Novel Therapies in Renal Cell Carcinoma

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There are many new therapies currently in clinical trials for the treatment of patients with renal cell carcinoma (RCC), including those targeting PD-1. A phase III trial comparing the PD-1 inhibitor nivolumab with the mTOR inhibitor everolimus among approximately 800 patients with advanced or metastatic clear cell RCC who have received 2 prior antiangiogenic therapies is currently underway, Sumanta Kumar Pal, MD, notes. The study’s primary endpoint is overall survival (OS). By blocking PD-1, the extent of T-cell anergy is decreased, promoting an antitumor immune response.

In addition to the study in comparison to everolimus, nivolumab is also being explored in combination with sunitinib or pazopanib. This study will help establish whether a PD-1 inhibitor can be combined with a standard of care, such as a TKI, Brian Rini, MD, explains. This trial was expanded to include nivolumab plus the CTLA-4 inhibitor ipilimumab, another checkpoint inhibitor that is approved for melanoma. Data reported at this year’s ASCO Annual Meeting regarding this combination were quite impressive in melanoma, says Rini. Ultimately, the goal would be to have a therapy that can cure patients in the frontline setting; however, many questions remain regarding dose, sequencing, combination therapy, and utility in upfront versus refractory settings.

Another promising agent, cabozantinib, is being explored in the phase III METEOR trial versus everolimus in patients with metastatic RCC. METEOR allowed for any number of prior therapies (except for an mTOR inhibitor). Patients were randomized 1:1 and followed for progression free survival, with OS as a secondary endpoint.

Cabozantinib inhibits, the mesenchymal epithelial transition (MET) receptor, VEGF, VEGFR2, and many other targets, according to Daniel J. George, MD. MET was one of the targets that had both prognostic and predictive importance for resistance to VEGF targeted therapy. At this point, cabozantinib is FDA approved for the treatment of patients with medullary thyroid cancer, and is also being explored in phase III studies in prostate cancer.

Moderator Robert Figlin, MD, mentions that there are also vaccines that are in clinical trials. One study is investigating whether a multipeptide cancer vaccine in combination with sunitinib can prolong survival in patients with metastatic or locally advanced RCC. There is also a trial underway to investigate a dendritic cell vaccine plus sunitinib in patients with RCC.

In adjuvant therapy, the majority of clinical trials have explored VEGF-directed therapies, Pal notes. The EVEREST study is examining the mTOR inhibitor everolimus as adjuvant therapy for patients with RCC. In general, since the eligibility varies across each adjuvant trial, it is challenging to decide who benefits the most from these therapies, Pal notes.