What Should I Do with My New Metastatic Clear Cell Renal Carcinoma Patients?

For the past few years, most patients have received sunitinib1 or pazopanib2 for new metastatic clear cell renal carcinoma.  Yet, the National Comprehensive Cancer Network (NCCN guidelines)3 also provide other preferred category 1 options in bevacizumab + interferon4 and temsirolimus5 specifically for those patients with poor prognostic features. 

Recently, the CaboSun trial has shown that cabozantinib is superior to sunitinib in regards to progression-free survival (PFS) in the first-line metastatic setting.6  It will be interesting to see whether practice patterns change, as cabozantinib is currently a very standard agent used in the second-line due to the data from the METEOR trial that showed superiority over everolimus for both PFS and overall survival (OS).7

Another standard option in the second-line setting is nivolumab, a PD-1 antibody.  In the CHECKMATE 025 trial, nivolumab was also proven to be superior over everolimus for both PFS and OS.8  Yet, nivolumab was not the first immunologic agent to be used for renal cell carcinoma.  Both interferon and interleukin-2 (IL2) were used prior to the development of tyrosine kinase inhibitors.  High-dose IL2 still offers an opportunity for a carefully selected patient population to have durable complete responses even more than a decade later, and it is still being offered in some institutions.9

The principle of renal cell carcinoma as a tumor susceptible to immunologic manipulation for therapy is even more evident today as we have newer, less toxic and extremely efficacious agents.  The opportunity to combine immuno-oncology agents together in the first-line is borne out in the recently fully accrued CHECKMATE 214 phase 3 trial where the nivolumab and ipilumumab combination is being tested against sunitinib as a control (NCT02231749).  Additional combinations of immuno-oncology agents with standard regulatory approved therapies are also being performed.  Atezolizumab, a PD-L1 antibody, is being combined with bevacizumab with sunitinib used in the comparator arm (NCT02420821).  This phase 3 trial is now also fully accrued.  We eagerly await the results of these trials, both of which will evaluate PFS and OS as dual primary endpoints.  Avelumab, another PD-L1 antibody, is being combined with axitinib compared with sunitinib in the control arm (NCT02684006).  This phase 3 trial just recently opened with the goal of enrolling n=583 patients to evaluate PFS.  Similarly, pembrolizumab is also being combined with axitinib and being directly compared to sunitinib in another phase 3 trial that has ongoing accrual (NCT02853331).  This trial is anticipated to be larger with an accrual goal of n=840, however both PFS and OS will be evaluated as dual primary endpoints.  Finally, a three-armed trial of lenvatinib/pembrolizumab vs. lenvatinib/everolimus vs. sunitinib is being performed (NCT02811861).  This ongoing randomized, phase 3 trial is evaluating PFS with an accrual goal of n=735.

For many years, renal cell carcinoma was a disease where immunotherapeutics were attempted but few patients responded.  The paradigm shift in the field came with the advent of tyrosine kinase inhibitors to target angeiogenesis inhibition and mTOR.  However, the field is rapidly reinventing immuno-oncology with novel agents that are tolerable enough to combine either with other approved therapeutics or other checkpoint inhibitors in this first-line metastatic disease space.  We avidly await the results of these trials and appreciate the patients who enroll on them.

Highlighted First-line Metastatic Clear Cell Renal Cell Carcinoma Combination Immuno-Oncology Trials with Ongoing Accrual
Written by: Evan Yu, MD

  1. Motzer RJ et al.  N Engl J Med 2007; 356:115-24.
  2. Sternberg CN et al.  J Clin Oncol 2010; 28:1061-8.
  3. NCCN Guidelines Version 2.2017 Kidney Cancer
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  5. Hudes G et al.  N Engl J Med 2007; 356:2271-81.
  6. Choueiri TK et al.  J Clin Oncol 2017; 35:591-7.
  7. Choueiri TK et al.  N Engl J Med 2015; 373:1814-23.
  8. Motzer RJ et al.  N Engl J Med 2015; 373:1803-13.
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