(UroToday.com) The 2024 GU ASCO annual meeting featured a session on the management of renal cell carcinoma with sarcomatoid features or variant histologies and a presentation by Dr. Thomas Powles discussing the management of non-clear cell renal cell carcinoma. Dr. Powles started his presentation by discussing the ESPN trial,1 which tested sunitinib versus everolimus among 68 patients with non-clear cell RCC, noting an overall response rate of 9% versus 3%, median progression free survival of 6.1 versus 4.1 months, and overall survival of 16.2 versus 14.9 months:
Dr. Powles used the example of the ESPN trial to emphasize that we almost exclusively tested clear cell RCC treatments in non clear cell RCC despite little biology to support this approach. Moreover, our pivotal studies were too small to make conclusions, and these therapies became adopted almost by default. Broad “renal cancer” approvals further complicated the situation. A purely non clear cell RCC trial was the phase II efficacy assessment of multiple MET kinase inhibitors in metastatic papillary renal carcinoma – PAPMET. The PAPMET SWOG trial randomized patients in a 1:1:1:1 fashion to receive either sunitinib 50 mg oral daily (6-week cycles: 4 weeks on/2 weeks off), cabozantinib 60 mg oral daily, crizotinib 250 mg oral twice daily, or savolitinib 600 mg oral daily:2
The response rate for cabozantinib was 23% compared to 4% for sunitinib, with a 4 months benefit for cabozantinib in overall survival (20 months vs 16 months). However, the median PFS was significantly higher with cabozantinib relative to sunitinib (HR 0.60, 95% CI 0.37-0.97).
McDermott et al.3 previously reported results of KEYNOTE-427, an open-label, single-arm, phase II study of pembrolizumab monotherapy as first line therapy in patients with advanced non-clear cell RCC. Among enrolled patients (n = 165), 71.5% had papillary RCC, 12.7% had chromophobe RCC, and 15.8% had unclassified RCC histology. In all patients, the objective response rate was 26.7%, the median duration of response was 29.0 months, and 59.7% of responses lasted ≥ 12 months. Overall, 91/165 (55.2%) experienced a reduction in tumor burden, 20/165 (12.1%) had a tumor burden reduction of >= 80%, and 7/165 (4.2%) experienced 100% tumor burden reduction:
With regards to combination therapy in papillary RCC, cabozantinib + atezolizumab was associated with a response rate in papillary RCC of 47% and cabozantinib + nivolumab was also associated with a response rate of 47%:
The KEYNOTE-B61 is the largest single arm study to date for non-clear cell RCC, presented at ASCO 2023 with long term follow-up on 158 patients. Patients in this trial were treated with pembrolizumab + lenvatinib with the following baseline characteristics.
Objective response rates varied by histology, with the greatest benefit seen among translocation and papillary RCC patients:
The following figure is a rough summary of the efficacy data in non-clear cell RCC assembled by Dr. Powles for response rate (y axis) vs PFS (x axis):
When considering overall survival for these studies, Dr. Powles emphasized that we should be cautious:
The above graph is for each study with over 25 patients with available data, which includes mixed population and papillary only populations. The box represents the median value for the studies and not the whole population, with each study comprising one data point. The summary slide is not robust enough to determine preferential treatments at this time.
There are 3 ongoing studies in first line therapy for advanced papillary RCC that were highlighted by Dr. Powles:
- Phase 3 RCT of ipilimumab + nivolumab versus sunitinib
- Phase 3 RCT (n = 291) of the novel multi-targeted TKI zanzalintinib + nivolumab versus sunitinib
- PAPMET-2: cabozantinib +/- atezolizumab
Dr. Powles then discussed savolitinib, which is a selective small molecule and potent inhibitor of MET, which was tested versus sunitinib in MET-driven papillary RCC in the SAVOIR trial.4 Unfortunately, this trial was not completed after accruing 60 patients, but nevertheless these patients were randomized to savolitinib (n = 33) and sunitinib (n = 27), with an objective response rate of 27% in the savolitinib group. The median PFS was not statistically different between the 2 groups: 7.0 months (95% CI, 2.8-NR) for savolitinib and 5.6 months (95% CI, 4.1-6.9) for sunitinib (HR 0.71, 95% CI, 0.37-1.36). Additionally, there was also no difference in OS between these groups (HR 0.51, 95% CI 0.21-1.17):
In a phase 2 study where savolitinib was added to durvalumab, the response rate was 53% for this combination in MET driven tumors, leading to the SAMETA randomized phase III study that is randomizing advanced papillary RCC in the first line to savolitinib + durvalumab versus durvalumab versus sunitinib:
Dr. Powles concluded his presentation by discussing the management of non-clear cell renal cell carcinoma with the following take-home points:
- The use of VEGF TKIs or PD1 therapy is not clearly supported by the biology, but we almost exclusively tested these agents. They have become the standard of care and the trials have been a lot less robust than we would like
- It is not possible to say one VEGF TKI is clearly superior to another, even for cabozantinib
- MET inhibition in MET driven tumors is perhaps the most logical approach. The addition of PD-L1 to MET is supported by phase II data and randomized phase III trials are ongoing
- Single arm VEGF/PD1 studies show response rates of 50% and most want to use this approach, however, overall survival data is immature
- We should avoid adjuvant pembrolizumab in patients with non-clear cell RCC
- Chromophobe cancer is a research desert, with lenvatinib + pembrolizumab probably having the best data
Presented by: Thomas Powles, MD, Barts Cancer Institute, London, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
References:
- Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in Metastatic Non-clear cell renal cell carcinoma (ESPN): A Randomized Multicenter phase 2 trial. Eur Urol 2016;69(5):866-874.
- Pal S, Tangen C, Thompson Jr E, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. The Lancet. 2021. S0140-6736(21)00152-5.
- McDermott DF, Lee JL, Ziobro M, et al. Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1029-1039.
- Choueiri TK, Heng DYC, Lee JL, et al. Efficacy of Savolitinib versus Sunitinib in Patients with MET-driven papillary renal cell carcinoma. JAMA Oncol. 2020;6(8):1247-1255.