Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Encorafenib · 7 trials · 5 indications
A DLT is defined as any adverse event or laboratory value that is assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring within the first 2 cycles of treatment.
OR is defined as confirmed Best Overall response (BOR) of either CR or PR as determined by BICR assessment per RECIST 1.1
DLT: Any AE/lab value during first 28 days (D) of treatment that met at least 1 criteria: AE/lab value unrelated to underlying disease,PD,intercurrent illness,concomitant medications resulting in inability to tolerate atleast 75% of planned dose intensity of study drug,fatigue grade (G)3\>14 consecutive D, interstitial lung disease G\>=2,rash,hand foot skin reaction G3\>14 consecutive D or G4,diarrhea G3 \>=48 hours or G4,nausea/vomiting G3\>=48 hours or G4,mucositis G\>=3,total bilirubin G\>=3, aspartate aminotransferase/alanine aminotransferase G\>=3 in conjunction with total bilirubin G\>=2 or G3 \>7 consecutive D or G4,Serum creatinine G\>=3,absolute neutrophil count G4 \>7 consecutive D, \>=G3 febrile neutropenia,G3 platelet count decreased with signs of bleeding,platelet count G4,ECG QTcF prolonged \>=G3,G\>=3 uveitis \>21 consecutive D,G4 confirmed by ophthalmic examination,paresthesia/dysesthesias G\>=3,other G\>=3 hematologic/nonhematologic toxicity except lymphocyte count decreased G\>=3.
PFS was defined as the time from date of randomization to earliest documented disease progression (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death due to any cause as assessed by BICR. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 millimeter (mm) for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Censoring details: no adequate baseline assessment, including no disease at baseline: participants were censored to randomization date; no PD, lost to follow-up, withdrawal of consent, PD or death \>12 (or 16) weeks after the last adequate tumor assessment, and start of new anticancer treatment: participants were censored to last adequate tumor assessment documenting no PD prior to new anticancer therapy, or missed assessments. Analysis was performed using Kaplan Meier method.
ORR was defined as the percentage of participants who achieved best overall response (BOR) of confirmed complete response (CR) or partial response (PR) according to RECIST v 1.1 as assessed by BICR. CR: complete disappearance of all target lesions (with the exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion.
ORR was defined as the percentage of participants who achieved BOR of confirmed CR or PR according to RECIST v 1.1 as assessed by BICR. CR: complete disappearance of all target lesions (with the exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion.
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants reporting AEs were reported in this outcome measure.
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants with dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants according to incidence of dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.
OS was defined as the time from randomization to death due to any cause.
ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of complete response (CR) or partial response (PR), where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 millimeter \[mm\] short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC/central review and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 square millimeter (mm\^2).
PFS was defined as the time from the date of randomization to the date of the first documented PD or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm\^2.
PFS per investigator, defined as the time from randomization until PD based on investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first:
Objective Response Rate (ORR) was defined as the percentage of participants who had achieved a confirmed best overall response (Complete Response \[CR\] or Partial Response \[PR\]) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was defined by the disappearance of all non-lymph node target lesions (where all target lesions were recorded with a length of 0 mm, and any pathological lymph nodes \[recorded as target lesion\] must have reduction in short axis to \<10 mm) and complete disappearance of all non-target lesions (where all non-target lesions were marked "Absent", and all lymph nodes must be non-pathological in size \[\<10 mm in short axis\]). PR was defined by a 30% or more decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. ORR was calculated with the exact 2-sided Clopper-Pearson 95% CI.
ORR: percentage of participants with confirmed complete response (CR) and partial response (PR). Response evaluation criteria in solid tumors (RECIST) v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions that had a reduction in short axis to less than (\<) 10 millimeter (mm). Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (\<10 mm short axis) and b) PR = at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Any radiological assessments taken more than 30 days after the last dose of study therapy or after antineoplastic agents other than study treatments taken by the participants was excluded from the best overall response derivation. Confirmation of CR or PR was to be at least 4 weeks apart from the previous radiological assessment.
