KEYNOTE-427: Pembrolizumab Shows Activity in Advanced Non–Clear Cell Kidney Cancer

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IMMUNOTHERAPY WITH the checkpoint inhibitor pembrolizumab may prove to be an effective option for patients with advanced non–clear cell renal cell carcinoma, according to results in cohort B of the KEYNOTE-427 trial, presented at the 2019 Genitourinary Cancers Symposium.1 Kidney cancers with a non–clear cell histology account for approximately 20% to 25% of cases, and data to guide treatment decisions in this population are limited. “Although studies show that programmed cell death protein 1 (PD-1) blockade is effective in clear cell renal cell carcinoma, less is known about this approach in non–clear cell renal cell carcinoma, said lead author David McDermott, MD, of Beth Israel Deaconess Medical Center, Boston.

David McDermott, MD

David McDermott, MD

There is currently no approved treatment for non–clear cell renal cell carcinoma in the United States. The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology in Kidney Cancer (NCCN Guidelines) currently recommend enrollment in clinical trials or treatment with sunitinib for patients with advanced non–clear cell renal cell carcinoma.

“Safe and effective treatment for non–clear cell renal cell carcinoma represents an unmet need,” Dr. McDermott told the audience.

Study Details

KEYNOTE-427, cohort B, was a single-arm, open-label, phase II trial. A total of 165 patients were treated with pembrolizumab. Baseline characteristics for the cohort were as expected for a late-stage kidney cancer trial. The majority were white (88%), two-thirds were male, and 68% had intermediate- or poor-risk disease. To be eligible, patients had to have a Karnofsky Performance Status (KPS) of at least 70%; and 75% had a KPS of at least 90%.


  • Approximately 20% to 25% of cases of kidney cancer are of a non–clear cell histology.
  • NCCN Guidelines recommend enrollment in clinical trials or sunitinib for patients with non–clear cell kidney cancer.
  • Safe and effective treatment remains an unmet need.

Patients included in the trial had not received previous systemic treatment for recurrent or metastatic non–clear cell renal cell carcinoma. During the study, they received pembrolizumab at 200 mg every 3 weeks or until disease progression or unacceptable toxicity.

Investigators reported that response rates were encouraging, especially in cases of papillary or undefined histology. There was a confirmed overall response rate of 24.8% (complete response, 4.8%; partial response, 20%). The disease control rate was 40.6%. Some durable responses were seen, and toxicity was manageable.

At a median follow-up of 11.1 months, the progression-free survival in the trial was 4.1 months, and the median overall survival was not reached. At 1 year, 72% of patients were alive.

Non–clear cell renal cell carcinoma is comprised of a diverse group of histologic types, including papillary (types 1 and 2), chromophobe, collecting duct, medullary, and translocation carcinoma.

Response rates were similar between International Metastatic Renal Cell Carcinoma Database Consortium favorable- and poor-risk groups (28.3% vs 23.2%, respectively), and complete responses were seen in both (9.4% vs 2.7%, respectively). 

In an exploratory analysis, programmed cell death ligand 1 (PD-L1) expression was associated with response. The overall response rate was 33.3% for patients in the PD-L1–high group (ie, ≥ 1%) compared with 10.3% in the PD-L1–low group (ie, < 1%). About two-thirds of patients enrolled in the trial were PD-L1–positive, suggesting that this therapy may benefit most patients with non–clear cell renal cell carcinoma, according to Dr. McDermott.

An analysis of response based on World Health Organization criteria for histology found that the overall response rate was 25.4% among 118 patients with the papillary subtype; 9.5% in 21 patients with chromophobe renal cell carcinoma; and 34.6% in 26 patients with unclassified histology. Complete responses were seen in all three groups.


  • Pembrolizumab showed activity in advanced non–clear cell kidney cancer.
  • Toxicity was as expected and manageable.
  • Further evaluation of pembrolizumab is warranted in advanced kidney cancer with non–clear cell histology.

Safety Profile

ABOUT TWO-THIRDS of patients experienced a treatment-related adverse event (64%). The most commonly reported adverse events were pruritus (18%), hypothyroidism (13%), fatigue (13%), and diarrhea (12%). Grade 3 to 5 treatment-related adverse events were reported in 11%, and 2 deaths were deemed treatment-related.

Immune-related adverse events were consistent with reports of pembrolizumab in other trials and other cancers. The most common immune-mediated adverse events of any grade included hypothyroidism (15%) and hyperthyroidism (7%). Ten patients (6%) discontinued therapy due to a treatment-related adverse event.

“We think the results of KEYNOTE-427 support further evaluation of the PD-1 blockade with pembrolizumab in patients with advanced non–clear cell kidney cancer,” Dr. McDermott said, adding that pembrolizumab should be considered an option for patients with non–clear cell renal cell carcinoma. 

DISCLOSURE: The KEYNOTE-427 trial was funded by Merck. Dr. McDermott is a consultant/advisor for Bristol-Myers Squibb, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, X4 Pharmaceuticals, and Array BioPharma; and has received research funding from Bristol-Myers Squibb and institutional research funding from Prometheus Laboratories.


1. McDermott DF, Lee J-L, Ziobro M, et al: First-line pembrolizumab monotherapy for advanced non-clear cell renal cell carcinoma: Results from KEYNOTE-427 cohort B. 2019 Genitourinary Cancers Symposium. Abstract 546. Presented February 16, 2019.

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