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Where are we at in 2020 with non-clear cell RCC?


Rana R. McKay, MD, highlights developments with immunotherapy and targeted agents in the treatment paradigm for non-clear cell renal cell carcinoma.

As we approach the end of 2020, non-clear cell (ncc) histology remains an unmet need in the treatment paradigm for patients with renal cell carcinoma (RCC), Rana R. McKay, MD, said during her discussion at the 38th Annual CFS meeting.1

Rana R. McKay, MD

Rana R. McKay, MD

“When we look at the outcomes of those with non-clear cell histology, they have a shorter time to treatment failure and shorter overall survival,” said McKay, an assistant professor of medicine and medical oncologist at the University of California, San Diego.

“Systemic treatment in nccRCC has mirrored clear cell RCC, though a more refined strategy based on the underlying disease pathogenesis should be sought after to develop treatment for these patients,” she added.

Over the past 5 years, several phase 2 studies, including the ESPN, ASPEN, and RECORD-3 trials, have demonstrated improved outcomes with frontline sunitinib (Sutent) over everolimus (Afinitor) in patients with nccRCC. This includes improved response and progression-free survival (PFS), as well as a signal of an overall survival (OS) benefit.

“What these studies demonstrated was that sunitinib was superior to everolimus for frontline treatment of non-clear cell RCC,” explained McKay; however, she added that, “There really has not been much improvement in terms of more recent randomized data beyond these phase 2 studies.”

Researchers now hope to break through this stagnation with immunotherapy, novel targeted agents, and new combination regimens, according to McKay.

As a first step, McKay said 2 retrospective studies demonstrated a role for immune checkpoint inhibitor therapy in nccRCC. The first was a small retrospective analysis showing that among patients with nccRCC treated with a PD-1/PD-L1 inhibitor, 4 (29%) of 14 patients with papillary histology had a response and 1 of 3 patients with translocation RCC had a response.2 There were no responses among 10 patients with chromophobe histology or among 11 patients with unclassified nccRCC.

A separate retrospective analysis which just focused on patients with nccRCC who had received nivolumab (Opdivo) also showed a signal with single-agent immunotherapy in RCC.3 Here, 1 of 6 patients with papillary type 1 histology had a response, as did 4 of 11 patients with unclassified nccRCC. There were no responses among patients with papillary type 2, chromophobe, or translocation histology.

Building on this foundation, there are prospective data for single-agent immune checkpoint inhibitor therapy in nccRCC from the KEYNOTE-427 pembrolizumab (Keytruda) trial.4 The nccRCC cohort of this trial included 165 patients with advanced or metastatic disease with no prior systemic therapy. In these patients, frontline pembrolizumab monotherapy induced an objective response rate (ORR) of 26.7%, including a complete response (CR) rate of 6.7% and a partial response rate of 20%. The stable disease rate was 30.9%. The median PFS was 4.2 months and the median OS was 28.9 months.

Moving beyond single-agent immunotherapy, McKay highlighted how immunotherapy combination regimens are emerging as a potential option for patients with sarcomatoid RCC. Three posthoc exploratory analyses from pivotal trials have shown highly promising data in this setting: among 51 patients with sarcomatoid RCC in the KEYNOTE-426 trial, pembrolizumab plus axitinib (Inlyta) induced an ORR of 59% with a CR of 12%; in 60 patients with this histology in the CheckMate-214 trial, the ORR with nivolumab plus ipilimumab (Yervoy) was 57% with a CR of 18%; and in the IMmotion-151 trial, atezolizumab (Tecentriq) plus bevacizumab (Avastin) induced an ORR of 49% and a CR of 10% in 68 patients with sarcomatoid RCC.

The success of these immunotherapy regimens in this population is surprising, given the historically poor outcomes in patients with this aggressive form of RCC, said McKay. She attributes the robust activity to the underlying disease biology of sarcomatoid RCC, which has a higher mutational burden than other forms of RCC.

Another approach researchers are employing to advance outcome in nccRCC is the development of new targeted agents. The open-label phase 3 SAVOIR trial compared the investigational, highly selective MET-tyrosine kinase inhibitor savolitinib with sunitinib in patients with MET-driven papillary RCC.

Although the study was closed early, data have been published for 60 patients, 33 who were randomized to savolitinib and 27 who were randomized to sunitinib.5 Results for the limited population showed a numerical, but not statistically significant, median PFS benefit with savolitinib over sunitinib: 7 months versus 5.6 months, respectively (HR, 0.71; P = .31). Also of note, the safety profile was superior with savolitinib, with fewer grade ≥3 adverse events and dose modifications.

Although it is not clear what the next step is with savolitinib, McKay said researchers in the field are moving forward with the goal of determining the most appropriate TKI for patients with papillary RCC. For example, an ongoing phase 2 study is comparing sunitinib with cabozantinib (Cabometyx) in this setting (NCT02761057).

In her concluding remarks, McKay noted othering ongoing clinical trials aiming to advance the nccRCC paradigm, including a phase 2 trial (NCT04413123) and the phase 3 CONTACT-03 trial (NCT04338269). The single-arm, open-label phase 2 trial is exploring the triplet of cabozantinib, nivolumab, and ipilimumab in patients with advanced nccRCC. The open-label, randomized CONTACT-03 trial is examining atezolizumab plus cabozantinib versus cabozantinib alone in patients with locally advanced or metastatic clear cell RCC or non-clear cell RCC (papillary and unclassified only).


1. McKay RR. Management of Non-Clear Cell RCC: What Do We Know? Presented at: 38th Annual CFS. November 4-6, 2020.

2. McKay RR, Bossé D, Xie W, et al. The clinical activity of PD-1/PD-L1 inhibitors in metastatic non-clear cell renal cell carcinoma. Cancer Immunol Res. 2018;6(7):758-765. doi: 10.1158/2326-6066.CIR-17-0475

3. Chahoud J, Msaouel P, Campbell MT, et al. Nivolumab for the treatment of patients with metastatic non-clear cell renal cell carcinoma (nccRCC): A single-institutional experience and literature meta-analysis [published online ahead of print September 9, 2019]. Oncologist. doi: 10.1634/theoncologist.2019-0372

4. Lee J-L, Ziobro M, Suarez C, et al. First-line pembrolizumab (pembro) monotherapy in advanced non-clear cell renal cell carcinoma (nccRCC): Updated follow-up for KEYNOTE-427 cohort B. J Clin Oncol 38, no. 15_suppl (May 20, 2020) 5034. doi: 10.1200/JCO.2020.38.15_suppl.5034

5. Choueiri TK, Heng DYC, Lee JL, et al. Efficacy of savolitinib vs sunitinib in patients with MET-driven papillary renal cell carcinoma: The SAVOIR phase 3 randomized clinical trial. JAMA Oncol. 2020;6(8):1247-1255. doi: 10.1001/jamaoncol.2020.2218

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