The European Commission ( EC ) has approved Keytruda ( Pembrolizumab ), the anti-PD-1 therapy, at a dose of 2 mg/kg every three weeks, for patients with locally advanced or metastatic non-small cell lung cancer ( NSCLC ) in patients whose tumors express PD-L1 and who have received at least one prior chemotherapy regimen.
Patients with EGFR or ALK positive tumor mutations should also have received approved therapy for these mutations prior to receiving Keytruda.
The approval is based on findings from KEYNOTE-010, a pivotal study which showed Keytruda significantly improved overall survival ( OS ) compared to standard of care chemotherapy.
KEYNOTE-010 is a global, open-label, randomized, pivotal phase 2/3 study evaluating Keytruda ( 2 mg/kg or 10 mg/kg every three weeks ) compared to standard of care chemotherapy ( Docetaxel, 75 mg/m2 every three weeks ) in 1,033 patients with squamous and non-squamous NSCLC who experienced disease progression after Platinum-containing systemic therapy and whose tumors expressed PD-L1.
The primary endpoints were overall survival and progression-free survival ( PFS ) and were assessed based on patients with any level of PD-L1 expression ( greater than or equal to 1% ) and in patients whose tumors express higher levels of PD-L1 ( greater than or equal to 50% ) – as reflected by tumor proportion score ( TPS ).
In the total study population ( all levels of PD-L1 expression ), both doses of Keytruda studied significantly improved overall survival compared with Docetaxel.
Specifically, Keytruda resulted in a 29% improvement in overall survival for the 2 mg/kg dose ( hazard ratio, HR=0.71 [ 95% CI, 0.58-0.88; P=0.001 ] ) and a 39% improvement in overall survival for the 10 mg/kg dose ( HR=0.61 [ 95% CI, 0.49-0.75; P less than 0.001 ] ), compared to Docetaxel.
Median overall survival for Keytruda was 10.4 months ( 95% CI, 9.4-11.9 ) and 12.7 months ( 95% CI, 10.0-17.3 ), respectively, compared to 8.5 months for Docetaxel ( 95% CI, 7.5-9.8 ).
Among patients with higher levels of PD-L1 expression ( a TPS score of 50% or greater ), overall survival was superior for both Keytruda doses compared with Docetaxel.
Specifically, Keytruda improved overall survival by 46% for the 2 mg/kg dose ( HR 0.54 [ 95% CI, 0.38-0.77; P=0.001 ] ) and by 50% for the 10 mg/kg dose ( HR 0.50 [ 95% CI, 0.36-0.70; P less than 0.001 ] ), compared to Docetaxel.
Median overall survival for Keytruda ( 2 mg/kg and 10 mg/kg, respectively ) was 14.9 months ( 95% CI, 10.4 to not reached ) and 17.3 months ( 95% CI, 11.8 to not reached ), compared to 8.2 months for Docetaxel ( 95% CI, 6.4-10.7 ).
Among patients in the total study population treated with Keytruda ( 2 mg/kg and 10 mg/kg, respectively ), median progression-free survival was 3.9 months ( 95% CI, 3.1-4.1 ) and 4.0 months ( 95% CI, 2.6-4.3 ), compared to 4.0 months for Docetaxel ( 95% CI, 3.1-4.2 ).
Keytruda numerically reduced the risk of progression or death ( PFS ) at both doses ( HR 0.88 [ 95% CI, 0.73-1.04 ] for 2 mg/kg; HR 0.79 [ 95% CI, 0.66-0.94 ] for 10 mg/kg ).
PFS results in the overall population were not statistically significant for either dose based on protocol-specified statistical testing requirements.
Patients with higher levels of PD-L1 expression who were treated with Keytruda had significantly prolonged progression-free survival compared to Docetaxel ( HR 0.58 [ 95% CI, 0.43-0.77; P=0.001 ] for 2 mg/kg; HR 0.59 [ 95% CI, 0.45-0.78; P less than 0.001 ] for 10 mg/kg ).
Among patients treated with Keytruda ( 2 mg/kg and 10 mg/kg, respectively ), median PFS was 5.2 months ( 95% CI, 4.0-6.5 ) and 5.2 months ( 95% CI, 4.1-8.1 ), compared to 4.1 months for Docetaxel ( 95% CI, 3.6-4.3 ).
The safety analysis supporting the European approval of Keytruda was based on 2,799 patients with advanced melanoma or NSCLC across three doses ( 2 mg/kg every three weeks or 10 mg/kg every two or three weeks ) in studies KEYNOTE-001, KEYNOTE-002 and KEYNOTE-010 combined.
The most common adverse reactions ( more than 10% ) with Keytruda were fatigue ( 24% ), rash ( 19% ), pruritus ( 18% ), diarrhea ( 12% ), nausea ( 11% ) and arthralgia ( 10% ).
The majority of adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.
Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Pembrolizumab 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.
Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast, and prostate cancers combined.
The two main types of lung cancer are non-small cell and small cell.
NSCLC is the most common type of lung cancer, accounting for about 85% of all cases.
The five-year relative survival rate for patients suffering from highly advanced, metastatic ( stage IV ) lung cancers is estimated to be 2%. ( Xagena )
Source: Merck, 2016