As reported in the Journal of Clinical Oncology by McDermott et al, findings in a cohort of the phase II KEYNOTE-427 study showed that pembrolizumab monotherapy produced durable responses as first-line treatment for advanced non–clear cell renal cell carcinoma.
In a separate cohort of the study, pembrolizumab has been examined as first-line treatment in advanced clear cell renal cell carcinoma.
Study Details
In the study, 165 patients with locally advanced or metastatic disease from sites in 10 countries received pembrolizumab at 200 mg every 3 weeks until disease progression, unacceptable toxicity, or for up to 24 months. Overall, 102 patients (61.8%) had a PD-L1 combined positive score (CPS) ≥ 1. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk status was favorable in 53 patients (32.1%) and intermediate/poor in 112 (67.9%).
In total, 71.5% of patients had papillary, 12.7% had chromophobe, and 15.8% had unclassified histology. The primary endpoint was objective response rate on Response Evaluation Criteria in Solid Tumors version 1.1.
Responses in Total Population
Median time from enrollment to data cutoff (February 2020) was 31.5 months (range = 22.7–38.8 months). Objective response was observed in 44 patients (26.7%), with complete response in 11 (6.7%). The disease control rate, including patients with stable disease for ≥ 6 months, was 43.0%. Overall, 55.2% of patients had a decrease in target lesions, including 12.1% with a reduction of ≥ 80%.
The median duration of response was 29.0 months (range = 2.8–31.6+ months), with responses lasting ≥ 12 months in 59.7% of responders. Median progression-free survival was 4.2 months (95% confidence interval [CI] = 2.9–5.6 months), with 12- and 24-month rates of 24.7% and 18.6%. Median overall survival was 28.9 months, with 12- and 24-month rates of 73.2% and 58.4%.
Responses According to Risk Category, PD-L1 Expression, and Histology
Among patients with favorable IMDC risk, the objective response rate was 31.0%, with complete response in 13.2%. Median duration of response was 11.0 months (range = 2.8–27.7+ months). Median progression-free survival was 5.3 months (95% CI = 2.9–8.2 months), and median overall survival was not reached (95% CI = 30.4 months–not reached).
In the intermediate/ poor IMDC risk group, the objective response rate was 24.1%, with complete response in 3.6%. Median duration of response was 29.0 months (range = 2.8–31.6+ months). Median progression-free survival was 4.0 months (95% CI = 2.8–6.2 months). Median overall survival was 24.5 months (95% CI = 16.7–30.0 months).
KEY POINTS
- Pembrolizumab produced objective response in 26.7% of patients, with a median response duration of 29.0 months.
- Responses were observed irrespective of IMDC risk status, PD-L1 expression status, or histology.
Among patients with PD-L1 CPS ≥ 1, the objective response rate was 35.3%, with complete response in 7.8%. Median duration of response was 29.0 months (range = 2.8+–31.6+ months). Median progression-free survival was 5.6 months (95% CI = 2.9–8.3 months). Median overall survival was 30.0 months (95% CI = 22.9–not reached).
For patients with CPS < 1, objective response was observed in 12.1%, with complete response in 5.2%. Median duration of response was 9.5 months (range = 2.8–26.0+ months). Median progression-free survival was 3.7 months (95% CI = 2.8–4.2 months). Median overall survival was 26.6 months (95% CI = 19.2 months to not reached).
Among patients with papillary, chromophobe, and unclassified histology, objective response rates were 28.8%, 9.5%, and 30.8%; median response durations ranged from 29.0 months to not reached; and median progression-free and overall survival were 5.5 months (95% CI = 3.9–6.9 months) and 31.5 months (95% CI = 25.5 months–not reached), 3.9 months (95% CI = 2.6–6.9 months) and 23.5 months (95% CI = 9.3 months–not reached), and 2.8 months (95% CI = 2.8–5.1 months) and 17.6 months (95% CI = 7.5 months–not reached).
Among 38 patients with sarcomatoid differentiation, objective response was observed in 42.1%. Median duration of response was 15.3 months (range = 2.8+–29.5+ months), median progression-free survival was 6.9 months (95% CI = 2.8–15.4 months), and median overall survival was 25.5 months (95% CI = 13.1–30.0 months).
Adverse Events
The most common treatment-related adverse events of any grade were pruritus (20.0%) and hypothyroidism (14.5%). Treatment-related grade ≥ 3 adverse events occurred in 17% of patients, with the most common being colitis (1.8%) and fatigue (1.8%). Immune-mediated adverse events occurred in 32.7% of patients (grade ≥ 3 in 8.5%), with the most common being hypothyroidism (15.8%), hyperthyroidism (6.7%), colitis (2.4%), and hepatitis (2.4%). Adverse events led to death in eight patients, with death in two patients considered related to treatment (1 due to pneumonia and 1 due to cardiac arrest).
The investigators concluded, “First-line pembrolizumab monotherapy showed promising antitumor activity in non–clear cell renal cell carcinoma. The safety profile was similar to that observed in other tumor types.”
David F. McDermott, MD, of Beth Israel Deaconess Medical Center, is the corresponding author for the Journal of Clinical Oncology.
Disclosure: The study was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, and by a grant from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
