ASCO 2019: CheckMate 214 Post-Hoc Analyses of Nivolumab plus Ipilimumab or Sunitinib in IMDC Intermediate/Poor-Risk Patients with Previously Untreated Advanced Renal Cell Carcinoma with Sarcomatoid Features

Chicago, IL ( The landscape of systemic therapy for metastatic renal cell carcinoma (mRCC) is rapidly changing. Beyond the addition of immune checkpoint inhibitor combinations (nivo/ipi), additional tyrosine kinase inhibitors (TKIs) (cabozantinib), there are now combination therapies that are demonstrating excellent responses rates in the first line. The recent data from KEYNOTE‑426 has led to the approval of axinitib/pemrbolizumab in the first line for mRCC, and as can be expected from this combination, it seems to have efficacy for good, intermediate and poor risk patients.

Certain histologic features are associated with worse clinical outcomes. In particular, patients with sarcomatoid RCC histology have poor prognosis and suboptimal outcomes with anti-VEGF targeted therapy. Up to 20% of advanced RCC can have sarcomatoid dedifferentiation. This histologic subtype may express PD-1 and PD-L1 at higher levels than ccRCC without sarcomatoid dedifferentiation, and therefore this may be a potential therapeutic option. More recently, certain non-TKI therapies have demonstrated improved efficacy in patients with intermediate/poor risk mRCC. In the phase 3 CheckMate 214 trial,the combination of nivolumab plus ipilimumab (N+I) demonstrated superior objective response rate (ORR) and overall survival (OS) vs sunitinib (S) in previously untreated pts with International Metastatic RCC Database Consortium (IMDC) intermediate/poor (I/P)-risk, clear-cell, advanced renal cell carcinoma (RCC). 

To help focus on sarcomatoid histology patients, the authors completed a post-hoc exploratory analysis of N+I vs S in CheckMate 214 patients with sarcomatoid histology (sRCC). The presence of sarcomatoid features was assessed by keyword search for “sarcomatoid” in patients with available local pathology reports accompanying pretreatment tumor samples. This search algorithm is seen below:

In CheckMate-214, a total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. With median follow-up of 25.2 months in the intermediate- and poor-risk patients, the 18-month overall survival rate was 75% with nivolumab plus ipilimumab and 60% with sunitinib. The median overall survival (OS) was not reached with nivolumab plus ipilimumab and was 26.0 months with sunitinib (P<0.001). The objective response rate was 42% versus 27% (P<0.001) and the complete response rate was 9% versus 1%.

Of the 1096 intention-to-treat pts, 842 (77%) had local pathology reports available. After reviewing the pathology reports, ultimately 112 randomized pts with I/P-risk disease had sRCC – 60 treated with N+I and 52 treated with sunitinib. Baseline characteristics of sRCC pts were balanced between arms, and can be seen below:
Notably, 47% vs 53% of I/P-risk sRCC pts in the N+I and S arms had tumor PD-L1 expression ≥1% at baseline, which was higher than in all I/P-risk patients (N+I, 26% vs S, 29%). 

In descriptive analyses performed at a minimum follow-up of 30 months, confirmed objective response rate (ORR) and complete response rate per investigator (RECIST v1.1), OS, and progression-free survival (PFS) per investigator were improved with N+I compared to suninitib alone in I/P-risk pts with sRCC. 

Response rates are summarized below: 
ORR was 56.7% in patients with sarcomatoid histology treated with nivo/ipi vs. 19% in those treated with sunitinib. This far exceeds the 41.9% vs. 29.4% difference seen in the entire cohort.

PFS and OS results are seen below:

There is early and persistent separation in the survival curves. These differences were maintained regardless of PD-L1 status (separate analysis).

No new safety signals were seen in sRCC patients compared to the original study. 

Based on this post-hoc descriptive subgroup analysis of CheckMate 214, the N+I combination demonstrated promising efficacy and prolonged survival compared to sunitib in previously untreated, I/P-risk, advanced clear-cell RCC with sarcomatoid features. The safety was comparable to the original larger cohort. 

They note that this justifies ongoing prospective studies of N+I in patients with sRCC.

Presented by: David F. McDermott, MD, Staff Physician, Beth Israel Deacoess Medical Center, Professor of Medicine, Harvard Medical School, Boston, MA 

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA 

  1. Motzer RJ et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.