Table 2.
Summary of trials leading to current FDA approvals for BRAF inhibitors. Independent review data are used whenever reported in the most updated analysis
| Vemurafenib | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| PFS, months (median) |
OS, months (median) |
ORR (%) |
||||||||
| Study | Phase | Population | Design | Drug | Control | Drug | Control | Drug | Control | Cohort |
| BRIM-3 study (NCT01006980)18, 19, 20 | Phase III | Patients with treatment-naive BRAF V600-mutated unresectable or metastatic melanoma | Patients were randomized to receive vemurafenib 960 mg orally twice daily (n = 337) or dacarbazine 1000 mg/m2 i.v. every 3 weeks (n = 338) | 6.9 For V600E (5.9 for V600K) | 1.6 For V600E (1.7 for V600K) | 13.6 For V600E (14.5 for V600K) | 9.7 For V600E (7.6 for V600K) | 57 | 9 | |
| NCT0094970221a | Phase II | Patients with previously treated BRAF V600-mutated metastatic melanoma | Patients received vemurafenib 960 mg orally twice daily (n = 132) | 6.8 | 15.9 | 53 | ||||
| NCT0137897522b | Phase II | Patients with BRAF V600-mutated melanoma who have metastatic disease in the brain | Patients received vemurafenib 960 mg orally twice daily (n = 146) and were categorized into two cohorts. Cohort 1 included patients with no prior local therapy for brain metastasis (n = 90) whereas cohort 2 included patients who progressed after prior local therapy (n = 56) | 3.7 | 8.9 | 33 For EC RR (18 for IC RR) | Cohort 1 | |||
| 4 | 9.6 | 23 For EC RR (18 for IC RR) | Cohort 2 | |||||||
| VE-BASKET (NCT01524978)23, 24, 25 | Phase II | Patients with BRAF V600-mutated nonmelanoma solid tumors | Patients received vemurafenib 960 mg orally twice daily (n = 172). A separate analysis included 22 patients with ECD and was the basis for FDA approved indication24 | 5.8 | 17.6 | 33 | Overall cohort (Responses seen in 13 cancers) |
|||
| 7.3 | NR | 42 | NSCLC | |||||||
| NR | NR | 62 | ECD/LCH | |||||||
| 12 | CGC | |||||||||
| 29 | ATC | |||||||||
| 4.5 (3.7 for combo) | 9.3 (7.1 for combo) | 0 (4 with combo) | CRC | |||||||
| Dabrafenib | ||||||||||
| BREAK-3 Study (NCT01227889)26,27c | Phase III | Patients with BRAF V600E-mutated unresectable or metastatic melanoma | Patients were randomized to receive dabrafenib 150 mg orally twice daily (n = 187) or dacarbazine 1000 mg/m2 i.v. every 3 weeks (n = 63) | 6.9 | 2.7 | 18.2 | 15.6 | 50 | 6 | |
| BREAK-MB Study (NCT01266967)28d | Phase II | Patients with BRAF V600E- or V600K-mutated melanoma who have metastatic disease in the brain | Patients received dabrafenib 150 mg orally twice daily (n = 172) and were categorized into two cohorts. Cohort A included patients with no prior local therapy for brain metastasis (n = 89) whereas cohort B included patients who progressed after prior local therapy (n = 83) | 16.1 For V600E (8.1 for V600K) | 33.1 For V600E (16.3 for V600K) | 28 For V600E (0 for V600K) | Cohort A | |||
| 16.6 For V600E (15.9 for V600K) | 31.4 For V600E (21.9 for V600K) | 23 For V600E (11 for V600K) | Cohort B | |||||||
| Trametinib | ||||||||||
| METRIC study (NCT01245062)29,30 | Phase III | Patients with BRAF V600E- or V600K-mutated unresectable or metastatic melanoma | Patients were randomized to receive trametinib 2 mg orally once daily (n = 214) or chemotherapy [dacarbazine 1000 mg/m2 i.v. every 3 weeks or paclitaxel 175 mg/m2 i.v. every 3 weeks] (n = 108) | 4.9 | 1.5 | 15.6 | 11.3 | 29 | 9 | |
| Dabrafenib + trametinib | ||||||||||
