Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma
Abstract
:1. Introduction
2. Results
2.1. Baseline Characteristics
2.2. Efficacy
2.3. Safety
- Pyrexia includes pyrexia, increased body temperature, hyperpyrexia, hyperthermia;
- Peripheral edema includes peripheral edema, local swelling, localized edema, edema, peripheral swelling;
- Vomiting includes vomiting, retching;
- Arthralgia includes arthralgia, arthropathy, joint stiffness;
- Rash includes rash, exfoliative rash, erythematous rash, follicular rash, generalized rash, macular rash, maculo-papular rash, papular rash, pruritic rash, vesicular rash;
- Visual impairment includes visual impairment, blurred vision, reduced visual acuity;
- Serous retinopathy includes retinal detachment, chorioretinitis, chorioretinopathy, cystoid macular edema, macular retinal pigment epithelium detachment, retinal pigment epithelium detachment, macular detachment, macular edema, metamorphopsia, retinal disorder, retinal exudates, retinal edema, retinal pigment epitheliopathy, retinopathy, subretinal fluid;
- Hemorrhage includes rectal hemorrhage, hematochezia, hematuria, cerebral hemorrhage, epistaxis, hemorrhoidal hemorrhage, menorrhagia, metrorrhagia, retinal hemorrhage, conjunctival hemorrhage, gastric ulcer hemorrhage, gastrointestinal hemorrhage, hematospermia, hemorrhagic cyst, intracranial tumor hemorrhage, polymenorrhea, subdural hematoma, uterine hemorrhage, hemorrhagic diarrhea, hemoptysis, mucosal hemorrhage, occult blood, post procedural hemorrhage, postmenopausal hemorrhage, pulmonary alveolar hemorrhage, tumor hemorrhage, vaginal hemorrhage, wound hemorrhage.
3. Discussion
4. Materials and Methods
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Characteristics | COMBI-v | coBRIM | COLUMBUS | |||
---|---|---|---|---|---|---|
D/T | V | V/C | V | E/B | V | |
Intent-to-treat population | 352 | 352 | 247 | 248 | 192 | 191 |
Age (year) Median (range) | 55 (18–91) | 54 (18–88) | 56 (23–88) | 55 (25–85) | 57 (20–89) | 56 (21–82) |
Male sex, n (%) | 208 (59) | 180 (51) | 146 (59) | 140 (56) | 115 (60) | 111 (58) |
ECOG performance score n/total n (%) | ||||||
0 | 248/350 (71) | 248/352 (70) | 184/243 (76) | 164/244 (67) | 136 (71) | 140 (73) |
1 | 102/350 (29) | 104/352 (30) | 58/243 (24) | 80/244 (33) | 56 (29) | 51 (27) |
2 | 0/350 | 0/352 | 1/243 (<1) | 0/244 | 0 | 0 |
Metastatic status n/total n (%) | ||||||
M0 | 14/351 (4) | 26/351 (7) | 21 (9) | 13 (5) | 9 (5) | 11 (6) |
M1a | 55/351 (16) | 50/351 (14) | 40 (16) | 40 (16) | 26 (14) | 24 (13) |
M1b | 61/351 (17) | 67/351 (19) | 40 (16) | 42 (17) | 34 (18) | 31 (16) |
M1c | 221/351 (63) | 208/351 (59) | 146 (59) | 153 (62) | 123 (64) | 125 (65) |
