Clinical Trials

Date: 2017-09-08

Type of information: Presentation of results at a congress

phase: 2

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

Company: Merck&Co (USA - NJ)

Product: pembrolizumab

Action mechanism:

• monoclonal antibody/immune checkpoint inhibitor. Keytruda® (pembrolizumab - MK-3475) is an 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. In April 2013, MK-3475 has received a Breakthrough Therapy designation for advanced melanoma from the FDA. In October 2014, the FDA has gralso anted Breakthrough Therapy Designation to Keytruda® (pembrolizumab) for the treatment of patients with Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy. In November 2015, the FDA has granted Breakthrough Therapy Designation to Keytruda® for the treatment of patients with microsatellite instability high (MSI-H) metastatic colorectal cancer.

Disease: advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma

Therapeutic area: Cancer - Oncology

Country: Australia, Canada, Chile, Colombia, Estonia, France, Israel, Italy, Japan, Republic of Korea, Lithuania, Peru, Portugal, Romania, Russian Federation, UK, USA

Trial details:

• KEYNOTE-059 is a registrational, phase 2 non-randomized, multi-cohort study (Cohorts 1, 2 and 3) investigating Keytruda® (pembrolizumab) in patients with advanced gastric or GEJ adenocarcinoma. Patients in Cohort 1 received Keytruda® monotherapy after two or more prior lines of therapy. Patients in Cohort 2 had received no prior therapy and received Keytruda® in combination with cisplatin (80 mg/m2 Q3W) and 5-fluorouracil (800 mg/m2 Q3W) or capecitabine (in Japan only, 1000 mg/m2 BID Q3W) as a first-line therapy. Patients in Cohort 3, which only enrolled patients whose tumors were positive for PD-L1, received Keytruda® monotherapy as a first-line therapy. In all cohorts, Keytruda® was given at 200 mg every three weeks for up to 24 months. The primary endpoints are safety (all cohorts) and ORR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key secondary endpoints are ORR and duration of response by RECIST v1.1, PFS, and OS. Data from Cohorts 1 and 2 were further assessed based on PD-L1 expression. Tumors were considered to have positive PD-L1 expression if the combined positive score (CPS) – as examined by tumor and immune cells – was equal to or greater than one. (NCT02335411)

Latest news:

