Clinical Trials

Date: 2014-11-16

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the Society of Melanoma Research (SMR) 2014 International Congress in Zurich, Switzerland

Company: Merck&Co (USA - NJ)

Product: Keytruda® (pembrolizumab)

Action mechanism:

Disease: ipilimumab-refractory advanced melanoma

Therapeutic area: Cancer - Oncology

Country:

Trial details:

KEYNOTE-002 is a global, randomized pivotal Phase 2 study (n=540) evaluating Keytruda® at doses of 2 mg/kg every three weeks (n=180) and 10mg/kg every three weeks (n=181) compared to investigator’s choice chemotherapy (n=179) (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide) in patients with ipilimumab-refractory advanced melanoma. In the study, 83 percent of patients had the most advanced stage of disease (M1c) and 73 percent of patients had received at least two prior systemic therapies including ipilimumab. The co-primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response and safety; and HRQoL as a pre-specified exploratory endpoint. Tumor response was assessed at week 12, then every 6 weeks through week 48, followed by every 12 weeks thereafter by independent, central, blinded radiographic review per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). Patients on chemotherapy with progressive disease as assessed by blinded central review were able to cross over to Keytruda®arms after three months. (NCT01704287)

Latest news:

* On November 16, 2014, Merck & Co announced that a pre-specified analysis of investigational data from a pivotal Phase 2 study (KEYNOTE-002) showed Keytruda® (pembrolizumab), the company’s anti-PD-1 therapy, substantially improved the primary endpoint of progression-free survival (PFS, as assessed by RECIST 1.1, independent central review) (HR 0.57 and 0.50 for 2 mg/kg and 10 mg/kg every three week doses, respectively), compared to chemotherapy (PKeytruda®  were 34 percent at the 2 mg/kg dose (95% CI, 27-41) (n=180) and 38 percent at the 10 mg/kg dose (95% CI, 31-45) (n=181), compared to 16 percent for chemotherapy (95% CI, 10-22) (n=179). The median duration of follow-up at the interim analysis was 10 months.
These findings, including pre-specified analyses of overall response rate (ORR), duration of response, safety and health-related quality of life (HRQoL), were presented in an oral session by Dr. Antoni Ribas, professor, Hematology/Oncology and Surgery, and director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles at the Society of Melanoma Research (SMR) 2014 International Congress in Zurich, Switzerland.
Keytruda® is indicated in the United States at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
For the pre-specified analysis of PFS, no significant differences were observed between Keytruda® doses (HR 0.91, range 0.71-1.16) (P<0.44). An assessment of PFS by investigator review was shown to be consistent with the central review findings. In addition, the PFS effect in favor of KEYTRUDA was consistent across all pre-specified sub-groups.
The objective of the pre-specified analysis was to evaluate the superiority of either dose of Keytruda® over chemotherapy for PFS (conducted after ? 270 PFS events at a 0.25% significance level) (one-sided) (estimated HR, 0.66). The study was designed with co-primary endpoints of PFS and overall survival. An evaluation of overall survival is planned at the pre-specified final analysis in 2015.
Additional Efficacy Data and Safety from the KEYNOTE-002 Study:
Overall response rates (confirmed) for KEYTRUDA were five to six times higher compared to chemotherapy. For KEYTRUDA, ORR was 21 percent at 2 mg/kg dose (95% CI, 15-28) and 25 percent at 10 mg/kg dose (95% CI, 19-32), compared to 4 percent for chemotherapy (95% CI, 2-9) (PIn a pre-specified exploratory analysis for HRQoL, patients treated with KEYTRUDA reported a significantly smaller decrement in health status/quality of life score compared to those treated with chemotherapy (based on European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire or “EORTC QLQ-C30”). The mean change from baseline at week 12 (difference in least squares) for KEYTRUDA compared to chemotherapy was 6.52 (P=0.011) at 2 mg/kg dose and 6.57 (p=0.009) at 10 mg/kg dose, respectively.
The incidence of adverse events was consistent with previously reported data for KEYTRUDA. Despite longer median treatment duration, the incidence of treatment-related, grade 3-5 adverse events was lower with KEYTRUDA at 2 mg/kg dose (11%) and at 10 mg/kg dose (14%) compared to chemotherapy (26%). Serious treatment-related adverse events were observed for KEYTRUDA at 2 mg/kg dose (8%) and 10 mg/kg dose (11%), and for chemotherapy (10%). Immune-related grade 3 adverse events observed for KEYTRUDA across doses included hepatitis (n=3), colitis (n=2), pneumonitis (n=3), hypophysitis (n=1) and iritis or uveitis (n=1). No grade 4/5 immune-related adverse events were reported. Three percent of patients receiving KEYTRUDA at 2 mg/kg dose and 7 percent at the 10 mg/kg dose, as well as 6 percent receiving chemotherapy discontinued treatment due to investigator assessed, treatment-related adverse events. One treatment-related death was reported for KEYTRUDA and none in the chemotherapy arm.

Is general: Yes