SEOUL—The last decade has brought a wave of new drugs to treat renal cell carcinoma, including a host of drugs that target the vascular endothelial growth factor (VEGF). This new class of drugs has greatly improved patient outcomes, but roughly 30 percent of patients treated with the drugs, which often have harsh side effects, do not respond. A study published in September suggests it may soon be possible to predict whether these drugs will be effective against a tumor, potentially preventing treatment regimes that are doomed to fail and steering patients to options that are more likely to succeed.
The study published in The Oncologist found that the expression levels of a key protein involved in tumor cell survival could predict how a tumor responds to standard first-line therapies targeting VEGF in patients with metastatic clear cell renal cell carcinoma (mCCRCC). The scientists behind the study say their findings could make it easier to create customized treatment options for individual patients.
The class of drugs that was the focus of the study, called VEGF-tyrosine kinase inhibitors (VEGF-TKIs), are used as first-line therapy for patients with mCCRCC. The most well known of these drugs include sunitinib, sorafenib and pazopanib.
These drugs, when used alone or in combination with immunotherapy, have the potential to improve survival in many patients. For many other patients, however, they are not effective, and there is currently no reliable way to predict whether that is likely to be the outcome. Moreover, some patients who do respond to these treatments develop resistance in the long term.
“The VEGF-TKIs are essential for treating patients with metastatic renal cell carcinoma, but this treatment approach suffers from a lack of predictive markers,” according to Heounjeong Go, a lead author of the study and researcher at the Asan Medical Center in Seoul, Korea.
Go’s team of researchers found that a protein known as the programmed death-1 (PD-1) receptor could offer a solution to the challenge of predicting the success of VEGF-TKIs. The scientists knew that PD-1 and its ligand, PD-L1, are key regulators of tumor growth and progression. They also knew that tumors with high levels of PD-L1 expression tended to be particularly aggressive and especially adept at evading the body’s natural anticancer immune response. What was not clear was whether there was a connection between a tumor’s PD-L1 levels and its response to VEGF-TKIs.
To explore the possible link, Go’s team began by examining PD-L1 levels in 91 mCCRCC patients treated with VEGF-TKI therapy. Tumor samples from each patient were tested for PD-L1 expression by immunohistochemical staining, and tumors that showed moderate or strong staining in at least 5 percent of tumor cells were considered positive for PD-L1 expression.
The results showed a clear connection between levels of PD-LI expression and response to VEGF-TKI therapy. The researchers found that 17.6 percent of the mCCRCC tumor samples tested positive for PD-L1 expression and that PD-L1-positive tumors were more likely than PD-L1-negative tumors to harbor other aggressive features, including higher tumor grade and sarcomatoid features. Only one in eight patients with PD-L1-positive tumors responded to VEGF-TKI therapy, compared with nearly half of patients with PD-L1-negative tumors. Moreover, patients with PD-L1-positive tumors also had worse outcomes than those with PD-L1-negative tumors, including worse overall survival and worse progression-free survival.
Go expects future research that builds on her study to 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.
“The increasing number of therapeutic agents for the treatment of mCCRCC presents an ever-increasing challenge in selecting treatment for individual patients,” said M. Dror Michaelson, editor of The Oncologist and clinical director of the Genitourinary Cancer Center at Massachusetts General Hospital in Boston, in a statement announcing publication of the study. “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.”