization can reprogram the immunosuppressive tumor microenvironment into an immunosupportive one. Tumors develop an abnormal tumor vasculature, which leads to tissue hypoxia and acidosis. These microenvironmental characteristics impede T effector cell infiltration into the tumor via multiple mechanisms, including PD-L1 upregulation on myeloid-derived suppressor cells (MDSC), dendritic cells, and cancer cells; increased regulatory T cells (Treg) and M2-like macrophage infiltration; production of immunosuppressive factors (e.g., VEGF and TGFβ); and impaired effector T-cell function. When delivered at an appropriate dose/schedule, antiangiogenic treatment using anti-VEGFR drugs such as sorafenib can promote vascular normalization by reprogramming the microenvironment and alleviating immunosuppression. Conversely, excessive dosing or duration of anti-VEGFR therapy could aggravate immunosuppression by reducing perfusion and further increasing hypoxia. Adapted and updated from ref. 7. Reprinted from Cancer Cell, Volume 26, Issue 5, Jain RK, Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia, Pages 605–622, Copyright 2014, with permission from Elsevier.

Owing to the clinically validated impact of anti-VEGFR therapy on tumor responses to immune checkpoint blockade, the role of these drugs has substantially changed in recent years. We posit that further understanding of optimal combinations of sorafenib (and anti-VEGF/R agents) with immunotherapy will be critical for optimal integration and feasibility of these combinations safely and effectively. This understanding will require continued efforts in innovative clinical trials and comprehensive clinical correlative studies. They will also require use of orthotopic models for each cancer type, to reproduce the features of the local immune microenvironment more faithfully, and thus increase the relevance of the preclinical studies (12).

The discovery and successful development of sorafenib have opened new avenues for clinical and basic research, which led to unexpected and exciting new directions. Learning the lessons from these unexpected treatment interactions may hold the key to more effective and safer treatments.