Combined Immune Checkpoint and VEGF Inhibition: Exciting yet Challenging Time for Renal Cancer Therapeutics


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The treatment paradigm for metastatic clear cell renal cell carcinoma continues to evolve at a rapid pace. We have recently approved agents that target the vascular endothelial growth factor receptor (VEGFR) pathway in the front-line setting—such as the tyrosine kinase inhibitor cabozantinib (Cabometyx)—with demonstrated superiority when compared with sunitinib (Sutent) in intermediate- and poor-prognosis patients. Phase III trials have also demonstrated the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) is superior to sunitinib in a similar population of patients, and on April 16, 2018, the U.S. Food and Drug Administration granted approval of this combination treatment of patients with intermediate- or poor-risk previously untreated advanced renal cell carcinoma.


We may have reached a point in kidney cancer therapy where endpoints such as progression-free survival and response rates may become less important than longer-term disease control.
— Robert A. Figlin, MD, FACP

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The recently reported study by Choueiri et al,1 reviewed in this issue of The ASCO Post, is one of a series of trials testing the concept of checkpoint blockade combined with agents that target the VEGF/VEGFR pathway—in this case avelumab (Bavencio) in combination with the VEGF inhibitor axitinib (Inlyta). The strength of such approaches is the continuing importance of directing therapy at the inherent biology of renal cancer, an approach that has changed the treatment paradigm over the past decade for patients with this disease with the targeting of the VEGF/VEGFR pathway. The challenges will be whether this combined approach will be superior to combined checkpoint blockade, or newer-generation tyrosine kinase inhibitors, as previously described. Unfortunately, many of the currently accruing pivotal trials are employing first-generation VEGF/VEGFR pathway inhibitors rather than investigating either a combined immunotherapy approach or newer approved targeted agents. Additionally, we may have reached a point in kidney cancer therapy where endpoints such as progression-free survival and response rates may become less important; looking at longer-term disease control as measured by unmaintained remissions, tail-of-the-curve benefits, and the value of each approach over a standard of care may be the outcomes that drive utility.

It remains an exciting time for renal cancer therapeutics, but also a challenging time, when cross-trial comparisons may not offer clinicians the best opportunity to define optimal treatment sequences. ■

Dr. Figlin is Professor, Medicine and Biomedical Sciences; Director, Division of Hematology Oncology; Deputy Director, Integrated Oncology Service Line; Deputy Director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles.

DISCLOSURE: Dr. Figlin has been a consultant/advisor to Johnson & Johnson, Pfizer, BMS, CBT Therapy, and Acceleron Pharma. 

REFERENCE

1. Choueiri TK, Larkin J, Oya M, et al: Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): An open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol 19:451-460, 2018.


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In a dose-finding, dose-expansion phase Ib trial (JAVELIN Renal 100) reported in The Lancet Oncology, Toni K. Choueiri, MD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and colleagues determined the maximum tolerated dose of the immune checkpoint inhibitor avelumab (Bavencio)...

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