Response to post-axitinib treatment in patients with metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is a biologically heterogeneous disease with distinct genetic and metabolic defects [1]. Over the past decade, recognition that von Hippel-Lindau (VHL) gene mutations cause overexpression of vascular endothelial growth factor (VEGF) and increased tumor angiogenesis has led to development of multiple agents targeting this protein and its receptor.

Currently approved therapies for treatment of patients with mRCC include bevacizumab (plus interferon alfa), a humanized monoclonal antibody that inhibits the VEGF ligand, and the multi-targeted receptor tyrosine kinase inhibitors, sunitinib, sorafenib, pazopanib and axitinib (VEGFr- TKIs) [2‐7]. Each agent has a slightly different affinity for the VEGF and platelet derived growth factor (PDGF) receptors, as well as for other receptor tyrosine kinases [8]. Mammalian target of rapamycin (mTOR) inhibitors, which include everolimus and temsirolimus [9, 10] are also approved for treatment of mRCC, and do not appear to have a direct effect on VEGF or its receptors.

The most recently Food and Drug Administration (FDA) approved agent for mRCC is axitinib, a second-generation, indazole derived molecule that binds selectively to the adenosine triphosphate (ATP)-binding intracellular domain of VEGFR-1, 2, and 3 at sub-nanomolar concentrations. The AXIS trial that led to the approval of axitinib was a phase 3, randomized controlled study comparing two VEGFr TKIs, axitinib and sorafenib, in patients whose disease progressed on initial systemic therapy [7]. Patients in each treatment arm had received first-line treatment with sunitinib (54 %), cytokines (35 %), bevacizumab (8 %), or temsirolimus (3 %). In the overall population, patients treated with axitinib experienced a significantly longer median progression free survival (PFS) than patients treated with sorafenib (6.7 vs. 4.7 months; P < 0.0001). Secondary endpoints included overall response rate (ORR), overall survival (OS), and safety and tolerability. ORR was 19.4 % (95 % Cl 15.4–23.9 %) versus 9.4 % (95 % CI 6.6–12.9 %) for axitinib and sorafenib, respectively. In the sub-group of sunitinib-refractory patients, median PFS was 4.8 months for patients treated with second-line axitinib and 3.4 months for patients treated with second-line sorafenib (P = 0.0107). In the subgroup of cytokine-refractory patients, median PFS was 12.1 months for patients treated with second-line axitinib and 6.5months for patients treated with second-line sorafenib (P < 0.0001) [11]. The longer median PFS values observed in cytokine-refractory patients relative to sunitinib-refractory patients points to partial cross-resistance with sequential VEGF-targeted therapy [11]. This suggests that targeting of the same pathway with sequential VEGFr-TKI therapy may follow a law of diminishing returns due to unknown mechanisms of increasing resistance [12].

Knowing that axitinib is the most biochemically potent of the approved VEGFr inhibitors, and that there is possibility of cross-resistance with sequential VEGF-targeting therapy, the response to therapy after progressing on axitinib is of clinical interest.

A retrospective review of patients from the Cleveland Clinic Taussig Cancer Center (CCF) and MD Anderson Cancer Center (MDACC) was thus undertaken to characterize and evaluate the response to subsequent systemic therapy in patients who had progressed on axitinib.

The standard of care in metastatic RCC is the empiric and sequential use of systemic therapies, most of which target VEGF. Previous retrospective and prospective evidence points to lack of complete cross-resistance to sequential VEGF-targeting therapies [14, 15], although in general the clinical activity decreases with drugs given later in the sequence. The reasons for development of resistance to initial therapy and factors affecting response to subsequent therapy are not well understood at present. The present analysis demonstrates that clinical responses (objective partial responses and stable disease) are possible if VEGF receptor inhibitors are given after axitinib, although in general the activity of subsequent therapy is less than that observed with axitinib.

It has been hypothesized that residual VEGF signaling after VEGF-targeted therapy could account for the activity of VEGF-targeted agents in this setting. Given the increased biochemical potency of axitinib, it was hypothesized that therapy (specifically VEGF-targeted therapy) after axitinib treatment may not result in clinical benefit. Our retrospective data suggests that clinical effect is seen in patients with metastatic RCC who receive systemic therapy after axitinib, not only as second but also as third line. Two thirds of our patients had received systemic therapy prior to axitinib and we still observed objective responses on subsequent therapies, median duration of therapy was over four months and seven patients remained on first subsequent therapy longer than axitinib. This may be explained by the therapeutic effect of different target engagement by the various VEGF multikinase inhibitors [16, 17]. Our study also delineates two populations, one that responds better to axitinib and another to subsequent therapy. This variable response emphasizes possible role of molecular biomarkers in guiding individualized patient management and improving outcomes.

There are limitations to this analysis. This is a retrospective review of a small number of patients at two specialized institutions with inability to overcome selection bias. Individual treating physicians at each institute did the tumor assessment, thus limiting the reliability and consistency of the percent changes in tumor burden and the assessment of objective response.

Further prospective trials are evaluating second-line treatment with approved or investigational agents in patients with mRCC who were refractory to previous treatment with a targeted agent. Other trials are evaluating the optimal sequence of targeted agents in treatment-naive patients with mRCC. Results of these trials may give us some insight into efficacy of sequenced VEGFR – TKIs and cross – resistance in metastatic renal cell carcinoma.

Objective responses and stable disease is observed with post-axitinib targeted therapy, although efficacy is generally less than that seen with axitinib. Prospective studies will help us understand if prior response or resistance to axitinib predicts for clinical benefit to subsequent therapy. Variable patient response to drugs in the same class warrants prospective studies to validate role of predictive biomarkers in guiding individualized therapies and improving outcomes.