Number of organs involved n/total n (%) | ||||||
<3 | 177/351 (50) | 201/352 (57) | NR | NR | 105/192 (54) | 104/191 (54) |
≥3 | 174/351 (50) | 151/352 (43) | 87/192 (45) | 87/191 (46) | ||
Elevated LDH n /total n (%) | 118/351 (34) | 114/352 (32) | 112/242 (46) | 104/242 (43) | 55/192 (29) | 52/191 (27) |
BRAF mutation n/total n (%) | ||||||
V600E | 312/346 (90) | 317/351 (90) | 170/194 (88) | 174/206 (84) | 170/192 (89) | 168/191 (88) |
V600K | 34/346 (10) | 34 /351 (10) | 24/194 (12) | 32/206 (16) | 22/192 (11) | 23/191 (12) |
Efficacy Outcome | COMBI-v [27,28] | coBRIM [30,31] | COLUMBUS [22,23,32] | |||
---|---|---|---|---|---|---|
D/T n = 352 | V n = 352 | V/C n = 247 | V n = 248 | E/B n = 192 | V n = 191 | |
PFS *,†, median (95% CI), mo | 11.4 (9.9−14.9) | 7.3 (5.8−7.8) | 12.3 (9.5–13.4) | 7.2 (5.6–7.5) | 14.8 (10.4−18.4) | 7.3 (5.7−8.5) |
HR (95% CI) | 0.56 (0.46−0.69) | 0.58 (0.46−0.72) | 0.49 (0.37−0.64) | |||
ORR * (95% CI), % | 64 (59−69) | 51 (46−56) | 70 (64−75) | 50 (44−56) | 75 (68−81) | 49 (42−57) |
Median DOR * (95% CI), mo | 13.8 (11.0−NR) | 7.5 (7.3−9.3) | 13.0 (11.1−16.6) | 9.2 (7.5−12.8) | 16.2 ** (11.1−20.4) | 8.4 ** (5.8− 11.0) |
Median OS (95% CI), mo | 25.6 (18.3−NR) | 17.2 (16.4−NR) | 22.3 (20.3−NE) | 17.4 (15.0−19.8) | 33.6 (24.4−39.2) | 16.9 (14.0−24.5) |
HR (95% CI) | 0.69 (0.53−0.89) | 0.69 (0.54−0.88) | 0.61 (0.47−0.79) |
AE type, n (%) | COMBI-v [9,27,28] | coBRIM [31,34] | COLUMBUS [22,23,32] | |||
---|---|---|---|---|---|---|
D/T n = 350 | V n = 349 | V/C n = 247 | V n = 246 | E/B n = 192 | V n = 186 | |
Any AE | 343 (98) | 345 (99) | 244 (98.8) | 240 (97.6) | 189 (98) | 185 (99) |
Any serious AE | 131 (37) | 122 (35) | 85 (34.4) | 64 (26) | 66 (34) | 69 (37) |
AE leading to death | 3 (1) | 3 (1) | 5 (2) | 3 (1.2) | 6 (3) | 2 (1) |
Any grade ≥3 AE | 183 (52) | 221 (63) | 176 (71.3) | 146 (59.3) | 111 (58) | 118 (63) |
Any dose interruptions/modifications | 192 (55) | 197 (56) | 110 (44.5) | 87 (35.4) | 102 (53) | 115 (62) |
Discontinuation due to AE | 44 (13) | 41 (12) | 37 (15) | 20 (8.1) | 29 (15) | 32 (17) |
ADR, % | D/T * n = 209 | V/C n = 247 | E/B † n = 192 | |||
---|---|---|---|---|---|---|
All Grades | Grade 3/4 | All Grades | Grade 3/4 | All Grades | Grade 3/4 | |
General | ||||||
Pyrexia | 57 ‡ | 7 | 28 | 2 | 18 | 4 |
Peripheral edema | 25 | 1.4 | 12.6 [31] | NR | 13 | 1 |
Chills | 31 | 0 | 10 | 0 | 0 | 0 |
Gastrointestinal disorders | ||||||
Nausea | 34 | 0.5 | 41 | 1 | 41 | 2 |
Vomiting | 25 | 1.0 | 24 | 1 | 30 | 2 |
Diarrhea | 30 | 1.4 | 60 | 6 | 36 | 3 |
Arthralgia | 26 | 0.9 | 36 [31] | 2.4 [31] | 26 | 1 |
Skin | ||||||
Rash | 42 | 0 | 73 [37] | 17 [37] | 22 | 1 |