| COMBI-d Study (NCT01584648)31,32 | Phase III | Patients with BRAF V600E- or V600K-mutated unresectable or metastatic melanoma | Patients were randomized to receive either a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) (n = 211) or dabrafenib and placebo (n = 212) | 9.3 | 8.8 | NR | NR | 68 | 55 | |
| COMBI-v Study (NCT01597908)33 | Phase III | Patients with BRAF V600E- or V600K-mutated unresectable or metastatic melanoma | Patients were randomized to receive either combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) (n = 352) or vemurafenib 960 mg orally twice daily (n = 352) | 11.4 | 7.3 | NR | 17.2 | 64 | 51 | |
| COMBI-MB Study (NCT02039947)34 | Phase II | Patients with BRAF V600E- or V600K-mutated melanoma with brain metastasis | Patients (n = 125) received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily in four cohorts. Cohort A (n = 76) included asymptomatic patients with BRAF V600E mutation who had no prior local brain therapy. Cohort B (n = 16) included asymptomatic patients with BRAF V600E mutation who had prior local therapy. Cohort C (n = 16) included asymptomatic patients with BRAF V600D/K/R mutations who had no prior local brain therapy. Cohort D (n = 17) included patients with symptomatic disease regardless of local therapy or mutation subtype | 5.6 | 10.8 | 58 | Cohort A | |||
| 7.2 | 24.3 | 56 | Cohort B | |||||||
| 4.2 | 10.1 | 44 | Cohort C | |||||||
| 5.5 | 11.5 | 65 | Cohort D | |||||||
| COMBI-AD (NCT01682083)35 | Phase II | Patients with completely resected BRAF V600E- or V600K-mutated stage III melanoma | Patients were randomized to receive either combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) (n = 438) or placebo (n = 432) for 12 months | NR (RFS) | 16.6 (RFS) | NR | NR | 37 (Recurrence) | 57 (Recurrence) | |
| Study BRF113928 (NCT01336634)36, 37, 38, 39 | Phase II | Patients with BRAF V600E-mutated metastatic NSCLC | Patients (n = 171) received dabrafenib 150 mg orally twice daily in cohort A (n = 78) or dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily in cohort B (n = 57) and cohort C (n = 36). Cohorts A and B included patients with at least one prior therapy. Cohort C included patients with treatment-naive disease | 5.5 | 12.6 | 33 | Cohort A | |||
| 10.2 | 18.2 | 68 | Cohort B | |||||||
| 10.8 | 17.3 | 64 | Cohort C | |||||||
| ROAR Trial; BRF117019 (NCT02034110)40, 41, 42, 43,56e | Phase II | Patients with BRAF V600E-mutated rare cancers, including anaplastic thyroid cancer (ATC) (n = 36), high-grade glioma (HGG) (n = 45), low-grade glioma (LGG) (n = 13), and biliary tract cancer (BTC) (n = 43) | Patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily | 5.5 | 14.5 | 53 | ATC | |||
| 9 | 14 | 47 | BTC | |||||||
| 14 | NR | 69 | LGG | |||||||
| 4.5 | 17.6 | 31 | HGG | |||||||
| NR | NR | 89 | HCL | |||||||
| NCI-MATCH Study (arm H); EAY131-H (NCT02465060)44 | Phase II | Patients with BRAF V600E-mutated cancers other than thyroid, melanoma, and CRC | Patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily (n = 35) | 11.4 | 28.6 | 38 | Overall cohort (Responses seen in 7 cancers) |
|||
| CTMT212X2101; Study X2101 (NCT02124772)45,55f | Phase I/II | Pediatric patients with BRAF V600-mutated solid tumors | Patients received dabrafenib 5.25 mg/kg/day and trametinib 0.032 mg/kg/day (n = 48) | 36.9 | 25 | LGG Cohort | ||||
| Encorafenib + binimetinib | ||||||||||
| COLUMBUS (NCT01909453)46, 47, 48g | Phase III | Patients with BRAF V600E- or V600K-mutated unresectable or metastatic melanoma | Patients were randomized to receive encorafenib 450 mg orally once daily in combination with binimetinib 45 mg twice daily (n = 192), encorafenib 300 mg orally once daily (n = 194), or vemurafenib 960 mg twice daily (n = 191) | 14.9 For combo |
