RCC: Multiple pathways provide therapeutic targets

The current state of targeted therapy and personalized medicine in renal cell carcinoma (RCC) is largely limited to the settings in which drugs were approved (first vs. later line) and the side effect profile of therapeutic agents matched with patient comorbidities, according to a presentation at the Society of Urologic Oncology annual meeting in San Antonio by Toni K. Choueiri, MD.

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“Folks have worked for the past 15 to 20 years on biomarkers [to predict response to therapies] in metastatic RCC, spanning cytokines (IL2, INF), VEGF-targeted agents, mTOR inhibitors, and PD-1 inhibitors,” explained Dr. Choueiri, of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston.

“Still, nothing is part of an algorithm that is clinically valid for patient care.”

In his presentation, “Targeted therapies and personalized medicine in kidney cancer,” Dr. Choueiri summarized many of the findings from The Cancer Genome Atlas analysis in clear cell RCC that extend beyond the importance of the VHL mutation (Nature 2013; 499:43-9). Specifically, several genes involved in chromatin regulation (eg, PRBM1, BAP1, SETD2) are frequently mutated, and some, including BAP1, may have prognostic value.

Furthermore, the metabolic shift in aggressive cancers may provide a potential therapeutic target.

“While this is a big area of research at several institutions, we have yet to see a drug that can target tumor metabolism in an effective way,” said Dr. Choueiri.

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Lastly, genes from the PI3K/Akt/mTOR pathway are also mutated in approximately 20% to 30% of patients. This has led to consideration of genomic alterations in this pathway as potential biomarkers to predict therapeutic response to mTOR inhibitors. In a study conducted at Dana-Farber, mutations in MTOR, TSC1, or TSC2 were more common in responders than non-responders (Clin Cancer Res 2016; 22:2445-52). However, a substantial fraction of responders had no mTOR pathway mutation identified.

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Dr. Choueiri noted that the VEGF “pathway” is less defined. PRBM1 mutations were more common in those with a partial or complete response for 3 or more years compared with those who progressed within 3 months (J Natl Compr Canc Netw 2016; 14:820-4). In the same study, TP53 mutations were only found in those who progressed early.

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Dr. Choueiri reported that some genetic mutations in RCC may impact response to VEGF therapy. For example, in an analysis of patients who received first-line sunitinib (Sutent) in the RECORD-3 trial, KDM5C mutations were associated with longer first-line progression-free survival (Eur Urol Oct 14, 2016 [Epub ahead of print]).

To conclude his presentation, Dr. Choueiri summarized recent findings for non-clear cell histologies. In a recent analysis of samples from the French RCC Network, copy number alterations in MET were present in 81% and 46 of papillary Type I and Type II tumors, respectively. (Clin Cancer Res 2014; 20:3411-21). Dr. Choueiri reported that a phase II clinical trial (NCT02127710) evaluating savolitinib, a pure MET inhibitor, has recently completed accrual. He also pointed to the Southwest Oncology Group PAPMET study (NCT02761057) that will compare sunitinib, cabozantinib (Cabometyx), crizotanib, and savolitinib in patients with papillary RCC. Correlative studies are planned to examine the prognostic significance of MET alterations.

Lastly, a recent study suggested that genomic alterations in NF2 and SMARCB1 may be associated with sensitivity to everolimus (Afinitor) and EZH2 inhibitors, respectively (Eur Urol 2016; 70:516-21).

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