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 clear cell renal cell carcinoma.
In a separate cohort of the study, pembrolizumab was examined as first-line treatment in advanced non–clear cell renal cell carcinoma.
Study Details
In the study, 110 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, 52 patients (47.3%) had a PD-L1 combined positive score (CPS) ≥ 1. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk status was favorable in 42 patients (38.2%) and intermediate/poor in 68 (61.8%). 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 35.9 months (range = 29.5–40.3 months). Objective response was observed in 40 patients (36.4%), with complete response in 4 (3.6%). The disease control rate, including patients with stable disease for ≥ 6 months, was 58.2%. Overall, 68.2% of patients had a decrease in target lesions, including 30.9% with a reduction ≥ 60%.
Median duration of response was 18.9 months (range = 2.3–37.6+ months), with responses lasting ≥ 12 months in 64.1% of responders. Median progression-free survival was 7.1 months (95% confidence interval [CI] = 5.6–11.0 months), with 12- and 24-month rates of 37.6% and 22.3%. Median overall survival was not reached, with 12- and 24-month rates of 88.2% and 70.8%.
KEY POINTS
- Pembrolizumab produced an objective response in 36.4% of patients, with a median response duration of 18.9 months.
- Responses were observed irrespective of IMDC risk status or PD-L1 expression status.
Responses According to Risk Category and PD-L1 Expression
Among patients with favorable IMDC risk, the objective response rate was 31.0%, with complete response in 2.4%. Median duration of response was 18.2 months (range = 4.2–37.6+ months), with 61.5% of responses lasting ≥ 12 months. Median progression-free survival was 9.7 months (95% CI = 5.6–12.4 months), with 12- and 24-month rates of 40.9% and 19.1%. The 12- and 24-month overall survival rates were 97.6% and 88.0%.
In the intermediate/poor IMDC risk group, the objective response rate was 39.7%, with complete response in 4.4%. Median duration of response was not reached (range = 2.3–34.3+ months), with responses lasting ≥ 12 months in 65.5% of responders. Median progression-free survival was 6.9 months (95% CI = 3.3–11.0 months), with 12- and 24-month rates of 35.5% and 24.4%. The 12- and 24-month overall survival rates were 82.4% and 60.3%.
Among patients with PD-L1 CPS ≥ 1, the objective response rate was 44.2%, with complete response in 5.8%. Median duration of response was 18.2 months (range = 2.8–34.3+ months), with responses lasting ≥ 12 months in 65.2% of responders. Median progression-free survival was 9.7 months (95% CI = 6.7–16.3 months), with 12- and 24-month rates of 40.3% and 26.2%. The 12- and 24-month overall response rates were 92.3% and 78.7%.
For patients with CPS < 1, objective response was observed in 29.3%, with complete response in 1.7%. Median duration of response was 19.7 months (range = 2.3–37.6 months), with responses lasting ≥ 12 months in 62.7% of responders. Median progression-free survival was 6.9 months (95% CI = 3.3–10.9 months), with 12- and 24-month rates of 35.3% and 18.7%. Overall survival rates at 12 and 24 months were 84.5% and 63.7%.
Adverse Events
The most common treatment-related adverse events of any grade were pruritus (30.0%), fatigue (29.1%), and diarrhea (22.7%). Grade ≥ 3 treatment-related adverse events were observed in 30.0% of patients, with the most common being colitis (5.5%) and diarrhea (3.6%). Immune-mediated adverse events of any grade occurred in 32.7% of patients (grade ≥ 3 in 15.5%), with the most common being hypothyroidism (13.6%), colitis (6.4%), and hyperthyroidism (5.5%). Adverse events led to death in three patients, with death considered related to treatment in one patient (due to pneumonia).
The investigators concluded, “Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced clear cell renal cell carcinoma, with durable responses across International Metastatic RCC Database Consortium categories. [The] safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.”
David F. McDermott, MD, of Beth Israel Deaconess Medical Center, is the corresponding author for the Journal of Clinical Oncology article.
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.
