David F. McDermott, MD

As reported in two articles in the Journal of Clinical Oncology by David F. McDermott, MD, of Beth Israel Deaconess Medical Center, and colleagues, the phase II KEYNOTE-427 study showed that pembrolizumab monotherapy produced durable responses as first-line treatment in cohorts of patients with advanced clear cell renal cell carcinoma and patients with advanced non–clear cell renal cell carcinoma.^1,2

Clear Cell Cohort

Study Details: In the clear cell renal cell carcinoma cohort,¹ 110 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 an objective response rate on Response Evaluation Criteria in Solid Tumors (RECIST) 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). An objective response was observed in 40 patients (36.4%), with a complete response in 4 (3.6%). The disease control rate, including patients with stable disease for at least 6 months, was 58.2%. Overall, 68.2% of patients had a decrease in target lesions, including 30.9% with a reduction of at least 60%.

Median duration of response was 18.9 months (range = 2.3–37.6+ months), with responses lasting at least 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%.

Responses According to Risk Category and PD-L1 Expression: Among patients with a favorable IMDC risk status, the objective response rate was 31.0%, with a 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 at least 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 a complete response in 4.4%. Median duration of response was not reached (range = 2.3–34.3+ months), with responses lasting at least 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 a PD-L1 CPS ≥ 1, the objective response rate was 44.2%, with a complete response in 5.8%. Median duration of response was 18.2 months (range = 2.8–34.3+ months), with responses lasting at least 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 a PD-L1 CPS < 1, an objective response was observed in 29.3%, with a complete response in 1.7%. Median duration of response was 19.7 months (range = 2.3–37.6 months), with responses lasting at least 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, 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%), 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. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.”

Non–Clear Cell Cohort

Study Details: In the non–clear cell renal cell carcinoma cohort,² 165 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 CPS ≥ 1. 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% chromophobe, and 15.8% unclassified histology. The primary endpoint was an objective response rate on RECIST 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). An objective response was observed in 44 patients (26.7%), with a complete response in 11 (6.7%). The disease control rate, including patients with stable disease for at least 6 months, was 43.0%. Overall, 55.2% of patients had a decrease in target lesions, including 12.1% with a reduction of at least 80%. Median duration of response was 29.0 months (range = 2.8–31.6+ months), with responses lasting at least 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 a favorable IMDC risk, the objective response rate was 31.0%, with a 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), with 12- and 24-month rates of 22.7% and 16.5%. Median overall survival was not reached (95% CI = 30.4 months to not reached), with 12- and 24-month overall survival rates of 92.5% and 72.4%.

In the intermediate/poor IMDC risk group, the objective response rate was 24.1%, with a 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), with 12- and 24-month rates of 25.8% and 19.8%. Median overall survival was 24.5 months (95% CI = 16.7–30.0 months), with 12- and 24-month rates of 64.1% and 50.3%.

Among patients with a PD-L1 CPS ≥ 1, the objective response rate was 35.3%, with a complete response in 7.8%. Median duration of response was 29.0 months (range = 2.8+ to 31.6+ months). Median progression-free survival was 5.6 months (95% CI = 2.9–8.3 months), with 12- and 24-month rates of 32.4% and 24.3%. Median overall survival was 30.0 months (95% CI = 22.9 to not reached), with 12- and 24-month rates of 74.4% and 60.2%.

For patients with a PD-L1 CPS < 1, an objective response was observed in 12.1%, with a 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), with 12- and 24-month rates of 13.0% and 9.7%. Median overall survival was 26.6 months (95% CI = 19.2 months to not reached), with 12- and 24-month rates of 70.7% and 55.2%.

Among patients with papillary, chromophobe, and unclassified histologies, objective response rates were 28.8%, 9.5%, and 30.8%, respectively, and median response durations ranged from 29.0 months to not reached. Median progression-free survival was 5.5 months (95% CI = 3.9–6.9 months) among patients with papillary histology, 3.9 months (95% CI = 2.6–6.9 months) among those with chromophobe histology, and 23.5 months (95% CI = 9.3 months to not reached) among those with unclassified histology. Overall survival was 31.5 months (95% CI = 25.5 months to not reached), 2.8 months (95% CI = 2.8–5.1 months), and 17.6 months (95% CI = 7.5 months to not reached), respectively.

Among 38 patients with sarcomatoid differentiation, an objective response was observed in 42.1%. Median duration of response was 15.3 months (range = 2.8+ to 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, 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%), 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 to be related to treatment (one due to pneumonia and one 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.” 

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. Dr. McDermott has served as a consultant or advisor to Alkermes, Array BioPharma, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genentech/Roche, Iovance Biotherapeutics, Jounce Therapeutics, Lilly, Merck, Novartis, Peloton Therapeutics, and Pfizer; has received institutional research funding from Alkermes, Bristol Myers Squibb, Genentech, Merck, Novartis, Peloton Therapeutics, and Prometheus Laboratories; has held other relationships with BIDMC; and has held uncompensated relationships with Aveo and X4 Pharmaceuticals.

REFERENCES

1. McDermott DF, Lee JL, Bjarnason GA, et al: Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma. J Clin Oncol 39:1020-1028, 2021.

2. McDermott DF, Lee JL, Ziobro M, et al: Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol 39:1029-1039, 2021.