The FDA ( Food and Drug Administration ) has approved Keytruda ( Pembrolizumab ), an anti-PD-1 therapy, in combination with Inlyta ( Axitinib ), a tyrosine kinase inhibitor, for the first-line treatment of patients with advanced renal cell carcinoma ( RCC ).
The approval was based on data from the pre-specified interim analysis of KEYNOTE-426, a randomized, multi-center, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC.
Patients were enrolled regardless of PD-L1 tumor expression status.
Randomization was stratified by International Metastatic RCC Database Consortium ( IMDC ) risk categories ( favorable versus intermediate versus poor ) and geographic region ( North America versus Western Europe versus Rest of the World ).
Patients with active autoimmune disease requiring systemic immunosuppression within the last two years were ineligible.
Patients were randomized ( 1:1 ) to one of the following treatment arms: Pembrolizumab 200 mg intravenously every three weeks up to 24 months in combination with Axitinib 5 mg orally, twice daily ( n=432 ), or Sunitinib 50 mg orally, once daily for four weeks and then off treatment for two weeks ( n=429 ).
Among the 861 patients, the study population characteristics were: median age of 62 years ( range, 26 to 90 ); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline Karnofsky Performance Status ( KPS ) of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate, and 13% poor.
Treatment with the Pembrolizumab-Axitinib combination continued until RECIST v1.1 ( modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ )-defined progression of disease or unacceptable toxicity.
The main efficacy outcome measures were OS and PFS as assessed by BICR according to modified RECIST v1.1. Additional efficacy outcome measures included ORR, as assessed by BICR.
The trial demonstrated statistically significant improvements in overall survival ( OS ), progression-free survival ( PFS ) and objective response rate ( ORR ) in patients randomized to receive the Pembrolizumab - Axitinib combination compared to Sunitinib.
With a median follow-up time of 12.8 months ( range, 0.1 to 22 months ), overall survival was significantly improved in patients who received the Pembrolizumab - Axitinib combination compared to Sunitinib ( hazard ratio, HR=0.53 [ 95% CI, 0.38-0.74 ]; p less than 0.0001 ).
Estimated 12-month OS rates were 90% ( 95% CI, 86-92 ) with the Pembrolizumab - Axitinib combination versus 78% ( 95% CI, 74-82 ) with Sunitinib.
Median OS was not reached with either treatment regimen.
Progression-free survival was also significantly improved with the Pembrolizumab - Axitinib combination compared to Sunitinib ( HR=0.69 [ 95% CI, 0.57-0.84 ]; p=0.0001 ).
Median PFS was 15.1 months ( 95% CI, 12.6-17.7 ) in patients receiving the Pembrolizumab - Axitinib combination versus 11.1 months ( 95% CI, 8.7-12.5 ) with Sunitinib.
In the study, the objective response rate was 59% for patients who received the Pembrolizumab - Axitinib combination ( 95% CI, 54-64 ) and 36% for those who received Sunitinib ( 95% CI, 31-40 ) ( p less than 0.0001 ), with a complete response rate of 6% and 2% and a partial response rate of 53% and 34%, for patients receiving the Pembrolizumab - Axitinib combination versus Sunitinib, respectively.
In KEYNOTE-426, the safety of Pembrolizumab in combination with Axitinib was investigated in patients with previously untreated, advanced RCC.
The median duration of exposure to the combination therapy of Pembrolizumab and Axitinib was 10.4 months ( range, 1 day to 21.2 months ).
Fatal adverse reactions occurred in 3.3% of patients receiving Pembrolizumab in combination with Axitinib.
Serious adverse reactions occurred in 40% of patients receiving Pembrolizumab in combination with Axitinib.
Serious adverse reactions in greater than or equal to 1% of patients receiving Pembrolizumab in combination with Axitinib included hepatotoxicity ( 7% ), diarrhea ( 4.2% ), acute kidney injury ( 2.3% ), dehydration ( 1% ), and pneumonitis ( 1% ).
Permanent discontinuation due to an adverse reaction of either Pembrolizumab or Axitinib occurred in 31% of patients; 13% Pembrolizumab only, 13% Axitinib only, and 8% both drugs.
The most common adverse reaction ( more than 1% ) resulting in permanent discontinuation of Pembrolizumab, Axitinib or the combination was hepatotoxicity ( 13% ), diarrhea / colitis ( 1.9% ), acute kidney injury ( 1.6% ), and cerebrovascular accident ( 1.2% ).
The most common adverse reactions ( greater than or equal to 20% ) in patients receiving in patients receiving Pembrolizumab and Axitinib were diarrhea ( 56% ), fatigue / asthenia ( 52% ), hypertension ( 48% ), hepatotoxicity ( 39% ), hypothyroidism ( 35% ), decreased appetite ( 30% ), palmar-plantar erythrodysesthesia ( 28% ), nausea ( 28% ), stomatitis / mucosal inflammation ( 27% ), dysphonia ( 25% ), rash ( 25% ), cough ( 21% ), and constipation ( 21% ).
Pembrolizumab is an anti-PD-1 therapy that works by increasing the ability of the immune system to help detect and fight tumor cells.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. ( Xagena )
Source: Merck, 2019