Targeting Src Adds No Benefit in VEGF-Resistant Metastatic Renal Cell Carcinoma

Thomas Powles, MD

Adding saracatinib to vascular endothelial growth factor (VEGF)-targeted therapy did not improve response rates or overall survival while adding to toxicity in VEGF-resistant metastatic renal cell carcinoma (mRCC). The findings come from a phase II study presented at ESMO 2014 by Thomas Powles, MBBS, MD, in which saracatinib was added to cediranib to determine if it would improve efficacy.

The study did demonstrate that cediranib appears to have modest activity in VEGF-resistant disease, said Powles, clinical professor of Genitourinary Oncology at Barts Cancer Institute in London, United Kingdom. The progression-free survival (PFS) associated with cediranib alone appears similar to that generated by other VEGF tyrosine kinase inhibitors (TKIs) in VEGF-resistant disease.

Cediranib is a potent oral inhibitor of VEGF tyrosine kinase-1, -2, and -3, and also c-kit and platelet-derived growth factor receptors. Phase II data show that cediranib as monotherapy in mRCC resulted in partial responses or stable disease in most patients, and was well-tolerated.

Patients with mRCC who are resistant to VEGF-targeted therapy have a poor outcome. These patients generally receive further targeted VEGF therapy. A non-receptor tyrosine kinase called Src may play a role in VEGF resistance, according to Powles.

Src has a key role in regulating a variety of cellular signal transduction pathways. It is thought to be critical in cellular regulation, proliferation, differentiation, migration, adhesion, invasion, angiogenesis, and immune function. Src appears especially important in the setting of advanced disease, as greater Src expression is observed with metastases. Targeted inhibition of Src signaling in tumors might therefore represent an effective therapeutic strategy in cancer.

Saracatinib is an orally available potent Src inhibitor that modulates multiple key signaling pathways in cancer. Powles and colleagues studied saracatinib in combination with cediranib in 138 patients with mRCC with a clear cell component who had progression of disease on VEGF-targeted therapy. In the phase II study, patients were randomized in a 1:1 ratio to cediranib and saracatinib or cediranib and placebo. The primary endpoint was progression free survival (PFS) by RECIST v1.1. The study was designed to detect a 50% improvement in PFS by adding saracatinib to cediranib.

Twenty percent of the study group had previously received immune therapy as initial treatment for metastatic disease. The study drug was given as second-line VEGF therapy in 96% and as third-line in 4%. By Memorial Sloan Kettering Cancer Center classification, 15% had good-, 70% had intermediate-, and 15% had poor-risk disease.

The median overall survival for the entire study cohort was 12 months. Median PFS was 3.9 months in the cediranib and saracatinib arm compared with 5.4 months in the cediranib monotherapy arm, for a hazard ratio (HR) of 1.18 with the combination (95% confidence interval [CI]: 0.94 to 1.48). Overall survival was also not significantly different at 10 months in the combination arm versus 14.2 months in the cediranib-alone arm (HR, 1.28; 95% CI: 1.00 to 1.63).

No patient in either group had a complete response. Partial responses occurred in 13% of the cediranib monotherapy arm and in 14% of the combination arm, and 53% and 46%, respectively, had stable disease. Disease progression was observed in 20% of the cediranib alone group versus 29% of the combination group.

In the combination arm, 16% required dose reduction and 20% discontinued treatment due to toxicity, compared with 9% and 13%, respectively, in the cediranib monotherapy arm. There was no significant difference in the frequency of key adverse events.

Although cediranib is a promising agent, “the timing might be wrong” for its inclusion in the treatment regimen for mRCC, said Manuela Schmidinger, MD, who was not involved in the study. Several drugs that target the VEGF axis are already available, and “it’s unlikely that cediranib will have a markedly different activity against mRCC when compared with approved VEGF receptor TKIs,” she said.

“In this context, further development may only be reasonable in combination, if the drug proves suitable for use in combination,” said Schmidinger, program director for Renal Cell Carcinoma at the Medical University of Vienna, Austria. Although Src makes sense as a target in combination with VEGF because several Src-mediated pathways contribute to tumor progression, it so far has yielded disappointing results in several tumor types, she said.