Acneiform dermatitis | 10 [33] | NR | 16 [31] | 2 [31] | 4.4 [23] | 0 [23] |
PPE syndrome | 5 [33] | NR | 6 [34] | 0 [34] | 6.2 [23] | 0 [23] |
cuSCC § | 3 | NR | 6 | NR | 2.6 | 0 |
Basal cell carcinoma | 3.3 | NR | 4.5 | NR | 1.6 | 0 |
LV dysfunction ¶ | 6 # | NR | 9 [34] | 2 [34] | 7 | 1.6 ** |
Creatine kinase increased †† | Not monitored ‡‡ | 79 | 14 | 58 | 5 | |
Photosensitivity ¶¶ | 2 [31] | NR | 46 | 4 | 4 [23] | 0.4 [23] |
Liver function tests †† | ||||||
ALT increased | 44 | 3.8 | 68 | 11 | 29 | 6 |
AST increased | 60 | 4.3 | 73 | 8 | 27 | 3 |
ALP increased | 50 | 1.0 | 71 | 7 | 21 | 1 |
Hemorrhage | 19 | 1.9 | 13 | 1 | 19 | 3.2 |
Ocular toxicity | ||||||
Serous retinopathy | Not monitored ## | 26 ††† | NR | 20 ††† | 3 | |
Visual impairment | NR | NR | 15 ‡‡‡ | <1 | 20 ‡‡‡ | 0 |
Uveitis | 2 [33] | NR | 2 [34] | NR | 4 | 0 |
Venous thromboembolism | 2.8 §§§ | NR | NR | NR | 6 | 0 |
ECG QT prolonged | 0.8 [33] | 0 [33] | NR | 1.6 [31] | 0.5 ### | 0 |
Hypertension | 25 | 6 | 15 | 4 | 11 | 6 |
Study Design Characteristic | COMBI-v | coBRIM | COLUMBUS |
---|---|---|---|
Population | Unresectable locally advanced or metastatic melanoma with BRAF V600E/K mutation | Unresectable locally advanced or metastatic melanoma with BRAF V600 mutation | Unresectable locally advanced or metastatic melanoma with BRAF V600E and/or V600K mutation |
Enrollment | 704 patients (June 2012–Oct 2013) | 495 patients (Jan 2013–Jan 2014) | 577 patients (Dec 2013–April 2015) |
Randomization | 1:1 | 1:1 | 1:1:1 |
Treatments | dabrafenib 150 mg BID + trametinib 2 mg QD | vemurafenib 960 mg BID + cobimetinib 60 mg QD | encorafenib 450 mg QD + binimetinib 45 mg BID |
vemurafenib 960 mg BID | vemurafenib 960 mg BID | vemurafenib 960 mg BID encorafenib 300 mg QD * | |
Investigator/Patient blinding | no | yes | no |
Prior systemic therapy permitted | none | none | first-line immunotherapy |
Primary endpoint | OS | PFS (local) | PFS (central) |
Secondary endpoints | PFS (local) ORR DOR | PFS (central) OS ORR DOR | PFS (local) OS ORR DOR TTR |
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Share and Cite
Hamid, O.; Cowey, C.L.; Offner, M.; Faries, M.; Carvajal, R.D. Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma. Cancers 2019, 11, 1642. https://doi.org/10.3390/cancers11111642
Hamid O, Cowey CL, Offner M, Faries M, Carvajal RD. Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma. Cancers. 2019; 11(11):1642. https://doi.org/10.3390/cancers11111642
Chicago/Turabian StyleHamid, Omid, C. Lance Cowey, Michelle Offner, Mark Faries, and Richard D. Carvajal. 2019. "Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma" Cancers 11, no. 11: 1642. https://doi.org/10.3390/cancers11111642