HRa (95 % CI) (vs Vem)

p-value (stratified log-rank)

0.61 (0.47, 0.79)

< 0.0001

HRa (95 % CI) (vs. Enco 300)

p-value (stratified log-rank)

0.81 (0.61,1.06)

0.061

Figure 2 Study CMEK162B2301, Part 1: Kaplan-Meier plot of interim overall survival (cut-off date: 7 November 2017)

Quality of Life (QoL) (cut-off date: 19 May 2016)

The Functional Assessment of Cancer Therapy-Melanoma (FACT-M), the European Organisation for Research and Treatment of Cancer's core quality of life questionnaire (EORTC QLQ-C30) and the EuroQoL-5 Dimension-5 Level examination (EQ-5D-5L) were used to explore patient-reported outcomes (PRO) measures of health-related Quality of Life, functioning, melanoma symptoms, and treatment-related adverse reaction. A definitive 10% deterioration in FACT-M and in EORTC QLQ-C30 was significantly delayed in patients treated with Combo 450 relative to other treatments.

The median time to definitive 10 % deterioration in the FACT-M score was not reached in the Combo 450 arm and was 22.1 months (95 % CI: 15.2, NE) in the vemurafenib arm with a HR for the difference of 0.46 (95 % CI: 0.29, 0.72). An analysis of time to definitive 10 % deterioration in

EORTC QLQ-C30 score provided with similar results.

Patients receiving Combo 450 reported no change or a slight improvement in the mean change from baseline EQ-5D-5L index score at all visits, whilst patients receiving vemurafenib or encorafenib reported decreases at all visits (with statistical significant differences). An eva luation of change over time in score yielded the same trend for EORTC QLQ-C30 and at all visit for FACT-M.

Study CMEK162B2301, Part 2

Part 2 of study CMEK162B2301 was designed to assess the contribution of binimetinib to the encorafenib and binimetinib combination.

The PFS for encorafenib 300 mg orally daily used in combination with binimetinib 45 mg orally twice daily (Combo 300, n = 258) was compared to the PFS for Enco 300 (n = 280, including 194 patients from Part 1 and 86 patients from Part 2). Enrolment in Part 2 started after all Part 1 patients were randomised.

Preliminary Part 2 data at a cut-off date of 9 November 2016 demonstrated the contribution of binimetinib with an improved median PFS estimate of 12.9 months (95 % CI: 10.1, 14.0) for Combo 300 compared to 9.2 months (95 % CI: 7.4, 11.0) for Enco 300 (Parts 1 and 2) per independent central review (BIRC). Similar results were observed per Investigator assessment.

The confirmed ORR per BIRC was 65.9 % (95 % CI: 59.8, 71.7) for Combo 300, and 50.4 % (95 % CI 44.3, 56.4) for Enco 300 (Parts 1 and 2). Median DOR for confirmed responses per BIRC was 12.7 months [95% CI: 9.3, 15.1] for Combo 300 and 12.9 months [95 % CI: 8.9, 15.5] for Enco 300.

The median duration of treatment was longer for Combo 300 vs. Enco 300, 52.1 weeks vs 31.5 weeks.

Cardiac electrophysiology

In the safety analysis of pooled studies of encorafenib 450 mg once daily in combination with 45 mg binimetinib twice daily (Combo 450), the incidence of new QTc prolongation > 500 ms was 0.7 % (2/268) in the encorafenib 450 mg plus binimetinib group, and 2.5 % (5/203) in the encorafenib single agent group. QTc prolongation of > 60 ms compared to pre-treatment values was observed in 4.9 % (13/268) patients in the encorafenib plus binimetinib group, and in 3.4 % (7/204) in the encorafenib single agent group (see section 5.1 of encorafenib SmPC).

Paediatric population