Clinical Trials

Date: 2017-09-10

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2017 Congress

Company: Merck&Co (USA - NJ)

Product: Keytruda® (pembrolizumab)

Action mechanism:

• monoclonal antibody/immune checkpoint inhibitor. Keytruda® (pembrolizumab - MK-3475) is an investigational, highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. MK-3475 is currently being studied in three clinical trials for advanced melanoma including a Phase III trial of MK-3475 versus ipilimumab in ipilimumab-naïve advanced melanoma patients (PN 006). Enrollment is complete in the advanced melanoma cohorts in the company’s Phase IB trial (PN 001) and the Phase II trial (PN 002) comparing two doses of MK-3475 versus chemotherapy in patients with advanced melanoma who have progressed after prior therapy. Pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide.
• Keytruda® is the first approved drug that blocks the PD-1 cellular pathway.

Disease: locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy (post-platinum failure)

Therapeutic area: Cancer - Oncology

Country: Australia, Austria, Belgium, Canada, Chile, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Republic of Korea, Netherlands, New Zealand, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Singapore, Spain, Sweden, Taiwan, Turkey, UK, USA

Trial details:

• In KEYNOTE-045, patients were randomized to receive either Keytruda® 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 OS and PFS, 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. (NCT02256436)

Latest news:

• • On September 10, 2017, Merck&Co announced updated results from the phase 3 KEYNOTE-045 trial evaluating Keytruda® (pembrolizumab), the company’s 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). Findings have been presented at the European Society for Medical Oncology (ESMO) 2017 Congress (Abstract #LBA37_PR and Abstract #851PD).
• Data in Second-Line Post-Platinum Failure Patients, KEYNOTE-045:  The trial was prematurely stopped after a pre-planned interim analysis demonstrated significantly longer OS with Keytruda® 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 ?10) (Keytruda® arm: n=74/270; chemotherapy arm; n=90/272).
• Data presented at ESMO (Abstract #LBA37_PR) 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 OS advantage with Keytruda® compared to chemotherapy in the second-line setting, regardless of PD-L1 expression. In the overall study population, data show a 30 percent reduction in the risk of death with Keytruda® (HR, 0.70 [95% CI, 0.57-0.86], p=0.0003), the median OS was 10.3 months with Keytruda® (95% CI, 8.0-12.3) and 7.4 months with chemotherapy (95% CI, 6.3-8.3), and the 18-month OS rate was 33.2 percent with Keytruda® compared to 19.7 percent with chemotherapy. Analysis of OS based on PD-L1 expression show a 42 percent reduction in the risk of death with Keytruda® (HR, 0.58 [95% CI, 0.39-0.86], p=0.0029) in patients whose tumors expressed PD-L1 (CPS ?10), the median OS was 8.0 months with Keytruda® (95% CI, 5.0-12.3) and 5.2 months with chemotherapy (95% CI, 4.2-7.5), and the 18-month OS rate was 30.0 percent with Keytruda® compared to 16.9 percent 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 PFS was 2.1 months with Keytruda® (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 percent with Keytruda® (pembrolizumab) compared to 4.8 percent with chemotherapy. In patients whose tumors expressed PD-L1 (CPS ?10), the median PFS was 2.1 months with Keytruda® (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 percent with Keytruda® compared to 5.3 percent 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 Keytruda® compared to chemotherapy in the overall study population, with an ORR of 21.1 percent in the Keytruda® arm (complete response rate (CR) of 7.8 percent and a partial response rate (PR) of 13.3 percent) and 11.0 percent in the chemotherapy arm (CR of 2.9 percent and a PR of 8.1 percent). The median time to response was 2.1 months in both treatment arms; 57.9 percent of responses in the Keytruda® arm were ongoing at the time of analysis compared to 20.0 percent in the chemotherapy arm. Median duration of response in patients with partial or complete responses had not yet been reached in the Keytruda® arm at the time of analysis (range: 1.6+ to 24.6+) with 67.0 percent 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 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve).
• In patients whose tumors expressed PD-L1, the ORR was 20.3 percent in the Keytruda® arm (CR of 6.8 percent and a PR of 13.5 percent) and 6.7 percent in the chemotherapy arm (CR of 2.2 percent and a PR of 4.4 percent). The median time to response was 2.0 months in the Keytruda® arm and 2.1 months in the chemotherapy arm; 73.3 percent of responses in the Keytruda® arm were ongoing at the time of analysis compared to 33.3 percent in the chemotherapy arm. The median duration of response in patients with partial or complete responses had not yet been reached in the Keytruda® arm at the time of analysis (range: 1.6+ to 23.5+) with 77.0 percent 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 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve).
• A second abstract including a subgroup analysis from KEYNOTE-045 (Abstract #851PD) was also accepted as a poster at ESMO and provides greater insight into the OS advantage with Keytruda® compared to the individual chemotherapy agents. The retrospective analysis showed a 27 percent reduction in the risk of death versus paclitaxel (HR, 0.73 [95% CI, 0.55-0.96]), a 21 percent reduction in the risk of death versus docetaxel (HR, 0.79 [95% CI, 0.59-1.07]), and a 35 percent reduction in the risk of death versus vinflunine (HR, 0.65 [95% CI, 0.49-0.87]). No statistically significant difference in PFS was seen between Keytruda® and each chemotherapy agent. Analyses of the secondary endpoints showed an ORR of 11.9 percent, 6.0 percent, and 17.2 percent with paclitaxel, docetaxel, and vinflunine, respectively, compared to 21.1 percent in the Keytruda® (pembrolizumab) arm.
• The safety profile of Keytruda®  was consistent with that observed in previously reported studies. Treatment-related adverse events (TRAEs) of any grade occurred in 62.0 percent in the Keytruda® arm and 90.6 percent in the chemotherapy arm. Grade 3 or higher TRAEs occurred in 16.5 percent and 50.2 percent of Keytruda®and chemotherapy patients, respectively. Immune-mediated adverse events occurred in 19.5 percent of patients in the Keytruda® arm and 7.5 percent in the chemotherapy arm. The discontinuation rate due to treatment-related adverse events was 7.1 percent of patients in the Keytruda® arm and 12.5 percent of patients in the chemotherapy arm. Deaths due to treatment-related adverse events occurred in four patients treated with Keytruda®, one patient treated with paclitaxel, and three patients treated with vinflunine.

Is general: Yes