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Adjuvant Therapy for Renal Cell Carcinoma?

Three randomized phase 3 trials of adjuvant therapy for high-risk renal cell carcinoma have led to conflicting results.  S-TRAC was the one trial with a positive outcome, as sunitinib prolonged disease-free survival (DFS) by a median of 1.2 years compared with placebo (6.8 versus 5.6 years; HR 0.76, 95% CI 0.59-0.98, p=0.03).1  Based on these results, the US FDA approved sunitinib for the adjuvant treatment of patients with high-risk renal cell carcinoma.  However, the ASSURE trial revealed negative results as median DFS was 5.8 years for sunitinib, 6.2 years for sorafenib and 6.6 years for placebo.2  The PROTECT trial also had negative results as pazopanib compared to placebo had a HR 0.86; 95% CI 0.70-1.06, p=0.17.3 The latter two negative trials all had very high treatment discontinuation rates due to toxicity, which likely contributed to the negative results.  Even the S-TRAC trial saw a significant side effect profile, and the risk/benefit ratio must be carefully considered if and when prescribing adjuvant sunitinib.

Given the controversy in the field with conflicting trial results and the known toxicity of these compounds, it is clear that other efficacious yet lower toxicity agents should be tested in the adjuvant setting for patients with high-risk renal cell carcinoma.  The promising results of PD-1/PD-L1 therapy in this field have afforded this opportunity.  For example, in the CHECKMATE 025 trial, nivolumab was proven to be superior over everolimus for both progression-free survival (PFS) and overall survival (OS) in previously treated advanced renal cell carcinoma.4  The found the nivolumab and ipilimumab combination to be superior versus sunitinib in patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma.5  The US FDA recently granted approval for this combination.  The IMmotion 151 randomized phase 3 trial of atezolizumab plus bevacizumab was also superior over sunitinib in previously untreated metastatic renal cell carcinoma.6  The principle is now clear that PD-1/PD-L1 monotherapy and combinations offer a benefit with acceptable tolerability in patients with advanced renal cell carcinoma.  

Additional combinations of these immuno-oncology agents are currently being investigated in advanced renal cell carcinoma.  Avelumab, another PD-L1 antibody, was combined with axitinib, with sunitinib in the control arm (NCT02684006), and this trial is now fully accrued.  This combination has garnered FDA breakthrough designation.  Similarly, pembrolizumab was also combined with axitinib and was directly compared to sunitinib in another phase 3 trial that has completed accrual (NCT02853331).  This trial is evaluating both PFS and OS as dual primary endpoints.  Finally, a three-armed trial of lenvatinib/pembrolizumab versus lenvatinib/everolimus versus sunitinib is still actively recruiting patients (NCT02811861).  This combination also has been granted FDA breakthrough designation.

Given the movement of immuno-oncology agents from second-line to first-line metastatic renal cell carcinoma patients, with outstanding efficacy and tolerability, it is logical to move even earlier into the adjuvant setting for those patients with high-risk features after nephrectomy.  This is ongoing now with adjuvant, randomized, phase 3 trials of pembrolizumab versus placebo and also atezolizumab versus placebo (see below).  Nivolumab is also being studied in a perioperative setting, where it is being administered just prior to surgery with adjuvant therapy to follow after cystectomy.  This phase 3 trial utilizes nivolumab compared to observation without placebo.  See below for more information on these promising clinical trials that hopefully will someday soon make the controversy of adjuvant therapy in high-risk renal cell carcinoma disappear.

Highlighted Adjuvant Therapy Trials for Patients with High-risk Renal Cell Carcinoma

References

  1. Ravaud A et al.  N Engl J Med 2016; 375:2246-54.
  2. Haas NB et al.  Lancet 2016; 387:2008-16.
  3. Motzer RJ et al.  J Clin Oncol 2017; 35:3916-23.
  4. Motzer RJ et al.  N Engl J Med 2015; 373:1803-13.
  5. Motzer RJ et al. N Engl J Med. 2018 Apr 5;378(14):1277-1290
  6. Motzer RJ et al. J Clin Oncol 36, no. 6_suppl 2018; Feb 20 578-578.
Written by: Evan Yu, MD