(UroToday.com) In the fourteenth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on treatment approaches for patients with non-clear cell renal cell carcinoma (nccRCC), Dr. Guillermo de Velasco presented on treatment approaches for patients with papillary renal cell carcinoma (RCC).
Based on data from The Cancer Genome Atlas, he emphasized that one of the most important things we know about papillary RCC is that it’s a very heterogenous disease. While there are lots of genetic differences between these tumors, clinically we treat patients similarly.
Taking a historical step backwards, Dr. de Velasco emphasized that the original treatment paradigms for papillary RCC were based on an extrapolation of data from the clear cell RCC literature. Based on those data, sunitinib was one of the first treatment approaches employed. It was compared, in two randomized controlled trials (ASPEN and ESPN), to everolimus in patients with non-clear cell renal cell carcinoma, demonstrating benefit in the papillary subset.
In keeping with trends seen in clear cell disease, combination therapy has therefore been explored. While relying on relatively old agents, only recently has there been published data on the combination of everolimus and bevacizumab. Perhaps more interesting is the recent data examining the combination of Lenvatinib and everolimus. However, these data are limited by small sample sizes (n=23), of which only a subset have papillary disease. Further, there is no evidence that an upfront combination approach is superior to a sequenced approach.
Dr. de Velasco then moved to what he described as “one of the most exciting areas in papillary disease” – an understanding of the importance of MET in papillary RCC oncogenesis. MET mutations are found in 13 to 15% of these tumors, most commonly with chromosomal gain of chromosomes 7 or 17. Overall, MET mutations or overexpression are identified in more than 80% of patients with papillary RCC, suggesting that this pathway may be a treatment target. One of the first trials to do this was a phase II study of foretinib in papillary RCC published in 2013. Among 74 included patients, the median progression-free survival was 9 months. Interestingly, responses were not specific to patients who had MET alterations, perhaps due to co-targeting of the VEGF pathway with this agent. In 2017, two other relevant paper were published: a phase II trial of savolitinib and a phase I/II trial of crizotinib. SAVIOR, the phase II trial of savolitinib closed early due to accrual failure, highlighting the importance of collaborative efforts to identify and accrue patients with these less common histologies. Interestingly, while underpowered as a result of this failure to accrue, subsequent publications of the SAVOIR trial in 2020 suggested benefit. In the mean time, Dr. Pal had designed and accrued the SWOG 1500 PAPMET trial which showed a progression-free survival, but not overall survival, benefit to cabozantinib compared to sunitinib in patients with papillary disease. While initially included savolitinib was dropped from this trial on early futility analysis.
However, the SAMETA trial is seeking to assess the role of savolitinib compared with durvalumab, compared to durvalumab alone or sunitinib, in patients with advanced papillary RCC.
In clear cell RCC, immunotherapy has formed the new standard of care. This treatment paradigm has also been assessed in non clear cell histology, of which the majority of the cohort has papillary disease. In this space, pembrolizumab monotherapy has shown promising efficacy and, based on data examining the combination of ipilimumab with nivolumab (which demonstrated similar progression-free survival), Dr. de Velasco suggested that the addition of ipilimumab didn’t appear to have significant benefit. In addition to combination dual immunotherapy based regimes, the combination of immunotherapy with tyrosine kinase inhibitors has also been assessed in advanced non clear cell RCC, including recent data from Dr. Chung-Han Lee assessing cabozantinib and nivolumab. Additionally, recent work examining the combination of erlotinib and bevacizumab suggested a particularly large benefit to this approach in patients with HLRCC, a finding which requires further work to understand.
As he closed, Dr. de Velasco emphasized that guidelines are changing for patients with papillary RCC and there are new treatment approaches currently being tested which will continue to change the treatment paradigm.
Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 International Kidney Cancer Symposium (IKCS) Europe Annual Hybrid Meeting, Antwerp, Belgium, Fri, Apr 22 – Sun, Apr 24, 2022.