Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma

Abstract

Purpose: Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non-clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC.

Methods: Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1.

Results: Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest).

Conclusion: First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.

Trial registration: ClinicalTrials.gov NCT02853344.

FIG 1.

Maximum change from baseline in target lesions (A),^a time to response and response duration (B), and Kaplan-Meier estimate of DOR (C) based on blinded independent central review. ^aMaximum change from baseline in target lesions by central review was assessed for patients who received ≥ 1 dose of pembrolizumab, had baseline imaging with measurable disease per RECIST v1.1, and had a postbaseline assessment (n = 155). +, ongoing response; CR, complete response; DOR, duration of response; PD, progressive disease; PR, partial response.

FIG 2.

Kaplan-Meier curves for (A) progression-free survival and (B) overall survival. NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 3.

ORR by patient subgroup. ^aFive patients had missing PD-L1 status. CPS, combined positive score; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; ORR, objective response rate; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma.