Opinion: Clinically meaningful synergy through combined inhibition of VEGF and PD1/PD-L1

The advent of immune checkpoint blockade has revolutionized the understanding of tumor biology and cancer medicine. Still, existing approved immune checkpoint inhibitors, albeit rightfully honored with a Nobel Prize, are regarded as “low hanging fruits” heralding an even brighter future for cancer immunotherapy. An ever-increasing number of signal seeking and confirmatory immunotherapy combination trials are recruiting patients around the globe with the prospect of harnessing ever-increasing benefits. This article describes the emerging pre-clinical and clinical evidence of synergistic immune modulation through combined inhibition of VEGF and Anti-PD1/PD-L1. It is not a comprehensive review, but rather the personal opinion of the author.

CHRISTIAN KERSTEN Overlege, PhD

Onkolog og koordinator Utprøvingsenheten ved onkologisk avdeling, Akershus Universitetssykehus

Seniorforsker Sørlandet Sykehus The vascular endothelial growth factor (VEGF) receptor and their ligands have been widely recognized as having central roles in physiological and pathological angiogenesis. VEGF inhibitors which have been in clinical use for well over a decade, were developed to revert the ‘angiogenic switch’ which leads to the pathological blood supply in tumors.

PRE-CLINICAL More recently, the immune modulating role of VEGF has gained widespread attention. In this regard, immune-evasion pathways, including overexpression of VEGF, have been linked to the development and progression of cancer. AntiVEGF therapies have in turn been shown to reduce VEGF-mediated immunosuppression within tumors and their microenvironment.1-3 Furthermore, anti-VEGF therapies may also enhance anti–programmed death (PD)-1 and anti–PD-ligand 1 (PD-L1) efficacy by reversing VEGFmediated immunosuppression and promoting T-cell infiltration in tumors, see figure 1.4,5

In the following, drugs targeting PD1 or PD-L1 are collectively referred to as checkpoint inhibitor therapy (CIT).

CLINICAL These intriguing pre-clinical findings have recently been supported through clinical trials combining anti-VEGF and CIT in multiple tumor types.

RENAL CELL CARCINOMA Not surprisingly, renal cell carcinoma, a highly VEGF-dependent cancer, has lead the way to clinical evidence of synergy by combining anti-VEGF and

Figure 1. Synergistic immune modulation through combined inhibition of VEGF and Anti-PD1/PD-L1 Modified from Roche and used with permission.

CIT. Different combinations of antiVEGF target (axitinib, cabozanitib) and CIT (nivolumab, pembrolizumab, avelumab) have been compared to anti-VEGF monotherapy with sunitinib in first line metastatic renal cell carcinoma .6-8

Notwithstanding the challenges of comparing cross-study results and responses in different prognostic subgroups, the picture is clear: combination therapies lead to clinically meaningful increases in overall survival (OS) with hazard ratios (HR) in the range of 0.53 – 0.60.7,9 The author is unaware of different responses depending on metastatic site, such as the liver. MUCOSAL MELANOMA Mucosal melanoma is a rare subgroup of melanoma, comprising 1-2% of melanomas in Caucasians. The fraction in the Asians is in the range of 20-25%. This melanoma subtype exhibits more aggressive growth, a lower tumor mutational burden, poorer response (close to none) to CIT, and poorer OS. Findings from a recent phase Ib trial combining axitinib (an anti-VEGF) and toripalimab (a CIT) in 29 Asian patients with mucosal melanoma were therefore promising.10 A response rate of 49%, a median PFS of 7.5 months and an immature mOS because of ongoing responses in 11/14 patients is unprecedented for patients with this tumor entity. HEPATOCELLULAR CARCINOMA AND NONSMALL CELL LUNG CANCER Clinical data indicating a synergistic role of combined anti-VEGF and CIT have been particularly pronounced in hepatocellular carcinoma (HCC)11 and liver metastases from non-small cell lung cancer (NSCLC).12 Neither the VEGF-inhibitor bevacizumab13 nor CIT with atezolizumab 14,15 alone have increased OS in advanced HCC, but the combination of CIT with atezolizumab and bevacizumab have (HR 0.58).11 In NSCLC, an OS gain due to the addition of atezolizumab to bevacizumab (HR 0.76), was particularly pronounced in patients with liver-metastases (HR 0.52).12

LIVER These clinical findings are intriguing since the liver is a frontline immune organ with the important task of detecting pathogens entering the body via the gut.16 Maintaining the fine balance between immunity and tolerance is therefore essential to liver function, but disturbed by primary or secondary malignancies. This disturbed balance often leads to excessive detrimental tumorpromoting inflammation and simultaneous immune suppression, which may partly explain the lack of effectiveness of CIT alone. Inhibition of VEGF may therefore be the necessary mechanism to skew the immune balance to favor a type I helper T lymphocyte response that can be released by CIT.

CONCLUSION There exists compelling evidence of clinically meaningful synergy by combining anti-VEGF and CIT in several tumors. Responses in the liver are particularly intriguing and deserve attention in dedicated studies or subgroup analyses.

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