Interim results from cohort A of KEYNOTE-427, a phase II trial evaluating pembrolizumab (Keytruda) as first-line treatment for advanced clear cell renal cell carcinoma (RCC), were presented by McDermott et al at the 2018 ASCO Annual Meeting (Abstract 4500).
Interim data showed an overall response rate (ORR) of 38.2% (95% confidence interval [CI] = 29.1–47.9) in patients who received pembrolizumab monotherapy as first-line therapy, the primary endpoint of the study. In a prespecified, exploratory subgroup analysis based on programmed cell death-ligand 1 (PD-L1 status), ORR was 50.0% (95% CI = 34.9–65.1) in patients whose tumors expressed PD-L1 (CPS ≥ 1). In a prespecified exploratory subgroup analysis based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model, ORR was 42.0% (95% CI = 30.2–54.5) in patients with intermediate/poor prognostic risk. This is the first presentation of phase II data for an anti–programmed cell death protein 1 (PD-1) monotherapy as first-line treatment for advanced clear cell RCC.
“Until now, there have been limited data evaluating anti–PD-1 monotherapy in the first-line treatment of advanced clear cell renal cell cancer,” said David F. McDermott, MD, lead study investigator and Director, Biologic Therapy and Cutaneous Oncology Programs, Beth Israel Deaconess Medical Center; Leader, Kidney Cancer Program, Dana-Farber/Harvard Cancer Center; Professor of Medicine, Harvard Medical School. “With an overall response rate of nearly 40% as monotherapy, these data from KEYNOTE-427 are encouraging for clinicians and for patients living with this difficult-to-treat cancer.”
Additional Data from KEYNOTE-427
KEYNOTE-427 is a single-arm, open-label, nonrandomized, multicohort, phase II study evaluating the safety and efficacy of pembrolizumab as monotherapy in patients with advanced RCC who have not received prior systemic therapy. Data presented at ASCO was from cohort A, which includes patients with advanced clear cell RCC (n = 110). The primary endpoint is ORR, according to RECIST v1.1, as assessed by independent central review. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety and tolerability.
With a median follow-up of 12.1 months (range, 2.5–16.8), pembrolizumab demonstrated an ORR of 38.2% (95% CI = 29.1–47.9), with a complete response rate of 2.7% and a partial response rate of 35.5%. Additionally, the DCR was 59.1% (95% CI = 49.3–68.4), and 67.2% of patients experienced a reduction in tumor burden. The median time to response was 2.8 months (range, 2.5–10.3) and, at the time of analysis, median DOR was not yet reached (range, 1.4+ to 12.5). Responses lasting for 6 months or more were observed in 74.8% of patients. In an analysis of PFS and OS endpoints, the median PFS was 8.7 months (95% CI = 6.7–12.2) and the 6-month PFS rate was 60.2%; OS was not reached (95% CI = not reached) and the 6-month OS rate was 92.7%.
ORR was also assessed in several prespecified, exploratory subgroups. In an analysis based on PD-L1 status, patients whose tumors expressed PD-L1 (CPS ≥ 1) (n = 46) had an ORR of 50.0% (95% CI = 34.9–65.1), with a complete response rate of 6.5% and a partial response rate of 43.5%. In patients whose tumors did not express PD-L1 (CPS < 1) (n = 53), ORR was 26.4% (95% CI = 15.3–40.3) (all responses were partial responses). Additionally, data were analyzed based on IMDC risk groups. In patients with favorable IMDC risk (n = 41), ORR was 31.7% (95% CI = 18.1–48.1). In patients with intermediate/poor IMDC risk (n = 69), ORR was 42.0% (95% CI = 30.2–54.5).
The safety of pembrolizumab was consistent with what has been seen in previous trials among patients treated with pembrolizumab monotherapy. Treatment-related grade 3–5 adverse events were reported in 22.7% of patients. The most common treatment-related adverse events with an incidence of 10% or more were pruritus (27.3%), fatigue (24.5%), diarrhea (19.1%), rash (15.5%), arthralgia (12.7%), and hypothyroidism (10%). The most common immune-mediated adverse events of any grade were hypothyroidism (10.9%), hyperthyroidism (4.5%), pneumonitis (4.5%), colitis (2.7%), hepatitis (1.8%), severe skin reaction (1.8%), and myositis (1.8%). Twelve patients discontinued treatment due to treatment-related adverse events. There was one treatment-related death due to pneumonitis.
KEYNOTE-427 enrolled 275 patients with advanced RCC across two cohorts: patients with clear cell RCC (cohort A) or patients with non–clear cell RCC (cohort B). Patients in both cohorts received pembrolizumab (200 mg fixed dose intravenously every 3 weeks) until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
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