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

Abstract

PURPOSE Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

Immune Checkpoint Inhibitor in First-Line Treatment of Metastatic Renal Cell Carcinoma: A Review of Current Evidence and Future Directions

“…Pembrolizumab may be a possible treatment option to TKI in those with favourable-risk disease with manageable toxicities. However, this study is limited by its single-arm design, therefore a phase III trial would be required to compare its efficacy and safety with sunitinib or ipilimumab with nivolumab (26).…”

New approaches to first-line treatment of advanced renal cell carcinoma

“… 35 In single-arm ICI monotherapy studies (phase Ib/II) of avelumab, pembrolizumab, and nivolumab, median PFS was 8.3 months, 7.1 months, and not determined, respectively, while ORR was 16%, 36%, and 17%, respectively. 33 , 34 , 36 …”

Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

“…Enobosarm in combination with CDK4/6 inhibitors has also been shown to be efficacious in the setting of endocrine or CDK4/6 inhibitor-resistant breast cancer models (which retain the expression of AR), suggesting that AR agonism may partially restore sensitivity to CDK4/6 inhibitors, thus positing that this combination may be an effective therapeutic strategy in the second-line treatment of ER+ metastatic breast cancer [ 16 ]. Together, these findings provided the motivation behind the phase III registration ARTEST study (ClinicalTrials.gov identifier NCT04869943) of enobosarm in endocrine therapy and CDK4/6 inhibitor-resistant ER+ metastatic breast cancer patients [ 133 ].…”