First-line pembrolizumab active in both clear cell, non-clear cell advanced kidney cancer
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Pembrolizumab monotherapy showed promising antitumor activity and durable response rates as initial treatment for both clear cell and non-clear cell advanced renal cell carcinoma.
In addition, pembrolizumab (Keytruda, Merck) appeared safe, exhibiting a safety profile similar to that seen in other tumor types, according to results of the phase 2 KEYNOTE-427 trial published in Journal of Clinical Oncology.
“Our research had two main goals,” David F. McDermott, MD, chief of medical oncology at Beth Israel Deaconess Medical Center, told Healio. “When the trial was designed, we understood that PD-1 blockade was active after the failure of VEGF blockade, so we aimed to understand the antitumor activity of pembrolizumab in treatment-naive patients with metastatic renal cell carcinoma. In addition, patients with non-clear cell renal cell carcinoma were excluded from PD-1 blockade trials based on historical evidence that cytokine-based immunotherapy was inactive.”
Clear cell renal cell carcinoma
As Healio previously reported, McDermott and colleagues assessed the efficacy, safety and tolerability of pembrolizumab among 110 patients (median age, 64 years; 78.2% men) with advanced clear cell renal cell carcinoma in cohort A of the open-label, single-arm KEYNOTE-427 trial.
Patients received 200 mg pembrolizumab every 3 weeks for no more than 2 years. Researchers assessed responses at week 12 and every 6 weeks thereafter after until week 54, when they switched to assessments every 12 weeks.
Objective response rate by RECIST version 1.1 served as the primary endpoint. Secondary endpoints included duration of response, PFS, OS, safety and tolerability.
Median time from baseline to data cutoff was 35.9 months (range, 29.5-40.3).
Results showed an ORR of 36.4% (95% CI, 27.4-46.1). Four patients (3.6%) had complete responses and 36 (32.7%) had partial responses. The disease control rate was 58.2% (95% CI, 48.4-67.5).
Median time to response was 2.8 months (range, 2.5-12.9) and median duration of response was 18.9 months (range, 2.3-36.4+), with Kaplan-Meier estimates showing 64.1% of patients maintaining response for at least 1 year. Researchers observed decreases in target lesions in 68.2% of patients, and 30.9% had reductions of at least 60%.
In addition, researchers observed median PFS of 7.1 months (95% CI, 5.6-11) and a PFS rates of 37.6% at 1 year and 22.3% at 2 years. Although median OS was not reached, OS rates were 88.2% at 1 year and 70.8% at 2 years.
Durable responses were observed across all International Metastatic RCC Database (IMDC) risk groups.
Grade 3 to grade 5 treatment-associated adverse events occurred among 30% of patients, including colitis (5.5%) and diarrhea (3.6%). One patient died of treatment-associated pneumonitis.
Non-clear cell renal cell carcinoma
Cohort B of KEYNOTE-427 included 165 patients (median age, 62 years; 66.1% men) with advanced non-clear cell renal cell carcinoma who received 200 mg pembrolizumab every 3 weeks for up to 2 years.
Most patients (71.5%) had confirmed papillary tumors, whereas 15.8% had unclassified and 12.7% had chromophobe renal cell carcinoma tumors. About two-thirds (67.9%) had IMDC intermediate-risk or poor-risk status , and 61.8% had a PD-L1 combined positive score (CPS) of at least 1 (61.8%).
ORR by RECIST version 1.1 served as the primary endpoint.
Median time from baseline to data cutoff was 31.5 months (range, 22.7-38.8).
Researchers reported an ORR of 26.7% (95% CI, 20.1-34.1). Mediation time to response was 2.8 months and median duration of response was 29 months, with 59.7% of responses lasting 1 year or longer. The ORR among patients with a PD-L1 CPS of at least 1 was 35.3% vs. 12.1% for those with a PD-L1 CPS of less than 1.
ORRs by histology were 30.8% (95% CI, 14.3-51.8) for unclassified tumors, 28.8% (95% CI, 20.8-37.9) for papillary tumors and 9.5% (95% CI, 1.2-30.4) for chromophobe tumors.
Median overall PFS was 4.2 months (95% CI, 2.9-5.6), with PFS rates of 24.7% at 1 year and 18.6% at 2 years. Median overall OS was 28.9 months (95% CI, 24.3 to not reached), with OS rates of 73.2% at 1 year and 58.4% at 2 years.
Treatment-associated adverse events occurred among 69.7% of patients, the most common of which included pruritus (20%) and hypothyroidism (14.5%). Two patients died of treatment-associated adverse events, including pneumonitis and cardiac arrest.
“The KEYNOTE-427 trial shows that PD-1 blockade is active in both clear cell and non-clear cell renal cell carcinoma,” McDermott said. “It likely drives much of the benefit for PD-1-based combination therapy in clear cell renal cell carcinoma. We are now working to understand which patients benefit most from single-agent therapy and what factors drive resistance to PD-1 blockade.”
References:
McDermott DF, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02363.
McDermott DF, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02365.
For more information:
David F. McDermott, MD, can be reached at Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215; email: dmcdermo@bidmc.harvard.edu.
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