| Arm | Type | Description |
|---|---|---|
| Triplet Arm | EXPERIMENTAL | Encorafenib and Binimetinib in combination with Pembrolizumab |
| Control Arm | ACTIVE_COMPARATOR | Pembrolizumab |
| Safety Lead-in Cohort 1 | EXPERIMENTAL | Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks |
| Safety Lead-in Cohort 2 | EXPERIMENTAL | Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks |
| Phase 3 Arm A | EXPERIMENTAL | Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks |
| Phase 3 Arm B | EXPERIMENTAL | Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks |
| Phase 3 Arm C | ACTIVE_COMPARATOR | Every two weeks: Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Every two weeks: Irinotecan 165 mg/m2 (90-minute IV infusion) Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 2400 or 3200 mg/m2 continuous IV infusion over 46 48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Oxaliplatin 130 mg/m2 (120-minute IV infusion) every 3 weeks Capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14 Bevacizumab (optional; given per prescribing instructions) |
| Cohort 3 Arm D | EXPERIMENTAL | Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks |
| Cohort 3 Arm E | ACTIVE_COMPARATOR | Irinotecan 180 mg/m2 (90-minute IV infusion) every 2 weeks, Leucovorin 400 mg/m2 (120-minute IV infusion) every 2 weeks, 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks, Bevacizumab (optional; given per prescribing instructions) |
| Safety Lead-in, Triplet Arm | EXPERIMENTAL | Encorafenib + binimetinib + cetuximab. |
| Doublet Arm | EXPERIMENTAL | Encorafenib + cetuximab. |
| LGX818 450 mg + MEK162 | EXPERIMENTAL | LGX818 450 mg QD + MEK162 45 mg BID |
| Vemurafenib | ACTIVE_COMPARATOR | Vemurafenib 960 mg BID |
| LGX818 300 mg + MEK162 | EXPERIMENTAL | LGX818 300 mg QD + MEK162 45 mg BID |
| LGX818 | EXPERIMENTAL | LGX818 300 mg QD |
| Arm A: encorafenib, cetuximab and pembrolizumab | EXPERIMENTAL | Participants receive encorafenib orally + cetuximab IV + pembrolizumab IV. |
| Arm B: pembrolizumab | ACTIVE_COMPARATOR | Participants receive pembrolizumab IV. |
| Treatment Period | EXPERIMENTAL | Study treatment with encorafenib and binimetinib will be self-administered orally without regard to food. Patients will receive the following per 28-day (± 3 days) cycle: * Encorafenib: 450 mg (6 × 75 mg capsule) once daily (QD) * Binimetinib: 45 mg (3 × 15 mg tablet) twice daily (BID) |
| LGX818 + MEK162 | EXPERIMENTAL | - |
| LGX818 + MEK162 + LEE011 | EXPERIMENTAL | - |
| LGX818 + MEK162 + BGJ398 | EXPERIMENTAL | - |
| LGX818 + MEK162 + BKM120 | EXPERIMENTAL | - |
| LGX818 + MEK162 + INC280 | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Encorafenib | DRUG | Encorafenib |
| Binimetinib | DRUG | Binimetinib |
| Pembrolizumab | DRUG | Pembrolizumab |
| Cetuximab | DRUG | Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial |
| Oxaliplatin | DRUG | Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial |
| Irinotecan | DRUG | Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial |
| Leucovorin | DRUG | Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial |
| 5-FU | DRUG | Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial |
| Capecitabine | DRUG | 150 mg or 500 mg Tablet |
| Bevacizumab | DRUG | Optional Injection for intravenous use 100 mg/vial or 400 mg/vial |
| Folinic Acid | DRUG | Standard of care. |
| 5-Fluorouracil | DRUG | Standard of care. |
| LGX818 | DRUG | LGX818- Orally 100 mg and 50 mg capsules |
| MEK162 | DRUG | MEK162- Orally 15 mg tablets |
| vemurafenib | DRUG | Tablets in bottles or blisters 240 mg |
| LEE011 | DRUG | Combination of LGX818 + MEK162 + LEE011 (Part II) |
| BGJ398 | DRUG | Combination of LGX818 + MEK162 + BGJ398 (Part II) |
| BKM120 | DRUG | Combination of LGX818 + MEK162 + BKM120 (Part II) |
| INC280 | DRUG | Combination of LGX818 + MEK162 + INC280 (Part II) |
Inclusion Criteria: * Male or female participants ≥ 18 years at the time of informed consent. * Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. * Histologically confirmed unresectable ...
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