Updated results from Cohort G of the phase 2 KEYNOTE-021 trial investigating Pembrolizumab ( Keytruda ), an anti-PD-1 therapy, in combination with Pemetrexed and Carboplatin ( Pem/Carbo ) in patients with previously untreated advanced nonsquamous non-small cell lung cancer ( NSCLC ), with or without PD-L1 expression, were presented at European Society for Medical Oncology ( ESMO ) Congress.
With an additional five months of follow-up, significant improvements observed in prior analyses were maintained, including improvements in overall response rate ( ORR ) and progression-free survival ( PFS ) for Pembrolizumab plus Pem/Carbo compared to Pem/Carbo alone.
With a median of 18.7 months of follow-up, more than half of patients in the Pembrolizumab combination arm responded to treatment compared to approximately one-third in the Pem/Carbo arm ( ORR of 56.7% vs. 31.7% [ 95% CI, 7.2-40.9 ], p=0.0029 ).
The risk of progression or death continued to be reduced by nearly half with Pembrolizumab plus Pem/Carbo compared to Pem/Carbo alone ( hazard ratio, HR 0.54 [ 95% CI, 0.33-0.88, p=0.0067 ] ).
In addition, despite the crossover design, a trend in improvement in overall survival continues to be seen for Pembrolizumab plus Pem/Carbo compared to Pem/Carbo alone ( HR, 0.59 [ 95% CI, 0.34-1.05, p=0.03 ] ).
KEYNOTE-021, Cohort G
Cohort G1 of the multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study evaluated the efficacy and safety of Pembrolizumab in combination with Pemetrexed and Carboplatin compared with Pemetrexed and Carboplatin in 123 patients with metastatic, nonsquamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting.
Patients were randomized to receive Pembrolizumab plus Pem/Carbo ( n=60 ) or Pem/Carbo alone ( n=63 ). Patients in the Pembrolizumab plus Pem/Carbo combination group received Pembrolizumab ( 200 mg ), Pemetrexed ( 500 mg/m2 ) and Carboplatin ( AUC 5 mg/mL/min ) every three weeks for four cycles followed by Pembrolizumab every three weeks.
In the Pem/Carbo group, patients received Pemetrexed ( 500 mg/m2 ) and Carboplatin ( AUC 5 mg/mL/min ) alone for four cycles.
At the investigator’s discretion, maintenance Pemetrexed ( 500 mg/m2 ) every three weeks was permitted in both treatment groups.
The major efficacy outcome measure was ORR as assessed by blinded independent central review ( BICR ) using Response Evaluation Criteria in Solid Tumors ( RECIST ) version 1.1.
Additional efficacy outcome measures were progression-free survival as assessed by BICR using RECIST 1.1, duration of response and overall survival.
Data presented at ESMO include five months of additional follow-up from prior presentations, for a median follow-up of 18.7 months ( range: 0.8-29.0 ).
In this analysis, Pembrolizumab plus Pem/Carbo combination group ( n=60 ) continued to show improvement over the group receiving Pem/Carbo alone ( n=63 ) in overall response rate, duration of response and progression-free survival.
ORR was 56.7% in the Pembrolizumab plus Pem/Carbo combination group compared to 31.7% in the Pem/Carbo group ( 95% CI, 7.2-40.9; p=0.0029 ).
The median duration of response had not been reached in either arm ( range: 1.4+ to 22.7+ with Pembrolizumab plus Pem/Carbo and 2.8 to 23.7+ in the Pem/Carbo group ).
At the time of analysis, 50% of responses were ongoing in the Pembrolizumab plus Pem/Carbo combination group compared to 40% in the Pem/Carbo group.
The patients in the Pembrolizumab plus Pem/Carbo arm had a 46% reduction in progression or death risk compared with Pem/Carbo alone ( HR 0.54 [95% CI, 0.33-0.88, p=0.0067 ] ).
The median progression-free survival was twice as long in the group receiving Pembrolizumab, with 19.0 months ( 95% CI, 8.5-not reached ) for Pembrolizumab plus Pem/Carbo compared to 8.9 months in the Pem/Carbo group ( 95% CI, 6.2-11.8 ).
At 12 and 18 months, progression-free survival in the Pembrolizumab plus Pem/Carbo combination group was 57% and 52%, respectively, compared to 37% and 29% in the Pem/Carbo group.
A trend toward improvement in overall survival ( OS ) was observed in the Pembrolizumab plus Pem/Carbo arm: the combination was associated with a 41% reduction in the risk of death ( HR, 0.59 [ 95% CI, 0.34-1.05, p=0.03 ] ).
The median overall survival was not reached ( range: 22.8-not reached ) in the Pembrolizumab plus Pem/Carbo combination group compared to 20.9 months ( range: 14.9-not reached ) in the Pem/Carbo group.
The safety findings were consistent with previously presented results from this study.
Grade 3-5 treatment-related adverse events ( TRAEs ) occurred in 41% of patients in the Pembrolizumab plus Pem/Carbo group.
TRAEs of any grade with an incidence of 15% or more in the Pembrolizumab plus Pem/Carbo group were fatigue ( 68% ), nausea ( 59% ), anemia ( 34% ), vomiting ( 31% ), rash ( 27% ), diarrhea ( 24% ), decreased appetite ( 22% ), AST increased ( 19% ), constipation ( 19% ), dysgeusia ( 19% ), ALT increased ( 17% ), blood creatinine increased ( 17% ), decreased neutrophils ( 17% ) and lacrimation increased ( 15% ).
The most common immune-mediated adverse events of any grade in patients receiving Pembrolizumab plus Pem/Carbo were hypothyroidism ( 14% ), hyperthyroidism ( 8% ), pneumonitis ( 7% ), infusion reactions ( 2% ), severe skin toxicity ( 2% ) and colitis ( 2% ).
There was one treatment-related death in a patient receiving Pembrolizumab plus Pem/Carbo and two in patients receiving Pem/Carbo alone. ( Xagena )
Source: Merck ( MSD ), 2017