(UroToday.com) The 2022 American Urological Association (AUA) Annual Meeting included the Society of Urologic Oncology (SUO) session and a presentation by Dr. Viraj Master discussing whether everyone should receive adjuvant therapy after resection of high-risk renal cell carcinoma (RCC). Dr. Master started his presentation by noting that the perfect adjuvant therapy would be inexpensive, easy to tolerate, active in microscopic disease, and would provide good outcomes. Until recently, the adjuvant therapy for high-risk kidney cancer has been a barren landscape, as evidenced by the following TKI trials:
The ASSURE trial randomly assigned patients 1:1:1 to receive 54 weeks of sunitinib 50 mg/day through the first 4 weeks of each 6-week cycle, sorafenib 400 mg twice per day throughout each cycle, or placebo1. The primary analysis for this trial showed no significant differences in disease-free survival, with a median disease-free survival of 5.8 years (IQR 1.6-8.2) for sunitinib (HR 1.02, 97.5% CI 0.85-1.23), 6.1 years (IQR 1.7- NE]) for sorafenib (HR 0.97, 97.5% CI 0.80-1.7), and 6.6 years (IQR 1.5-NE) for placebo. Furthermore, there was no difference in overall survival between the groups:
Even in an updated analysis among high-risk patients, there was no difference in disease-free survival or overall survival. Subsequently, the S-TRAC trial showed that adjuvant sunitinib prolonged disease-free survival versus placebo in patients with loco-regional RCC at high risk of recurrence after nephrectomy (HR 0.76, 95% CI 0.59-0.98, p = 0.03):
However, Dr. Master emphasized that they do not use adjuvant sunitinib at Emory University. A subsequent pooled analysis of the ASSURE (n = 1943), S-TRAC (n = 615), and PROTECT (n = 1135)3 trials showed again that VEGF TKI was not associated with improved DFS (HR 0.92, 95% CI 0.83-1.03)4. Additionally, adjuvant VEGF TKI was associated with higher grade 3-4 adverse events (OR 5.89, p < 0.001). So, perhaps adjuvant immunotherapy trials are to the rescue? Dr. Master highlighted that several trials are accruing, completed accrual, and published:
Dr. Master notes that on April 26, 2022, there was an update on the PROSPER trial, which is a phase 3 trial testing adjuvant nivolumab, stating that “the addition of perioperative nivolumab does not appear to improve RFS compared to standard of care surgery alone for patients with clinical stage T2 and higher primary kidney cancer.”
Dr. Master then discussed the one published adjuvant immunotherapy trial, KEYNOTE-5645. This trial was a phase III multicenter trial of pembrolizumab versus placebo in patients with histologically confirmed ccRCC. Risk groups were defined as follows:
- Intermediate-high risk disease: pT2, grade 4 or sarcomatoid, N0 M0; or pT3, any grade, N0 M0
- High-risk disease: pT4, any grade, N0 M0; or pT any stage, any grade, N+ M0
- M1 no evidence of disease: primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy
The trial schema for KEYNOTE-564 is as follows:
The key figure from this trial according to Dr. Master is DFS by investigator in the intention to treat population:
In the melanoma literature, adjuvant pembrolizumab works, but Dr. Master notes that it took 10 years of follow-up to see a difference in survival. All of a sudden at the Emory tumor boards, it seemed that every patient was getting referred for adjuvant pembrolizumab. As such, it is important to dig into the details of this trial. Referring back to the Kaplan-Meier curve for DFS by investigator in the intention to treat population, Dr. Master highlighted that at 36 months of follow-up the two curves collapse. As urologists, Dr. Master notes that we know that the vast majority of recurrences occur during the 2-3 years post-operatively. Thus, this therapy with this particular cohort of patients does not really show a benefit during the entirety of the time window we would expect to see recurrences. Looking closer at the patients included in the trial, Dr. Master notes that 34.6% of patients were low grade (1 or 2):
On further analysis of the subgroups, Dr. Master highlights that region is quite interesting, specifically the European Union demonstrating a significant benefit (HR 0.49, 95% CI 0.32-0.74). Interestingly, the strongest DFS signal was seen among 26 patients in the pembrolizumab arm who are M1 NED either synchronously or metachronously (HR 0.29, 95% CI 0.12-0.69):
Dr. Master highlighted that the adverse events/immune-mediated adverse events in KEYNOTE-564 are real. These include (i) 32% any grade 3-5 adverse events, (ii) 21% discontinuation for adverse events (vs 2% in the placebo arm), (iii) two deaths in the pembrolizumab arm, and (iv) 8.6% grade 3-4 immune-mediated adverse events (vs 0.6% in placebo). Additionally, the colitis and pneumonitis adverse events can be very debilitating.
