Expression levels of a key protein involved in tumor cell survival appear to predict response to standard first-line therapy in patients with metastatic clear cell renal cell carcinoma (mCCRCC), according to a new study published in The Oncologist. These findings suggest an opportunity to tailor the selection of treatment for patients with mCCRCC.

Vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs), including sunitinib, sorafenib and pazopanib, are currently recommended as first-line therapy for patients with mCCRCC. When used alone or in combination with immunotherapy, the VEGF-TKIs can improve survival in many patients with mCCRCC. However, up to 30% of patients do not respond to treatment with VEGF-TKIs, and still others will develop resistance to these drugs over time. At present, there are no tools for identifying which patients will derive a benefit from VEGF-TKIs, and which patients may show a better response to other treatment options.

"The VEGF-TKIs are essential for treating patients with metastatic renal cell carcinoma, but this treatment approach suffers from a lack of predictive markers," said Heounjeong Go, MD, PhD, of University of Ulsan College of Medicine, Asan Medical Center, in Seoul, Korea.

The programmed death-1 (PD-1) receptor and its ligand, PD-L1, are key regulators of tumor growth and progression. Tumors with high levels of PD-L1 expression are especially adept at evading the body's natural anticancer immune response, making these tumor types particularly aggressive.

In the current study, Dr. Go and her research team examined the association between tumor PD-L1 levels and treatment outcomes in 91 patients with mCCRCC treated with VEGF-TKI therapy. Tumor samples from each patient were tested for PD-L1 expression by immunohistochemical staining. Tumors with moderate or strong staining in at least 5% of tumor cells were considered positive for PD-L1 expression.

In total, 17.6% of the mCCRCC tumor samples tested positive for PD-L1 expression. The PD-L1-positive tumors were more likely than PD-L1-negative tumors to harbor other aggressive features, including higher tumor grade (P = 0.031) and sarcomatoid features (P = 0.014).

The analysis showed that PD-L1 positivity significantly predicted worse treatment response. Only 1 in 8 patients (12.5%) with PD-L1-positive tumors responded to VEGF-TKI therapy, compared with nearly half of patients (46.7%) with PD-L1-negative tumors (P=0.012).

Patients with PD-L1-positive tumors also had worse outcomes than those with PD-L1-negative tumors, including worse overall survival (P=0.038) and worse progression-free survival (P=0.013).

"As a predictor of treatment response and overall prognosis, PD-L1 expression may be helpful for determining the value of VEGF-TKI therapy in patients with mCCRCC," Dr. Go said. Future research may focus on the role of alternate therapies, including agents targeting the PD-1 pathway, in patients with mCCRCC who are less likely to respond to VEGF-TKIs.

M. Dror Michaelson, MD, Clinical Director of the Genitourinary Cancer Center at Massachusetts General Hospital in Boston and an Editor of The Oncologist, commented, "The increasing number of therapeutic agents for the treatment of mCCRCC presents an ever-increasing challenge in selecting treatment for individual patients. With the exciting emergence of checkpoint inhibitors and other immuno-oncology strategies, ongoing research must focus on identification of predictive factors of response to different classes of agents. The study by Dr. Go et al. suggests that prospective clinical trials should analyze and hopefully validate PD-L1 expression as an important biomarker of response."