Phase 3
N=921
Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma
Melanoma
Bottom Line
View on ClinicalTrials.gov: NCT01909453 ↗Enrolled (actual)
921
Serious AEs
39.7%
Results posted
Jul 2021
Primary outcome: Primary: Part 1: Progression Free Survival (PFS) by BIRC in Combo 450 Group as Compared to Vemurafenib Group — 14.9; 7.3 Months
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- LGX818 (Drug); MEK162 (Drug); vemurafenib (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Pfizer
- Primary completion
- Nov 2016
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Progression Free Survival (PFS) by BIRC in Combo 450 Group as Compared to Vemurafenib Group |
14.9; 7.3 | — |
| PRIMARY Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group |
14.9; 9.6 | — |
| SECONDARY Part 2: PFS by BIRC in Combo 300 Group as Compared to LGX818 Group |
12.9; 7.4; 9.2 | — |
| SECONDARY Part 1: Overall Survival (OS) |
33.6; 23.5; 16.9 | — |
| SECONDARY Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 |
98.4; 99.5; 100; 43.8; 37.0; 41.9 | — |
| SECONDARY Part 1: Number of Participants With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.03 |
28; 12; 17; 0; 1; 0 | — |
| SECONDARY Part 1: Number of Participants With Newly Occurring Notably Abnormal Vital Signs |
3; 7; 9; 6; 10; 4 | — |
| SECONDARY Part 1: Number of Participants With Newly Occurring Notable Electrocardiogram (ECG) Values |
113; 74; 84; 32; 24; 28 | — |
| SECONDARY Part 1: Number of Participants With Worst Post-Baseline Left Ventricular Ejection Fraction (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade |
120; 159; 160; 62; 18; 17 | — |
| SECONDARY Part 1: Number of Participants With Dermatologic-related Adverse Events of Special Interest (AESI) Graded According to the NCI-CTCAE v4.03 |
0; 1; 5; 1; 0; 13 | — |
| SECONDARY Part 1: Number of Participants With Ocular-related AESI Graded According to the NCI-CTCAE v4.03 |
1; 0; 0 | — |
| SECONDARY Part 2: Percentage of Participants With AEs and SAEs as Graded by NCI-CTCAE, Version 4.03 |
98.4; 97.6; 98.9; 38.1; 36.9; 37.0 | — |
| SECONDARY Part 2: Number of Participants With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.03 |
23; 6; 18; 2; 0; 1 | — |
| SECONDARY Part 2: Number of Participants With Newly Occurring Notably Abnormal Vital Signs |
10; 3; 10; 16; 1; 11 | — |
| SECONDARY Part 2: Number of Participants With Newly Occurring Notable ECG Values |
146; 35; 109; 45; 7; 31 | — |
| SECONDARY Part 2: Number of Participants With Worst Post-baseline LVEF Values by MUGA Scans or Transthoracic ECHO, by CTCAE Grade |
172; 70; 229; 77; 9; 27 | — |
| SECONDARY Part 2: Number of Participants With Dermatologic-related AESI Graded According to the NCI-CTCAE v4.03 |
0; 0; 1; 2; 0; 1 | — |
| SECONDARY Part 2: Number of Participants With Ocular-related AESI Graded According to the NCI-CTCAE v4.03 |
4; 0; 0 | — |
| SECONDARY Part (P) 2: Overall Survival (OS) |
27.1; 19.4; 22.7 | — |
| SECONDARY Part 1 and Part 2: Objective Response Rate (ORR) |
63.0; 50.5; 40.3; 65.9; 50.0; 50.4 | — |
| SECONDARY Part 1 and Part 2: Time to Objective Response (TTR) |
1.9; 2.0; 2.1; 1.9; 1.9; 1.9 | — |
| SECONDARY Part 1 and Part 2: Disease Control Rate (DCR) |
92.2; 84.0; 81.7; 90.7; 79.1; 82.5 | — |
| SECONDARY Part 1 and Part 2: Duration of Response (DOR) |
16.6; 15.2; 12.3; 12.7; 7.5; 12.9 | — |
| SECONDARY Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale |
NA; 30.5; 22.1; NA; NA; 20.5 | — |
| SECONDARY Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) |
23.9; 14.7; 16.6; 18.4; 9.5; 11.1 | — |
| SECONDARY Part 1 and Part 2: Change From Baseline in the FACT-M Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit |
52.39; 52.76; 52.01; 52.08; 51.13; 52.24 | — |
| SECONDARY Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit |
0.74; 0.76; 0.73; 0.75; 0.73; 0.75 | — |
| SECONDARY Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit |
66.72; 66.07; 64.74; 65.95; 67.39; 66.48 | — |
| SECONDARY Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit |
74.68; 74.46; 72.31; 73.04; 74.20; 74.38 | — |
| SECONDARY Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit |
82.10; 83.18; 80.71; 80.67; 81.45; 82.63 | — |
| SECONDARY Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit |
80.69; 80.91; 78.54; 81.37; 78.31; 80.09 | — |
| SECONDARY Part 1 and Part 2: Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) |
136; 139; 135; 189; 60; 199 | — |
| SECONDARY Part 1: Plasma Concentrations of LGX 818 |
18.6; 58.1; 1640; 1190; 6860; 4090 | — |
| SECONDARY Part 2: Plasma Concentrations of LGX 818 |
5.02; 0.0145; 39.7; 1360; 1370; 1250 | — |
| SECONDARY Part 1: Plasma Concentrations of MEK162 |
2.95; 426; 832; 330; 81.0; 68.1 | — |
| SECONDARY Part 2: Plasma Concentrations of MEK162 |
1.68; 366; 642; 287; 72.3; 73.2 | — |
| SECONDARY Part 1 and Part 2: Time to Definitive 1 Point Deterioration in ECOG PS |
NA; 26.7; 18.2; NA; 10.2; 19.2 | — |
Summary
This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized.
Part 1:
Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms:
1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm)
2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or
3. vemurafenib 960 mg BID (denoted as vemurafenib arm)
Part 2:
Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms:
1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or
2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)
Eligibility Criteria
Inclusion Criteria
- Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV)
- Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization
- Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), except the administration of BRAF or MEK inhibitors
- Evidence of at least one measurable lesion as detected by radiological or photographic methods
- ECOG performance status of 0 or 1
- Adequate bone marrow, organ function, cardiac and laboratory parameters
- Normal functioning of daily living activities
Exclusion Criteria
- Any untreated central nervous system (CNS) lesion
- Uveal and mucosal melanoma
- History of leptomeningeal metastases
- History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease
- Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 weeks prior to randomization
- History of Gilbert's syndrome
- Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor
- Impaired cardiovascular function or clinically significant cardiovascular diseases
- Uncontrolled arterial hypertension despite medical treatment
- HIV positive or active Hepatitis B, and/or active Hepatitis C
- Impairment of gastrointestinal function
- Patients with neuromuscular disorders that are associated with elevated CK
- Pregnant or nursing (lactating) women
- Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
Other protocol-defined inclusion/exclusion criteria may apply
Data sourced from ClinicalTrials.gov (NCT01909453). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.