An Evolving Role for AXL in Metastatic Renal Cell Carcinoma

In this issue of Clinical Cancer Research, Terry and colleagues explore the role that tumoral expression of AXL plays in resistance to anti-PD-1 therapy after progression on angiogenesis targeted therapy (1). Over the past five years, immune checkpoint inhibitors (ICI) became a cornerstone of treatment for metastatic renal cell carcinoma (mRCC), either alone or in combination with angiogenesis targeted therapies. Despite meaningfully improving survival, the majority of patients with mRCC develop resistance to anti–PD-1 therapy with few biomarkers that predict a poor outcome on treatment. Terry and colleagues found that high tumoral AXL expression was associated with inferior response to anti–PD-1 therapy and increased programmed death ligand 1 (PD-L1) expression, but not associated with changes in the immune cell populations of the tumor microenvironment (TME). Increased PD-L1 expression has been associated with a poor prognosis in mRCC, but has not been consistently predictive of response to anti–PD-1 therapy. In this study, the addition of high tumoral AXL expression to high PD-L1 expression identified patients with a particularly poor prognosis. Given the role VHL loss plays in clear cell RCC tumorigenesis, the authors assessed whether the impact of AXL expression differed by VHL status. They discovered that the influence of AXL on clinical outcomes and PD-L1 expression was primarily observed in tumors with VHL loss. In sum, this article suggests that high AXL expression adversely impacts clinical outcomes with anti–PD-1 therapy, and of equal importance, it shows that preexisting biomarkers in mRCC may be improved by accounting for molecular covariates.

AXL is a member of the TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) family that are universally expressed on professional phagocytes in tissue, that is, dendritic cells and macrophages, select immune cell populations in the blood, and nonimmune cells, such as endothelial cells, neurons, or oligodendrocytes (Fig. 1; ref. 2). In normal tissue, AXL and the other TAM receptors function in efferocytosis, the clearance of dead cells, to remove antigens and prevent autoimmune disease. The results presented by Terry and colleagues suggest that AXL expression is associated with resistance to ICI, and there is growing evidence that TAM receptors contribute to resistance to ICI through multiple mechanisms including: decreased tumor antigen presentation, suppression of proinflammatory cytokines, alterations to the immune cell landscape of TME, epithelial-mesenchymal transition, and upregulation of PD-L1 (2). Preclinical data support the clinical observation by Terry and colleagues that PD-L1 expression is associated with AXL expression. Efferocytosis mediated by TAM receptors induces PD-L1 expression through Akt and PI3K pathway signaling (3). In the context of cancer, AXL and TAM receptor activation increases the clearance of tumor antigens via efferocytosis and decreases the activity of CD8⁺ T cells by upregulating PD-L1, which facilitates immune evasion (Fig. 1).

AXL is a promising biomarker to inform treatment selection and a therapeutic target for patients with mRCC. Previous preclinical and clinical studies have shown that AXL expression is associated with resistance to sunitinib (4, 5). The data presented by Terry and colleagues are preliminary on whether AXL is associated with response to anti–PD-1 therapy, with overall prognosis, or both. In the Nivoren cohort, low AXL was associated with improved response, while in the Braun cohort, low AXL was more strongly associated with improved overall survival (OS). Interestingly, when combined with PD-L1 status, AXL expression was more convincingly associated with OS. Given how TAM receptors influence PD-L1 and the TME, it would be interesting to evaluate whether Tyro3 and MerTK expression affects the associations between AXL, PD-L1, and outcomes with anti–PD-1 therapy.

Clinically, TAM receptor inhibition, including AXL, has improved survival for patients with mRCC alone and in combination with ICI. Cabozantinib inhibits multiple RTKs, including AXL and the TAM family, MET, VEGFR-1–3, RET, and FLT3, and prolongs progression-free survival verse sunitinib (6). More recently, the combination of cabozantinib and nivolumab improved OS when compared with sunitinib (7). Sitravatinib is another inhibitor of the TAM family and other RTKs, including MET, VEGFR, RET, and FLT3, that is being studied in combination with ICI for patients with mRCC (NCT04518046). Now, we should test whether AXL plus PD-L1 status can identify patients who will derive maximal benefit from cabozantinib or sitravatinib plus nivolumab, such as those with high AXL and PD-L1 status. Furthermore, ongoing clinical trials are testing selective inhibitors of AXL in patients with mRCC (AVB-S6–500 + cabozantinib, NCT04300140) and in patients with solid tumors (bemcentinib, glesatinib).

Looking forward, the data presented by Terry and colleagues generates novel clinical and preclinical hypotheses that warrant further investigation. In the Terry and colleagues study, AXL expression was measured in tissue obtained prior to progression on angiogenesis-targeted therapy, and it is unknown how AXL and PD-L1 status at the time of ICI initiation affects the association with clinical outcomes. This study reiterates the importance of simultaneously evaluating multiple biomarkers using biologic rationale, and it is critical that we continue to incorporate other biomarkers that influence the TME and alternative resistance pathways. In this context, there may be a growing role for machine-assisted analytic approaches as biomarkers from different “omic” platforms are incorporated. Finally, there is growing recognition of the interaction between RTKs, such as the TAM family, and the TME, so further mechanistic studies are warranted using patient-derived tumor tissue from clinical trials.

D.J. George reports non-financial support from Bayer; grants and personal fees from Astellas, AstraZeneca, Janssen Pharmaceuticals, BMS, and Pfizer; grants from Calithera and Novartis; grants, personal fees, and non-financial support from Exelixis and Sanofi; personal fees from AACR, Axess Oncology, Capio Biosciences, Constellation Pharma, EMD Serono, Flatiron, IdeoOncology, Ipsen, Merck Sharp & Dohme, Michael J Hennessey Assoc, Millennium Med Publishing, Modra Pharmaceuticals, Myovant Sciences, NCI GU, Nektar Therapeutics, Physician Education Resource, Propella Therapeutics, RevHealth LLC, and UroGPO; personal fees and non-financial support from UroToday; and personal fees from Xcures outside the submitted work. N. Agarwal reports consultancy to Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to N. Agarwal's institution was provided by AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. No disclosures were reported by the other author.