BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy

Figures & data

Figure 1 The MAPK signaling cascade.

Note: Adapted with permission of Khan et al, from Future of radiation therapy for malignant melanoma in an era of newer, more effective biological agents. Khan MK, Khan N, Almasan A, Macklis R. OncoTargets and Therapy. 2011;4:137–148. Permission conveyed through Copyright Clearance Center, Inc. Copyright © 2011 Khan et al, publisher and licensee Dove Medical Press Ltd.⁶⁹
Abbreviation: GTP, guanosine triphosphatase.

Table 1 Efficacy of concomitant BRAF ± MEKi and radiotherapy in MBM

Reference	Radiation + BRAFi ± MEKi patients (n)	BRAFi ± MEKi	BRAFi timing	Radiation regimen	Median dose (Gy)/median number of fractions	Median survival radiation alone (months)	Median survival radiation + BRAFi ± MEK (months)	Toxicity
								Toxicity type	Radiation alone (%)	Radiation + BRAFi ± MEKi (%)
Narayana et al^Citation54	12	VMF	Concurrent	SRS ± PBRT/WBRT	20/1 (SRS) 30/15 (PBRT/WBRT)	N/A	13.7	RN	N/A	8.3
Gaudy-Marqueste et al^Citation55	30	VMF or DAB	Concurrent, before, or after	SRS*	20–28/1	N/A	6.2	RN	N/A	0
Ahmed et al^Citation56	24	VMF	Concurrent (held 2/3 days before/after)**	SRS	24/1	N/A	7.2	RN	N/A	4.2
Ly et al^Citation57	17	VMF or DAB	Concurrent and after	SRS	20/1	NR	NR	ITH	23	60.7
Patel et al^Citation58	15	VMF or DAB	Concurrent, before, or after	SRS	21/1	NR	NR	SRN	11.1	28.2
Xu et al^Citation59	17	VMF or DAB	Concurrent and after	SRS*	20/1	1	13	RN ITH	8.6 8.6	17.6 29.4
Patel et al^Citation60	6	DAB + TRA	Concurrent, before, or after	SRS	21/1	NR	20	RN	N/A	0
Peuvrel et al^Citation66	1	VMF	Concurrent	SRS	20/1	N/A	NR	RN	N/A	100
Liebner et al^Citation65	1	VMF	After	SRS	27/3, 22/1, 24/4***	N/A	NR	RN	N/A	100
Liebner et al^Citation65	1	VMF	Before and after	SRS	30/5	N/A	NR	RN	N/A	100
Lee et al^Citation67	1	DAB	Concurrent	SRS	NR	N/A	NR	ITH	N/A	100

Notes:

* These studies utilized GKRS, while the remaining studies used LINAC-based SRS.

** Before specifically refers to delivering SRS within five half lives of stopping BRAFi.

*** Three lesions were treated with differing SRS fractionation schemes.

Abbreviations: BRAFi, BRAF inhibitor; MEKi, MEK inhibitor; MBM, melanoma brain metastases; VMF, vemurafenib; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy; PBRT, partial brain radiation therapy; N/A, not applicable; NR, not reported; RN, radiation necrosis; DAB, dabrafenib; ITH, intratumoral hemorrhage; SRN, symptomatic radiation necrosis; TRA, trametinib; GKRS, Gamma Knife Radiosurgery; LINAC, linear accelerator.

Table 2 Currently ongoing or recently completed prospective clinical trials of BRAFi ± MEKi or radiation therapy for MBM

NCTN number	Trial type	Intervention	Main eligibility	Cohorts	Planned enrollment	Primary outcome
NCT01378975	Phase 2	VMF	Histologically confirmed BRAF-mutated melanoma with measurable metastatic MBM at least ≥0.5 cm ± symptoms, ECOG PS 0–1	Previously untreated Previously treated	146	Best overall response rate in Cohort A
NCT01781026	Phase 2	VMF	Neoadjuvant therapy in BRAF V600E- or K-mutated melanoma, with ≥1 untreated MBM not immediately amenable to local treatment before definitive surgery, ablation, or radiation at a target of 8 weeks following VMF, ECOG PS <3	Single arm	2	Intracranial response
NCT02039947	Phase 2	DAB + trametinib	Histologically confirmed BRAF V600E-, K-, D-, or R-mutated melanoma with ≥1 measurable MBM, ECOG PS 0–2	V600E, asymptomatic, no prior local therapy V600E, asymptomatic, prior local therapy V600D/K/R, asymptomatic, ± prior local therapy V600D/K/R, symptomatic, ± prior local therapy	120	Intracranial response rate
NCT02537600	Phase 2	VMF + cobimetinib	Histologically confirmed BRAF-mutated melanoma with ≥1 measurable MBM between 5 mm and 40 mm, ECOG PS ≤2	Neurologically asymptomatic, no prior local therapy Neurologically asymptomatic, prior local therapy Neurologically symptomatic, ± prior local therapy	137	Intracranial response rate in Cohort A
NCT01978236	Phase 2	DAB ± trametinib	Histologically confirmed BRAF V600E/K-mutated melanoma with ≥11 measurable MBM ≥1 cm but ≤4 cm that can be treated with surgical resection and no immediate local therapy, at least 2 extracranial lesions easily accessible for biopsy, ECOG PS 0–2	DAB DAB + trametinib	30	Concentrations and tissue distribution of DAB, its metabolites, and trametinib in MBM, extracranial metastases, and peripheral blood on day of surgery in Cohort B
NCT01721603	Phase 2	DAB + GKRS	Histologically confirmed BRAF V600E-mutated melanoma with ≤4 untreated MBM (at least one >0.5 cm) with no MBM >3 cm, ECOG PS 0–2	Single arm	39	6-month DBMFS

Abbreviations: BRAFi, BRAF inhibitor; MEKi, MEK inhibitor; MBM, melanoma brain metastases; VMF, vemurafenib; ECOG PS, Eastern Cooperative Oncology Group performance status; DAB, dabrafenib; GKRS, Gamma Knife Radiosurgery; DBMFS, distant brain metastasis-free survival.

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