Recent first-line trials, such as ASPEN, ESPN, and RECORD-3 have demonstrated only modest activity of VEGFR TKI and mTOR inhibition in non-clear cell RCC. ASPEN and ESPN trials demonstrate a slight advantage in favor of sunitinib over everolimus, and therefore sunitinib represents the standard of care for first-line treatment for non-clear cell advanced RCC. Previous studies have demonstrated non-clear cell RCCs to be less responsive to immunotherapy than clear cell RCC. Additionally, a 2014 study demonstrated that non-clear cell RCCs have significant variability in their expression of PD-L1. Previous retrospective studies of checkpoint inhibitors in non-clear cell RCC have demonstrated some anti-tumoral activity.
Reviewing KEYNOTE-427, Dr. Rose concluded that this was the first prospective data of immune checkpoint inhibition in non-clear cell RCCs. This study has documented oncologic activity for pembrolizumab in non-clear cell RCCs with a durable response, although response rates are inferior to clear cell cohorts. Future randomized trials are needed as mono- or dual-therapy pembrolizumab is worthy of future investigation.
Targeted therapy with immune checkpoint inhibition may be synergistic. An ideal agent would have document activity against non-clear cell RCCs, non-overlapping toxicity, and biologic rationale for synergy/immunomodulation. MET is a membrane-bound tyrosine kinase; activation of which induces cell proliferation and survival via complex intracellular signaling cascades. However, high MET protein levels by tumor staining may not correlate with response.
In CALPYSO, savolitinib and duravalumab demonstrated activity against non-clear cell RCC with acceptable toxicity. However, the study did not reach the pre-specified endpoint for further study in combination. It is unclear this combination is better than sequential treatment given no signal of synergy and additive toxicity. Dr. Rose stated that trials of a biomarker selected non-clear cell RCC are challenging to accrue, but necessary with coordinated efforts. Currently, PAPMET, a 4 arm trial is ongoing, evaluating sunitinib, cabozantinib, crizotinib, and savotinib for treatment naïve metastatic papillary RCC. We actively await the results of trials like these to help elucidate the challenging treatment of advanced or metastatic non-clear cell RCCs.
Presented by: Tracy L. Rose, MD, MPH, Department of Medical Oncology, University of North Carolina, Chapel Hill, North Carolina