Long-Term Follow-Up Data Reinforce Efficacy of Pembrolizumab-Based Combinations in Advanced Renal Cell Carcinoma
核心洞察
Extended follow-up from the KEYNOTE-426 trial demonstrates sustained overall survival and progression-free survival benefits with pembrolizumab plus axitinib versus sunitinib at 5 years in clear cell renal cell carcinoma (搜索) patients.
The combination of lenvatinib plus pembrolizumab shows durable responses across different patient populations, with treatment-naïve patients achieving a 77.5% objective response rate and median overall survival of 55.8 months.
Both pembrolizumab-based combinations maintain manageable safety profiles with no new safety signals identified in long-term follow-up analyses.
Extended follow-up data from two major clinical trials continue to demonstrate the sustained efficacy of pembrolizumab-based combination therapies in patients with advanced renal cell carcinoma (搜索) (RCC), reinforcing their position as standard-of-care first-line treatments.
KEYNOTE-426 Five-Year Analysis Shows Sustained Benefits
Results from a 5-year analysis of the phase 3 KEYNOTE-426 trial presented at the 2023 ASCO Annual Meeting showed that pembrolizumab plus axitinib maintained significant overall survival (OS) and progression-free survival (PFS) benefits over sunitinib monotherapy in patients with clear cell renal cell carcinoma (搜索).
At a median follow-up of 67.2 months, the median PFS in the intention-to-treat population receiving the doublet was 15.7 months versus 11.1 months with sunitinib monotherapy, representing a 31% reduction in the risk of disease progression or death (HR, 0.69; 95% CI, 0.59-0.81). The 60-month PFS rates were 18.3% versus 7.3%, respectively.
The median OS with pembrolizumab plus axitinib was 47.2 months compared to 40.8 months with sunitinib alone, translating to a 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.71-0.99). The 60-month OS rates in the investigative and control arms were 41.9% and 37.1%, respectively.
"These improvements with the combination are observed despite the high percentage of subsequent therapy received in both arms, but especially in the sunitinib arm," said Dr. Brian I. Rini, lead study author and professor of medicine in the Division of Hematology Oncology at Vanderbilt University Medical Center. "These data continue to support pembrolizumab plus axitinib as a standard of care for this population."
Response Rates and Duration
The doublet induced an objective response rate (ORR) of 60.6% in the intention-to-treat population, comprised of a complete response rate of 11.6%, partial response rate of 49.1%, and stable disease rate of 22.7%. In comparison, the sunitinib arm achieved an ORR of 39.6%, with a 4.0% complete response rate and 35.7% partial response rate.
The duration of response with the combination was 23.6 months versus 15.3 months with monotherapy, with 26.0% and 14.4% of patients, respectively, remaining in response at 60 months.
Risk-Stratified Outcomes
In patients with favorable-risk disease, the median OS was 60.3 months with pembrolizumab plus axitinib versus 62.4 months with sunitinib (HR, 1.10; 95% CI, 0.79-1.54). However, the combination showed a PFS advantage with a median of 20.7 months versus 17.9 months (HR, 0.76; 95% CI, 0.57-1.02).
For patients with intermediate- or poor-risk disease, there was a strong OS signal favoring the combination. The median OS was 42.2 months versus 29.3 months with sunitinib (HR, 0.76; 95% CI, 0.62-0.93), with 60-month OS rates of 38.0% and 30.4%, respectively.
Lenvatinib Plus Pembrolizumab Shows Durable Responses
Long-term follow-up from the phase 1b/2 Study 111/KN146 trial, presented at the 2023 Kidney Cancer Research Summit, demonstrated continued benefit with lenvatinib plus pembrolizumab across different patient populations with metastatic RCC.
Treatment-naïve patients achieved an ORR of 77.5% compared with 52.9% in previously treated, immune checkpoint inhibitor-naïve patients and 58.7% in ICI-pretreated patients. The median duration of response was 24.2 months, 9 months, and 14.1 months, respectively.
"The responses remained durable in a subset of patients who were previously treated but ICI naïve, but also in patients who received ICIs as prior systemic therapy," said Dr. Chung-Han Lee, an assistant attending physician at Memorial Sloan Kettering Cancer Center.
Survival Outcomes by Treatment History
In the treatment-naïve group, the median PFS was 22.1 months, with 18-month, 24-month, and 30-month PFS rates of 67.2%, 48.0%, and 33.6%, respectively. The median OS reached 55.8 months in this population.
For previously treated, ICI-naïve patients, the median PFS was 11.8 months with a median OS of 30.3 months. In ICI-pretreated patients, the median PFS was 11.6 months with a median OS of 32.1 months.
Safety Profile Remains Manageable
No new safety signals were identified with longer follow-up in either study. In the lenvatinib plus pembrolizumab study, grade 3 or higher treatment-related adverse events were reported in 66.2% of patients overall, with the most common being hypertension (22.1%), proteinuria (11.0%), and diarrhea (6.9%).
For treatment-naïve patients, the median time to first dose reduction with lenvatinib was 6.5 months, compared to 2.9 months for previously treated ICI-naïve patients and 2.1 months for ICI-pretreated patients.
Clinical Implications
These extended follow-up analyses provide robust evidence supporting the long-term efficacy of pembrolizumab-based combinations in advanced RCC. The sustained benefits observed across different risk groups and treatment histories reinforce the role of these regimens as preferred first-line options for patients with metastatic disease.
The data are particularly notable given the high rates of subsequent therapy received by patients in both studies, suggesting that the initial treatment choice continues to impact long-term outcomes despite the availability of multiple effective subsequent treatments in the RCC landscape.