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Pembrolizumab, overall survival benefit over chemotherapy with nearly two years follow-up in previously treated patients with advanced urothelial carcinoma, post-Platinum failure


Updated results from the phase 3 KEYNOTE-045 trial evaluating Pembrolizumab ( Keytruda ), an anti-PD-1 therapy, in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after Platinum-containing chemotherapy ( post-Platinum failure ), were presented at ESMO ( European Society for Medical Oncology ) Congress.

Data have shown that with median follow-up of 22.5 months, Pembrolizumab continues to demonstrate an overall survival ( OS ) benefit over investigator’s choice of Paclitaxel, Docetaxel or Vinflunine as a second-line therapy, post-Platinum failure, regardless of PD-L1 expression ( hazard ratio, HR=0.70 [ 95% CI, 0.57-0.86 ], p=0.0003 ).

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.

KEYNOTE-045 is an open-label, randomized phase 3 trial of Pembrolizumab compared to investigator’s choice of chemotherapy ( Paclitaxel, Docetaxel or Vinflunine ) in patients with locally advanced or metastatic urothelial cancer with disease progression on or after Platinum-containing chemotherapy.
The trial was prematurely stopped after a pre-planned interim analysis demonstrated significantly longer overall survival with Pembrolizumab compared to chemotherapy ( median follow-up, 14.1 months ).
Efficacy was assessed in the overall study population ( n=542 ), as well as in patients with PD-L1 expression, defined as a combined positive score of 10 or more ( CPS greater than or equal to 10 ) ( Pembrolizumab arm: n=74/270; chemotherapy arm; n=90/272 ).

In KEYNOTE-045, patients were randomized to receive either Pembrolizumab 200 mg every three weeks ( n=270 ) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously, every three weeks ( n=272 ): Paclitaxel 175 mg/m2, Docetaxel 75 mg/m2, or Vinflunine 320 mg/m2.
The dual primary endpoints were overall survival and progression-free survival, as assessed by blinded independent central review ( BICR ) per RECIST ( Response Evaluation Criteria in Solid Tumors ) v1.1; key secondary endpoints included ORR, as assessed by BICR per RECIST 1.1, duration of response and safety.
Efficacy was assessed in all patients, as well as in patients with PD-L1 expression.

Data presented at ESMO include four months of additional follow-up ( data cut-off, May 19, 2017; median follow up, 22.5 months ) and continue to show a superior overall survival advantage with Pembrolizumab compared to chemotherapy in the second-line setting, regardless of PD-L1 expression.

In the overall study population, data have shown a 30% reduction in the risk of death with Pembrolizumab ( HR, 0.70 [ 95% CI, 0.57-0.86 ], p=0.0003 ), the median overall survival was 10.3 months with Pembrolizumab ( 95% CI, 8.0-12.3 ) and 7.4 months with chemotherapy ( 95% CI, 6.3-8.3 ), and the 18-month overall survival rate was 33.2% with Pembrolizumab compared to 19.7% with chemotherapy.

Analysis of overall survival based on PD-L1 expression show a 42% reduction in the risk of death with Pembrolizumab ( HR, 0.58 [ 95% CI, 0.39-0.86 ], p=0.0029 ) in patients whose tumors expressed PD-L1 ( CPS greater than or equal to 10 ), the median overall survival was 8.0 months with Pembrolizumab ( 95% CI, 5.0-12.3 ) and 5.2 months with chemotherapy ( 95% CI, 4.2-7.5 ), and the 18-month overall survival rate was 30.0% with Pembrolizumab compared to 16.9% with chemotherapy.

As previously reported, there was no significant difference in progression-free-survival ( PFS ) between treatment arms in the overall study population ( HR, 0.96 [ 95% CI, 0.79-1.16 ], p=0.32 ).
The median progression-free survival was 2.1 months with Pembrolizumab ( 95% CI, 2.0-2.2 ) and 3.3 months with chemotherapy ( 95% CI, 2.4-3.5 ); the 18-month PFS rate was 15.3% with Pembrolizumab compared to 4.8% with chemotherapy.
In patients whose tumors expressed PD-L1 ( CPS greater than or equal to 10 ), the median progression-free survival was 2.1 months with Pembrolizumab ( 95% CI, 1.9-2.1 ) and 3.2 months with chemotherapy ( 95% CI, 2.2-3.5 ); the 18-month PFS rate was 16.3% with Pembrolizumab compared to 5.3% with chemotherapy ( HR, 0.93 [ 95% CI, 0.65-1.33 ], p=0.32 ).

Analyses of the secondary endpoints showed nearly double the overall response rate ( ORR ) with Pembrolizumab compared to chemotherapy in the overall study population, with an ORR of 21.1% in the Pembrolizumab arm ( complete response rate [ CR ] of 7.8% and a partial response rate ( PR ) of 13.3% ) and 11.0% in the chemotherapy arm ( CR of 2.9% and a PR of 8.1% ).
The median time to response was 2.1 months in both treatment arms; 57.9% of responses in the Pembrolizumab arm were ongoing at the time of analysis compared to 20.0% in the chemotherapy arm.
Median duration of response in patients with partial or complete responses had not yet been reached in the Pembrolizumab arm at the time of analysis ( range: 1.6+ to 24.6+ ) with 67.0% of responses ongoing at 12 months ( calculated per Kaplan-Meier curve ); in the chemotherapy arm, the median duration of response was 4.4 months ( range: 1.4+ to 24.0+ ) with 35.0% of responses ongoing at 12 months ( calculated per Kaplan-Meier curve ).

In patients whose tumors expressed PD-L1, the ORR was 20.3% in the Pembrolizumab arm ( CR of 6.8% and a PR of 13.5% ) and 6.7% in the chemotherapy arm ( CR of 2.2% and a PR of 4.4% ).
The median time to response was 2.0 months in the Pembrolizumab arm and 2.1 months in the chemotherapy arm; 73.3% of responses in the Pembrolizumab arm were ongoing at the time of analysis compared to 33.3% in the chemotherapy arm.
The median duration of response in patients with partial or complete responses had not yet been reached in the Pembrolizumab arm at the time of analysis ( range: 1.6+ to 23.5+ ) with 77.0% of responses ongoing at 12 months ( calculated per Kaplan-Meier curve ); in the chemotherapy arm, the median duration of response was 4.4 months ( range: 1.5+ to 20.8+ ) with 40.0% of responses ongoing at 12 months ( calculated per Kaplan-Meier curve ).

The safety profile of Pembrolizumab was consistent with that observed in previously reported studies.
Treatment-related adverse events ( TRAEs ) of any grade occurred in 62.0% in the Pembrolizumab arm and 90.6% in the chemotherapy arm.
Grade 3 or higher TRAEs occurred in 16.5% and 50.2% of Pembrolizumab and chemotherapy patients, respectively.
Immune-mediated adverse events occurred in 19.5% of patients in the Pembrolizumab arm and 7.5% in the chemotherapy arm.
The discontinuation rate due to treatment-related adverse events was 7.1% of patients in the Pembrolizumab arm and 12.5% of patients in the chemotherapy arm.
Deaths due to treatment-related adverse events occurred in four patients treated with Pembrolizumab, one patient treated with Paclitaxel, and three patients treated with Vinflunine. ( Xagena )

Source: Merck ( MSD ), 2017

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