The European Commission has approved Keytruda ( Pembrolizumab ), anti-PD-1 therapy, in combination with Pemetrexed ( Alimta ) and Platinum chemotherapy for the first-line treatment of metastatic nonsquamous non-small cell lung cancer ( NSCLC ) in adults whose tumors have no EGFR or ALK positive mutations.
This approval, the first in European Union for an anti-PD-1 therapy in combination with chemotherapy, is based on data from the pivotal phase 3 KEYNOTE-189 trial in patients with metastatic nonsquamous NSCLC regardless of PD-L1 tumor expression status, which has demonstrated a significant survival benefit for the combination of Pembrolizumab with chemotherapy as compared with standard-of-care chemotherapy alone, reducing the risk of death in these patients by half ( hazard ratio, HR=0.49 [ 95% CI, 0.38-0.64 ]; p less than 0.00001 ).
Keytruda has been approved at the dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
Keytruda is also approved in European Union as a monotherapy for the first-line treatment of metastatic squamous or nonsquamous NSCLC in patients whose tumors have high PD-L1 expression ( tumor proportion score [ TPS ] of 50% or more ) with no EGFR or ALK positive tumor mutations ( KEYNOTE-024 ) and for previously-treated patients with locally advanced or metastatic NSCLC whose tumors express PD-L1 ( TPS of 1% or more ) and who have received at least one prior chemotherapy regimen ( KEYNOTE-010 ).
The approval was based on data from KEYNOTE-189, a phase 3, multicenter, randomized, active-controlled, double-blind trial.
Key eligibility criteria were metastatic nonsquamous NSCLC, no prior systemic treatment for metastatic NSCLC, and no EGFR or ALK genomic tumor aberrations.
Patients with autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
Patients were randomized to receive Pembrolizumab 200 mg, Cisplatin or Carboplatin, and Pemetrexed intravenously every three weeks for four cycles followed by Pembrolizumab 200 mg for up to 24 months and Pemetrexed every three weeks ( n=410 ); or placebo with Cisplatin or Carboplatin and Pemetrexed intravenously every three weeks for four cycles followed by Pemetrexed every three weeks ( n=206 ). Treatment continued until progression of disease or unacceptable toxicity, or a maximum of 24 months.
For patients who completed 24 months of therapy or had a complete response, treatment with Pembrolizumab could be reinitiated for disease progression and administered for up to one additional year.
Primary efficacy outcome measures were overall survival ( OS ) and progression-free survival ( PFS ) as assessed by blinded independent central review ( BICR ) using RECIST v1.1 ( modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ ).
Secondary efficacy outcome measures were overall response rate ( ORR ) and duration of response ( DOR ).
Patients receiving placebo plus chemotherapy who experienced disease progression could cross over to receive Pembrolizumab as monotherapy.
In KEYNOTE-189, there was a statistically significant improvement in overall survival and progression-free survival for patients randomized to Pembrolizumab in combination with Pemetrexed and Platinum chemotherapy compared with Pemetrexed and Platinum chemotherapy alone, with a reduction in the risk of death by 51% ( HR=0.49 [ 95% CI, 0.38-0.64 ]; p less than 0.00001 ) and a 48% reduction in the risk of progression or death ( HR=0.52 [ 95% CI, 0.43-0.64 ]; p less than 0.00001 ).
The overall response rate was 48% ( 95% CI, 43-53 ) for patients randomized to Pembrolizumab in combination with Pemetrexed and Platinum chemotherapy compared to 19% ( 95% CI, 14-25 ) for patients randomized to Pemetrexed and Platinum chemotherapy alone ( p less than 0.0001 ).
The median duration of response ( DOR ) for patients randomized to receive Pembrolizumab in combination with Pemetrexed and Platinum chemotherapy was 11.2 months ( range, 1.1+ to 18.0+ months ) compared to 7.8 months ( range, 2.1+ to 16.4+ months ) for patients randomized to receive Pemetrexed and Platinum chemotherapy alone.
The safety of Pembrolizumab in combination with Pemetrexed and Platinum chemotherapy was evaluated in 488 patients with nonsquamous NSCLC receiving 200 mg, 2 mg/kg or 10 mg/kg Pembrolizumab every three weeks, in two clinical studies ( KEYNOTE-189 and KEYNOTE-021 ). In this patient population, the most frequent adverse reactions were nausea ( 47% ), anemia ( 37% ), fatigue ( 38% ), neutropenia ( 22% ), decreased appetite ( 21% ), diarrhea ( 20% ) and vomiting ( 19%) .
Incidences of grade 3-5 adverse reactions were 47% for Pembrolizumab combination therapy and 37% for chemotherapy alone. ( Xagena )
Source: MSD, 2018