• • On September 8, 2017, Merck&Co announced the presentation of data from all three cohorts of the registrational, phase 2 KEYNOTE-059 trial at the European Society for Medical Oncology (ESMO) 2017 Congress. The trial is investigating the use of Keytruda® (pembrolizumab) in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, including new data in treatment-naïve patients. Overall, results showed antitumor activity and durability of response with Keytruda® across multiple lines of therapy, with higher response rates observed in PD-L1-positive (CPS ?1) patients:
• In heavily pre-treated patients, Keytruda® monotherapy (Cohort 1) showed an overall response rate (ORR) of 12 percent (95% CI, 8-17) in all patients and 16 percent (95% CI, 11-23) in patients with PD-L1 positive tumors. In treatment-naïve patients, Keytruda®  in combination with chemotherapy (Cohort 2) showed an ORR of 60 percent (95% CI, 39-79) in all patients and 69 percent (95% CI, 41-89) in patients with PD-L1 positive tumors. In treatment-naïve patients with PD-L1 positive tumors, Keytruda®  monotherapy (Cohort 3) showed an ORR of 26 percent (95% CI, 12-45).
• Results presented from KEYNOTE-059 were based on an analysis of efficacy, safety and PD-L1 expression from 315 patients across the study’s three cohorts. Patients were considered PD-L1 positive if they had a PD-L1 combined positive score of one or more (CPS ?1). Findings showed:
• Cohort 1: Keytruda® (pembrolizumab) as monotherapy in patients whose disease progressed on or after two or more prior lines of therapy (n=259). Forty-eight percent of these patients had received three or more lines of prior therapy. The efficacy analysis in all patients, with or without PD-L1 expression, showed an ORR of 12 percent (95% CI, 8-17), with complete responses (CR) in three percent (95% CI, 1-6) and partial responses (PR) in nine percent (95% CI, 6-13) of patients. In patients whose tumors expressed PD-L1 (n=148), the ORR was 16 percent (95% CI, 11-23), with CR in three percent (95% CI, 1-8) and PR in 13 percent (95% CI, 8-19) of patients. In PD-L1 negative patients (n=109), the ORR was six percent (95% CI, 3-13), with CR in three percent (95% CI, 1-8) and PR in four percent (95% CI, 1-9) of patients. Median duration of follow-up was 5.6 months (range: 0.5-24.7). In all patients, 42 percent (n=95) experienced a reduction in target lesion size. Median duration of response was 14.2 months (range: 2.4-19.4+).
• In all patients, median progression-free survival (PFS) was two months (95% CI, 2.0-2.1), with a six-month PFS rate of 14.6 percent; the median overall survival (OS) was 5.5 months (95% CI, 4.2-6.5), with a six-month OS rate of 45.7 percent. In patients whose tumors expressed PD-L1, the median PFS was 2.1 months (95% CI, 2.0-2.1), with a six-month PFS rate of 18.2 percent; the median OS in these patients was 5.8 months (95% CI, 4.4-7.8), with a six-month OS rate of 48.4 percent. In PD-L1 negative patients, the median PFS was two months (95% CI, 1.9-2.0), with a six-month PFS rate of 9.9 percent; the median OS was 4.6 months (95% CI, 3.2-6.5), with a six-month OS rate of 42.9 percent. Cohort 2: Keytruda® (pembrolizumab) in combination with chemotherapy in treatment-naïve patients (n=25). The efficacy analysis in all patients showed an ORR of 60 percent (95% CI, 39-79), with CR in four percent (95% CI, 0-20) and PR in 56 percent (95% CI, 35-76) of patients. In patients whose tumors expressed PD-L1 (n=16), the ORR was 69 percent (95% CI, 41-89), with no complete responses (95% CI, 0-22) and PR in 69 percent (95% CI, 41-89) of patients. In PD-L1 negative patients (n=8), the ORR was 38 percent (95% CI, 9-76), with CR in 13 percent (95% CI, 0-53) and PR in 25 percent (95% CI, 3-65) of patients. Median duration of follow-up was 13.8 months (range: 1.8-24.1). Across all patients, 96 percent (n=24) experienced a reduction in target lesion size. Median duration of response was 4.6 months (range: 2.6-20.3+). In all patients, median PFS was 6.6 months (95% CI, 5.9-10.6), with a six-month PFS rate of 68.0 percent; the median OS was 13.8 months (95% CI, 8.6-not reached), with a six-month OS rate of 76.0 percent. Cohort 3: Keytruda® as monotherapy in treatment-naïve patients whose tumors expressed PD-L1 (n=31). The efficacy analysis showed an ORR of 26 percent (95% CI, 12-45), with CR in seven percent (95% CI, 1-21) and PR in 19 percent (95% CI, 8-38) of patients. Median duration of follow-up was 17.5 months (range: 1.7-20.7). Seventy-seven percent of patients (n=24) experienced a reduction in target lesion size. The median duration of response was 9.6 months (range: 2.1-17.8+). The median PFS was 3.3 months (95% CI, 2.0-6.0), with a six-month PFS rate of 34.9 percent; the median OS was 20.7 months (95% CI, 9.2-20.7), with a six-month OS rate of 72.9 percent. The safety profile of Keytruda® was consistent with that observed in previously reported studies. In Cohorts 1, 2 and 3, Grade 3-5 treatment-related adverse events (TRAEs) occurred in 46 (18%), 19 (76%), and 7 (23%) patients, respectively. In Cohort 1, Grade 3-5 TRAEs were anemia (3%), fatigue (2%), and dehydration (1%); TRAEs led to discontinuation in seven patients (3%) and death in two patients (1%). In Cohort 2, Grade 3/4 TRAEs were neutropenia (24%), stomatitis (20%), anemia (8%), decreased platelet count (8%), decreased appetite (8%), and fatigue (8%). TRAEs in Cohort 2 led to discontinuation in three patients (12%); there were no treatment-related deaths. In Cohort 3, Grade 3-5 TRAEs occurred in seven patients (23%); there was one treatment-related death (3%) and no discontinuations due to TRAEs.
• In Cohorts 1, 2 and 3, Grade 3 or higher immune-mediated adverse events occurred in 13, four, and three patients, respectively. In Cohort 1, Grade 3 immune-mediated adverse events were colitis (n=3), pneumonitis (n=2), thyroiditis (n=1), and hypothyroidism (n=1); there were no Grade 4-5 immune-mediated adverse events. In Cohort 2, Grade 3 immune-mediated adverse events were palmar-plantar erythrodysesthesia (n=2), nephrotic syndrome (n=1), rash (n=1), and maculopapular rash (n=1); there were no Grade 4-5 immune-mediated adverse events. In Cohort 3, Grade 3 immune-mediated adverse events were colitis (n=1) and rash (n=1); there was one Grade 5 adverse event (pneumonitis).

 

Is general: Yes