First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B.

Abstract

546 Background: PD-1/L1 pathway inhibitors are effective in clear cell (cc)RCC, but efficacy of PD-1 inhibitors (or any therapy) in nccRCC has not been established. KEYNOTE-427 is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced ccRCC (cohort A) and nccRCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed nccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts were followed after PD for overall survival. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Secondary end points included duration of response (DOR) and population description by International Metastatic RCC Database Consortium (IMDC) risk. Exploratory end points: ORR by histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). 68% of patients were at intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At a median follow-up duration of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CRs, 33 [20%] PRs); median DOR was not reached. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified nccRCC. ORR (95% CI) was 28.3% (16.8-42.3) with favorable and 23.2% (15.8-32.1) with intermediate/poor IMDC risk and 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS<1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts; 6% discontinued due to TRAEs. 6 pts died due to AEs, 2 of which were TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in nccRCC, especially with papillary or unclassified histology. Safety profile of pembro was generally as expected. Clinical trial information: NCT02853344.

Tumour immune microenvironment in primary and metastatic papillary renal cell carcinoma

“…Among RCC types, most studies assessing efficacy of immune therapy have focused on ccRCC . Variable preliminary results on the performance of immune check‐point inhibitors in non‐ccRCC are forthcoming in two studies . McDermott et al .…”

Real-world evidence on first-line treatment for metastatic renal cell carcinoma with non-clear cell and sarcomatoid histologies: are sunitinib and pazopanib interchangeable?

“…One evaluated atezolizumab plus bevacizumab and showed a response rate of 25% for nccRCC [29]. In the other, pembrolizumab was associated with response rates of 25.4% with papillary, 9.5% with chromophobe and 34.6% with unclassified nccRCC [30]. Certainly, in order to improve the outcomes in these subgroups of patients, the distinct behaviour of each histologic subtype needs to be recognised.…”

Evolving Epidemiologic Trends of Renal Cell Cancer by Histologic Subtype: An Updated Analysis of the California Cancer Registry

“…Small retrospective analyses do suggest a response to immune checkpoint inhibitor therapy in patients with nccRCC [17]. More recently, pembrolizumab has been studied in a singlearm, open-label, Phase 2 study (KEYNOTE-427), with a cohort of nccRCC patients who were treatment naïve [18]. This study of 165 patients demonstrated an objective response rate (ORR) of 24.8% overall; there was a suggestion towards differences in responses by subtype, with an ORR of 25.4% seen in patients with papillary subtype and of 9.5% seen in patients with chromophobe subtype.…”