7.3 For vemurafenib (9.6 for encorafenib) | 33.6 For combo |
16.9 For vemurafenib (23.5 for encorafenib) | 64 For combo |
41 For vemurafenib (52 for encorafenib) | |
| Encorafenib + cetuximab | ||||||||||
| BEACON CRC (NCT02928224)49, 50, 51 | Phase III | Patients with previously untreated BRAF V600E-mutated metastatic colorectal cancer | Patients were randomized to receive either a doublet combination of encorafenib (300 mg orally once daily) and cetuximab (400 mg/m2 initial dose then 250 mg/m2 once a week) (n = 220), triplet combination of encorafenib, cetuximab, and binimetinib (45 mg twice daily) (n = 224), or control of investigator’s choice [cetuximab + irinotecan or cetuximab + FOLFIRI] (n = 221) | 4.3 For doublet |
1.5 For control (4.5 for triplet) | 9.3 For doublet |
5.9 For control (9.3 for triplet) | 20 For doublet |
2 For control (27 for triplet) | |
| Vemurafenib + cobimetinib | ||||||||||
| coBRIM Trial (NCT01689519)52, 53, 54 | Phase III | Patients with previously untreated BRAF V600-mutated unresectable or metastatic melanoma | Patients (n = 495) received vemurafenib 960 mg orally twice daily and were randomized to receive cobimetinib 60 mg orally once daily D1-21 of an every 28-day cycle (n = 247) or matching placebo (n = 248) | 12.6 | 7.2 | 22.5 | 17.4 | 70 | 50 | |
ATC, anaplastic thyroid carcinoma; BTC, biliary tract cancer; CGC, cholangiocarcinoma; CRC, colorectal cancer; EC, extracranial; ECD, Erdheim–Chester disease; FDA, Food and Drug Administration; HCL, hairy cell leukemia; HGG, high-grade glioma; IC, intracranial; LCH, Langerhans cell histiocytosis; LGG, low-grade glioma; NR, not reached; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
Investigator-assessed ORR was 57% with a concordance of 83% between investigators’ assessment and assessment by independent review committee (IRC).
Investigator-assessed extracranial ORR was 32% and 23%, whereas intracranial ORR was 29% and 23% for cohorts 1 and 2, respectively.
Investigator-assessed ORR was 53% and 19% for dabrafenib and control, respectively.
In the original paper published in Lancet Oncology, investigator and IRC assessments were discordant in 72 (42%) patients. Per the investigators, the discordance between the investigator and review committee response assessment, particularly for intracranial disease, led to a blinded adjudication, in which investigator assessments were upheld in two-thirds of cases. Therefore, the reported investigator-assessed overall ORR for BREAK-MB was 38% and 31% in patients with V600E mutation in cohorts A and B, respectively (0% and 28% in patients with V600K); which is quite different from the IRC-assessed ORR which is reported in the Table 2. It is of note that the intracranial ORR was 39% and 31% for patients with V600E; and 7% and 22% for patients with V600K in cohorts A and B, respectively.
Investigator-assessed ORR was the primary endpoint in the ROAR study and was reported as 56%, 51%, 69%, 33%, and 89% in ATC, BTC, LGG, HGG, and HCL, respectively. Table contains IRC-reported ORR for ATC, BTC, LGG, and HGG but not HCL since it was not reported in the original study.
Investigator-assessed ORR was 53% in the combination group.
By local review, ORR was observed in 76%, 58%, and 49% in combination, encorafenib monotherapy, and vemurafenib groups, respectively.