Perioperative Management of Clear Cell Renal Cell Carcinoma

In a presentation at the 2022 Great Debates and Updates in Genitourinary Oncology meeting, Bradley McGregor, MD, Dana-Farber Cancer Institute, Boston, MA, gave an update on the perioperative management of clear cell renal cell carcinoma (RCC).

Adjuvant therapy in RCC has evolved from radiotherapy to cytokines to the introduction of targeted therapies. The success of targeted therapy in the metastatic setting with improving disease-free survival (DFS) has given rise to multiple studies exploring the role of tyrosine kinase inhibitors (TKIs) in this space.

Randomized controlled trials investigating the role of adjuvant TKIs in RCC included the ASSURE trial with 1 year of sunitinib or sorafenib, the SORCE with 3 years of sorafenib, the S-TRAC trial with 1 year of sunitinib, the PROTECT trial with 1 year of pazopanib, and the ATLAS trial with 3 years of axitinib. Across the board, these trials showed no clinically meaningful improvement in disease-free survival with the exception of the S-TRAC trial, which focused on the highest risk patients and included strict dosing to maintain dose intensity.

Another trial, EVEREST, looking at the mTOR inhibitor, everolimus, has completed approval and should release results soon.

This conflicting data led investigators to question the importance of dose intensity. An analysis of the ASSURE trial focused on those highest risk patients and found no difference in DFS and no difference in outcomes by the average dose achieved per 6-week cycle. “Longer-term follow-up may be helpful to explain the conflicting results between the S-TRAC and ASSURE trials but given the lack of improvement in overall survival and toxicity profile, sunitinib has not been readily adapted in clinical practice, despite the FDA approval,” said Dr McGregor.

There are ongoing trials looking at the role of adjuvant immunotherapy in RCC, including KEYNOTE-564 evaluating pembrolizumab vs placebo, IMmotion010 with atezolizumab vs placebo, CheckMate-914 with nivolumab plus ipilimumab vs nivolumab plus placebo vs placebo, PROSPER with nivolumab vs active monitoring, and RAMPART with durvalumab plus tremelimumab vs durvalumab vs active monitoring. KEYNOTE-564 is the only trial that has been presented.

KEYNOTE-564 included patients with histologically confirmed clear cell RCC who were randomized in a 1:1 ratio to pembrolizumab or placebo. Patients were stratified by metastatic status (M0 vs M1) and the M0 group was further stratified by performance status (0 vs 1) and US vs non–US. The primary end point was DFS per investigator with a secondary end point of overall survival (OS) and safety.

In the initial analysis, at 24 months follow-up, there was an improvement in DFS at 77% with pembrolizumab vs 68% with placebo (hazard ratio [HR] 0.68; P = .001). At 30 months follow-up, the improvement in DFS was maintained at 78.3% with pembrolizumab vs 67.3%, with placebo (HR 0.63; P <.0001).

The 24-month OS was 96.6% with pembrolizumab vs 93.5% with placebo (HR 0.54; P = .0164) and 30-month OS was 96.2% vs 93.8%, respectively (HR 0.52; P = .0048). “That is not statistically significant given the design of the trial, but certainly trending in the right direction,” said Dr McGregor.

Safety results show about 30% of patients experience grade 3 to 5 adverse events (AEs) with a 20% discontinuation rate. The most common immune-mediated AEs were hypothyroidism (21.1%) and hyperthyroidism (11.9%). Other immune related AEs included pneumonitis (2.3%), adrenal insufficiency (2%), and type 1 diabetes mellitus (1.6%).

“I think this is exciting data, it's been approved by FDA. It is something I certainly talk about with my patients,” said Dr McGregor.

What about the neoadjuvant space? The TKI that has been studied the most in the neoadjuvant space is axitinib. Data has demonstrated the ability of axitinib to reduce tumor size with a 28.3% reduction tumor diameter and no disease progression or increase in complications. Again, in the NAXIVA trial, patients were given axitinib for up to 8 weeks and then went on to radical nephrectomy with thrombectomy. The overall response rate was 31% and 41% of patients experienced reduced extent of surgery, with no increase in morbidity or mortality.

Another area of study in the neoadjuvant space is adding immunotherapy to TKI. The Neovax trial is looking at a combination of axitinib and avelumab in the neoadjuvant space for up to 12 weeks. The overall response rate was 30%, median tumor downsizing was 20%, and of 12 patients who had a partial response, 82% remain disease-free within 24 months of follow-up. In addition, there were no safety signals or increase in surgical complications.

“What is the appropriate duration of therapy? Can we intensify therapy? Are there better criteria for selection outside the clinical data? These are questions that we need to answer as we look to continue to advance the treatment for our patients in that perioperative space,” concluded Dr McGregor.

Source:
McGregor B. Peri-Operative Management of Clear Cell Renal Cell Carcinoma (ccRCC). Presented at: 2022 Great Debates and Updates in Genitourinary Oncology; March 9-11, 2022; virtual. Accessed March 30, 2022.