Dr. Campbell began by exploring the historical and present use of high dose Interleukin-2 (IL-2), as the initial form of immunotherapy used for renal cell carcinoma. The use of this drug helped to elucidate the fact that there are immune system factors that can be harnessed in a percentage of patients to treat their malignancy. More recently, with the discovery of immune checkpoint targetable ligands and receptors, such as PD-1/PD-L1 and CTLA4, it became increasingly clear that by blocking certain immune cell/tumor interactions, the immune system could be used to help destroy malignant cells.
The immune checkpoint inhibitors were found to have substantial activity in a wide range of solid tumors, including melanoma, lung cancer, and multiple urologic malignancies. Furthermore, these drugs were felt to be well tolerated, with an acceptable toxicity profile.
He then discussed the challenges in determining if there are biomarkers that can help predict a patient’s response to the immune checkpoint inhibitors. It was initially felt that expression of PD-L1 in tumor cells would be a positive prognosticator about response to PD-1/PD-L1 receptor antagonists, however this turned out to be more complicated than initially thought, and PD-L1 expression does not directly correlate with treatment response.
There are immunotherapy agents now approved for treatment of metastatic renal cell carcinoma, and there are multiple others that are being studied. Nivolumab was the first drug to be FDA approved based on the CheckMate 025 study which compared Everolimus to Nivolumab and showed a better objective response rate in the patients on Nivolumab (HR 5.98, p < 0.0001) with an ongoing response in 44% of initial responders.
One of the current and future pathway of study for immunotherapy agents is combination therapy. The CheckMate 214 study which compared combination immunotherapy with nivolumab plus ipilimumab versus sunitinib in patients with metastatic renal cell carcinoma. Patients with intermediate or poor risk disease based on International Metastatic Renal Cell Carcinoma Database (IMDC) criteria showed that combination therapy showed a significant improvement in objective response rate, but did not show an improvement in progression free survival. In the favorable risk group, Sunitinib was superior to combination Nivolumab plus Ipilimumab.
Dr. Campbell then discussed the study design of the upcoming phase 1b JAVELIN Renal 100 trial which compares Avelumab plus Axitinib as first line treatment in advance clear cell renal cell carcinoma. Additionally there are several trials upcoming that combine Pembrolizumab with other drugs, including Axitinib, Epacadostat, and Lenvatinib.
He acknowledges that while we have learned so much about the role the immune system plans in cancer surveillance and treatment, we have uncovered many more questions that remain to be answered. Dr. Campbell believes the next several years will be an exciting time in the treatment of metastatic renal cell carcinoma as we understand more about the underlying biology and hopefully use this knowledge to improve survival in our patients.
Presented By: Matthew T. Campbell, MD
Written by: Brian Kadow, MD. Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia PA at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA