IKCS 2021: Systemic Therapy for Non-Clear Cell: Recent and Future Studies  

(UroToday.com) The International Kidney Cancer Symposium 2021 annual hybrid meeting included a non-clear cell renal cell carcinoma (RCC) session and a presentation by Dr. Bradley McGregor discussing recent and future studies of systemic therapy for non-clear cell RCC. Dr. McGregor started by highlighting that non-clear cell RCC has worse outcomes than clear cell RCC. In a retrospective analysis of 4,528 patients treated with VEGF/mTOR inhibitors (n = 4,235 clear cell RCC; n = 337 non-clear cell RCC) in Pfizer sponsored phase II and III trials, non-clear cell RCC patients had worse PFS (6.1 vs 8.5 months) and OS (15.7 vs 20.2 months):1

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There are distinct histologic and genomic features of non-clear cell RCC subtypes, which include papillary, chromophobe, translocation, collecting duct, medullary, and sarcomatoid, and summarized in the following figure:

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Over the last several years, more focus has been put on trials/outcomes of non-clear cell RCC, several of which Dr. McGregor presented at the IKCS meeting. In a post-hoc analysis of the phase III CheckMate 214 trial, Tannir and colleagues assessed the outcomes of nivolumab + ipilimumab versus sunitinib among patients with advanced sarcomatoid RCC. Among the 1,096 randomized patients in CheckMate 214, 139 patients with sarcomatoid RCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months of minimum follow-up in patients with sarcomatoid RCC and intermediate/poor-risk disease, the median OS favored nivolumab + ipilimumab (NR, 95% CI 25.2- NE) versus sunitinib (14.2 months, 95% CI 9.3-22.9; HR 0.45 95% CI 0.3-0.7):

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Additionally, PFS benefits with nivolumab + ipilimumab were similarly observed (median 26.5 vs. 5.1 months; HR 0.54, 95% CI 0.33-0.86). Confirmed objective response rate was 60.8% with nivolumab + ipilimumab versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. 

The role of cytotoxic chemotherapy in variant histology RCC has also been evaluated. For collecting duct RCC, cisplatin + gemcitabine has demonstrated an objective response rate of 26% and a PFS benefit of 7.1 months. Among patients with renal medullary carcinoma, platinum-based chemo has been suggested even in patients with localized disease +/- bevacizumab. First presented at ESMO 2021, the BONSAI trial was a phase 2 trial that assessed frontline cabozantinib among 23 patients with metastatic collecting duct renal cell carcinoma. The median follow-up time was 8 months over which the median PFS was 6 months. Objective response rate was 35% (1 complete response and 7 partial responses), with a summary of the tumor response as follows:

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DNA sequencing was successful in 21 (91%) patients and all tumors were microsatellite stable, and no association between tumor mutational burden and response to cabozantinib was observed. The most affected pathways were chromatin-modifying enzymes (46%) and adaptive immune system (23%). Responsive patients (PFS > 6 months) showed a high frequency of mutations affecting deubiquitination, cell-cell communication, and TGF-b signaling. Non-responders were frequently mutated in chromatin remodeling, transcriptional regulation, and WNT pathways. 

With regards to targeted therapy and non-clear cell RCC subtypes, early trials tested sunitinib versus everolimus and included the ESPN,3 ASPEN,4 and RECORD-3,5 with the following summarizing the results: 

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 First presented at GU ASCO 2021 and subsequently published in Lancet,6 the PAPMET (SWOG 1500) trial randomized patients with papillary RCC to sunitinib versus cabozantinib versus crizotinib versus savolitinib: 

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Median PFS, median OS, and the objective response rate favored cabozantinib versus sunitinib:

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 The SAVOIR trial was an open-label, randomized phase III trial assessing savolitinib versus sunitinib in patients with central confirmation of a MET-driven tumor. There were 60 patients randomized (savolitinib n = 33; 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):

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Recently, Hutson et al.8  published results of a single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with non-clear cell RCC. There were 31 patients enrolled (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2) with the best overall response being a partial response (8 patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall objective response rate of 26% (95% CI 12-45). The median PFS was 9.2 months (95% CI 5.5-NE), and median OS was 15.6 months (95% CI 9.2-NE). The objective response rate and clinical benefit rate broken down by histology is as follows: 

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McDermott et al. also recently published results of an open-label, single-arm, phase II study of pembrolizumab monotherapy as first line therapy in patients with advanced non-clear cell RCC in the Journal of Clinical Oncology.9 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. The objective response rate by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median PFS was 4.2 months (95% CI, 2.9 to 5.6) and the 24-month PFS rate was 18.6%. The median OS was 28.9 months (95% CI, 24.3 months to not reached) and the 24-month OS rate was 58.4%.

Several other single arm combination trials have also recently presented data among patients with non-clear cell RCC/variant histology, summarized as follows:

  1. Nivolumab + ipilimumab (n=46)
    1. Objective response rate: 19.6% (95% CI 9.4-33.9%)
    2. Median PFS: 3.7 months (95% CI 2.7-4.6%)
    3. Median OS: 21.2 months (95% CI 16.6-NR)
  2. Atezolizumab + cabozantinib (n=30)
    1. Objective response rate: 33%
    2. Median duration of response: 7.9 months (range: 1.0 – 8.3 months)
    3. Grade 3/4 treatment related adverse events: 30%
  3. Cabozantinib + Nivolumab
    1. NFS2 mutations (n=6) objective response rate: 83%
    2. FH mutations (n=5) objective response rate: 80%
    3. SETD2 mutations (n=6) objective response rate: 17%


Dr. McGregor summarized new opportunities in non-clear cell RCC with the following table:


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There are also ongoing and upcoming phase 2 and phase 3 trials, including the phase 3 SAMETA trial assessing savolitinib + durvalumab versus sunitinib versus durvalumab in MET driven tumors: 

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 Dr. McGregor concluded his presentation of recent and future studies for systemic therapy for non-clear cell RCC with the following take-home messages:

  • There are specific therapeutic approaches for each subtype of RCC (renal medullary carcinoma/collecting duct carcinoma RCC versus papillary RCC versus chromophobe RCC)
  • There have been multiple advances across non-clear cell RCC subtypes, including VEGF inhibitors, chemotherapy, and combination regimens (ie. immunotherapy, VEGF, mTOR)
  • Histology directed therapy is the ultimate goal


Presented by: Bradley McGregor, MD, Clinical Director, Senior Physician, Instructor in Medicine, Lank Center for Genitourinary Oncology, Harvard Medical School, Dana-Farber Cancer Institute

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 International Kidney Cancer Symposium (IKCS) 2021 Annual Congress, November 5 and 6, 2021.


  1. de Velasco G, McKay RR, Lin X, et al. Comprehensive analysis of survival outcomes in non-clear cell renal cell carcinoma patients treated in clinical trials. Clin Genitourin Cancer. 2017 Dec;15(6):652-660.e1.
  2. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021 Jan 1;27(1):78-86.
  3. 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.
  4. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): A multicentre, open-label, randomized phase 2 trial. Lancet Oncol 2016 Mar;17(3):378-388.
  5. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32(25):2765-2772.
  6. Pal SK, Tangen C, Thompson IM, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: A randomized, open-label, phase 2 trial. Lancet. 2021 Feb 20;397(10275):695-703.
  7. 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.
  8. Hutson TE, Michaelson MD, Kuzel TM, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021 Aug;80(2):162-170.
  9. 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.