Regarding restricted mean disease-free survival, this type of analysis shows the population average of event-free survival time experienced during a fixed study follow-up time period. This quantity is estimated by the area under the Kaplan-Meier curve from the date of randomization up to a particular follow-up time point. In KEYNOTE-564, the difference between restricted mean disease-free survival estimated from the two treatment groups at a pre-specified follow-up time point can be used as an alternative or supplemental measure of treatment effect in addition to the hazard ratio. The positive restricted mean disease-free survival differences in the table show favorable treatment effect was observed with pembrolizumab versus placebo:
The lower bounds of 95% CIs for restricted mean disease-free survival difference were greater than 0 and the magnitude of restricted mean disease-free survival difference increased over evaluated follow-up time points of 12, 18, and 24 months. All of the above indicates a meaningful improvement in disease-free survival with treatment of pembrolizumab compared to placebo. The overall survival analysis was immature at data cutoff date. Nevertheless, the restricted mean disease-free survival differences were all positive at 12, 18, and 24 months, and the magnitude of restricted mean disease-free survival difference increased over time. However, based on these results, Dr. Master questions if the two arms are really that different based on these small differences in DFS/OS.
Regarding the cost of therapy, recent data was presented at GU ASCO 2022. This data showed that adjuvant RCC costs more than $100,000/patient and that adjuvant pembrolizumab was not cost-effect for all trial patients at a population level at 5 years after treatment. However, adjuvant pembrolizumab was found to be cost-effective in a subset of high-risk patients at 5 years. So, who are the patients that are developing recurrence and should receive immunotherapy? Looking at data from Leibovich et al.5, they assessed 3,633 patients with nonmetastatic clear cell RCC, papillary RCC, and chromophobe RCC, developing prognostic models for progression-free (PFS) and cancer-specific survival (CSS). Specific to clear cell RCC, the c-index for PFS was 0.83 and for CSS was 0.86. Based on the risk score model, Dr. Master says somewhere around 8-9 points may make sense to consider treating patients with adjuvant therapy:
Correa and colleagues6 looked at predictors of DFS, OS, and early disease progression in the ASSURE trial, with early disease progression defined as a DFS event within 1 year of randomization. Based on 5 common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) the C-statistics at 1 year were 78.4% and 81.9% for DFS and OS, respectively, and 75.1% in the early disease progression model. Based on the following point system, anyone with >8.5 points should be considered for adjuvant therapy:
Based on the following table, Dr. Master notes that if you were to simply look at the numbers, among 86% in the total cohort, using the ASSURE DFS nomogram, 96% of the T2G4 patients would not be predicted to recur:
Furthermore, even the pT3 patients (assuming grade 3), only 80% of those patients were destined to have a recurrence. Thus, patients with T3/T4 or N+ tumors, or certainly the M1 NED patients would be those that may benefit from adjuvant pembrolizumab.
Finally, some translation points may inform us regarding patient selection. First, CD8 T-cell infiltration predicts progression-free survival after surgery among renal cell carcinoma patients. Second, CD8 T cell response is independent of tumor size, stage, subtype, and demographic factors.
Dr. Master concluded his presentation by discussing whether everyone should receive adjuvant therapy after resection of high-risk RCC with the following summary points:
- Adjuvant pembrolizumab is not cheap and is not particularly easy to tolerate
- Adjuvant pembrolizumab may be active in microscopic disease
- As of yet, there is no overall survival benefit
- The patients that are potentially most likely to benefit are those that are: (i) pM1 NED s/p metastasectomy, (ii) pN1, or (iii) pT3 > 7 cm with sarcomatoid features
Presented by: Viraj Master, Department of Urology, Emory University, Atlanta, GA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.
- Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387(10032):2008-2016.
- Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.
- Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(35):3916-3923.
- Sun M, Marconi L, Eisen, et al. Adjuvant vascular endothelial growth factor-targeted therapy in renal cell carcinoma: A systematic review and pooled analysis. Eur Urol. 2018 Nov;74(5):611-620.
- Leibovich BC, Lohse CM, Cheville JC, et al. Predicting oncologic outcomes in renal cell carcinoma surgery. Eur Urol. 2018 May;73(5):772-780.
- Correa AF, Jegede OA, Haas NB, et al. Predicting disease recurrence, early progression, and overall survival following surgical resection for high-risk localized and locally advanced renal cell carcinoma. Eur Urol. 2021 Jul;80(1):20-31.