Dr. Robert J. Motzer to Discuss Development of TKIs in mRCC

Dr. Robert J. Motzer to Discuss Development of TKIs in mRCC

Dr. Robert J. Motzer
Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology of Memorial Sloan Kettering Cancer Center (MSKCC), will discuss the development and approval of tyrosine-kinase inhibitors (TKIs) for renal cell carcinoma (RCC) during his keynote lecture on February 10, touching on pivotal trials and controversies. He will also note key studies and predict how these drugs will be used in the future.

Dr. Motzer is well-known for his pioneering research on TKIs, a class of drugs that transformed the treatment of metastatic RCC (mRCC) by improving patient response rates and progression-free survival (PFS) rates. The average survival rate has improved from less than a year before 2005 to 3 years currently.1

Early in his career at MSKCC, Dr. Motzer was instrumental in creating a risk system for prognosticating and counseling patients with mRCC. The MSKCC/Motzer risk score has since been incorporated into clinical trial methodology for the study of TKIs.

Paradigm Shift in Treatment

Dr. Motzer was the principal or senior principal investigator on pivotal clinical trials that led to the U.S. Food and Drug Administration (FDA) approval of seven drugs, including four VEGF/VEGFR TKIs: sunitinib,2 axitinib,3 lenvatinib (combined with everolimus),4 and cabozantinib.5 He also led trials on two mTOR inhibitors, everolimus and temsirolimus, and the checkpoint inhibitor nivolumab.

The FDA approved sunitinib as a first-line treatment for mRCC in 2006.2 “The paradigm shifted when our phase III trial showed that sunitinib was more effective than interferon alpha and improved the prognosis for patients with advanced RCC,” Dr. Motzer said. “The results also spurred more interest in conducting research on anti-VEGF therapy for this disease.”

One area of research was whether other TKIs had less toxicity and side effects than sunitinib. Dr. Motzer led the large COMPARZ phase III trial comparing sunitinib to pazopanib. Although the two drugs had similar efficacy, pazopanib had a better safety profile and health-related quality of life for patients.1 “However, more work needs to be done to develop even better safety profiles for TKIs including recognizing and managing toxicity,” Dr. Motzer said.

Researchers also began looking at second-line treatments for patients who didn’t respond well to sunitinib or pazopanib. Dr. Motzer was the senior principal investigator of the AXIS phase III trial comparing axitinib, a newer anti-VEGF drug, to sorafenib, a standard second-line treatment since 2005.6 The study showed that axitinib extended PFS, and as a result, the drug was approved by the FDA as a second-line treatment.3,7

Dr. Motzer and other investigators also looked at drugs that targeted the MET pathway, which can inhibit resistance to antiangiogenic therapy. Cabozantinib, a TKI that targets VEGF and MET, was approved by the FDA as another second-line treatment in 2016.5

Combination Therapy

“A limitation of these classes of drugs is that complete remission is rare, and patients eventually build up resistance,” Dr. Motzer said.

He described two therapeutic approaches that can delay resistance. The first is to combine different classes of drugs. Dr. Motzer recently led a randomized three-arm trial comparing everolimus, lenvatinib, and lenvatinib plus everolimus in patients with mRCC. The median PFS rate for lenvatinib plus everolimus was double the median PFS rate for lenvatinib and more than double the median PFS rate for everolimus.8 The results led the FDA to approve the drug combination in 2016 after one antiangiogenic treatment has failed.4

A second promising approach is combining anti-VEGF therapy, such as axitinib, with immune checkpoint inhibitors, such as avelumab or pembrolizumab. “These anti-VEGF/checkpoint inhibitor combinations are likely to change first-line treatment of advanced RCC,” Dr. Motzer said.

Choosing the right combination of first- and second-line treatments, however, is influenced by the comorbidities and precondition of the patient, he said. “A major challenge and focus of current research is to identify tumor-specific biomarkers to predict a specific response to a specific agent. I hope that in the next few years, we have developed biomarkers to guide therapy for individualized treatment.”  

–Christine Lehmann