Therapeutic efficacy and safety of combined BRAF and MEK inhibition in patients with malignant melanoma: a meta-analysis

Figures & data

Figure 1 Flow diagram of the study selection process.

Table 1 Summary of the characteristics of the studies included in the meta-analysis

Reference (year)	Trial design	Patients (N)	Age, years, median (range)	Treatment regimen	Quality score
Long et al (2017)^Citation9	Phase III	423
	D+T vs D	211 (D+T)/212 (D)	55.5 (23–89)	D (150 mg, bid)+T (2 mg, qd) vs D (150 mg, bid)	5
Johnson et al (2014)^Citation10	Phase I/II	45
	D+T	45 (D+T)	51.0 (18–82)	D (150 mg, bid)+T (2 mg, qd)	4
Long et al (2015)^Citation11	Phase III	423
	D+T vs D	211 (D+T)/212 (D)	56.5 (22–86)	D (150 mg, bid)+T (2 mg, qd) vs D (150 mg, bid)	5
Larkin et al (2014)^Citation12	Phase III	495
	V+C vs V	247 (V+C)/248 (V)	55.0 (23–88)	V (960 mg, bid)+C (60 mg, qd) vs V (960 mg, bid)	4
Schadendorf et al (2015)^Citation13	Phase III	423
	D+T vs D	211 (D+T)/212 (D)	55.0 (25–85)	D (150 mg, bid)+T (2 mg, qd) vs D (150 mg, bid)	3
Robert et al (2015)^Citation14	Phase III	704
	D+T vs V	352 (D+T)/352 (V)	55.0 (18–91)	D (150 mg, bid)+T (2 mg, qd) vs V (960 mg, bid)	4
Corcoran et al (2015)^Citation15	Phase I/II	43
	D+T	43 (D+T)	55.0 (42–69)	D (150 mg, bid)+T (2 mg, qd)	3
Flaherty et al (2012)^Citation16	Phase I/II	423
	D+T vs D	211 (D+T)/212 (D)	58 (27–79)	D (150 mg, bid)+T (2 mg, qd) vs D (150 mg, bid)	6

Abbreviations: bid, twice daily; C, cobimetinib; D, dabrafenib; qd, every day; T, trametinib; V, vemurafenib.

Figure 2 Forest plot analysis of the efficiency outcomes of combined BRAF and MEK inhibition versus BRAF inhibition alone. (A) Overall response rate, (B) progression-free survival, and (C) overall survival.

Abbreviations: CI, confidence interval; IV, inverse variance; M–H, Mantel–Haenszel; SE, standard error.

Table 2 RR of adverse events between combined targeted therapy and monotherapy

Subgroup	Control		Analysis number	All-grade RR	95% CI	P-value
	Combined therapy	Monotherapy
Pyrexia
Combined BRAF and MEK inhibition vs BRAF alone	922	852	11–14, 16	2.00	1.40–2.84	0.0001
Dabrafenib+trametinib vs dabrafenib	318	264	11, 16	2.22	1.76–2.81	<0.00001
Vemurafenib+cobimetinib vs vemurafenib	254	239	12	1.17	0.85–1.61	0.32
Dabrafenib+trametinib vs vemurafenib	350	349	14	2.51	2.00–3.15	<0.00001
Nausea
Combined BRAF and MEK inhibition vs BRAF alone	922	852	11–14, 16	1.41	1.03–1.94	0.03
Dabrafenib+trametinib vs dabrafenib	318	264	11, 16	1.64	1.03–2.62	0.04
Vemurafenib+cobimetinib vs vemurafenib	254	239	12	1.63	1.24–2.15	0.0004
Dabrafenib+trametinib vs vemurafenib	350	349	14	1.03	0.84–1.26	0.77
Diarrhea
Combined BRAF and MEK inhibition vs BRAF alone	922	852	11–14, 16	1.50	1.08–2.06	0.01
Dabrafenib+trametinib vs dabrafenib	527	475	11, 16	1.44	0.76–2.71	0.26
Vemurafenib+cobimetinib vs vemurafenib	254	239	12	2.02	1.61–2.54	<0.0001
Dabrafenib+trametinib vs vemurafenib	350	349	14	1.23	1.01–1.50	0.04
Vomiting
Combined BRAF and MEK inhibition vs BRAF alone	922	852	11–14, 16	1.87	1.52–2.31	<0.0001
Dabrafenib+trametinib vs dabrafenib	318	264	11, 16	1.94	1.28–2.94	0.002
Vemurafenib+cobimetinib vs vemurafenib	254	239	12	1.75	1.16–2.65	0.008
Dabrafenib+trametinib vs vemurafenib	350	349	14	1.90	1.41–2.56	<0.0001
Arthralgia
Combined BRAF and MEK inhibition vs BRAF alone	922	852	11–14, 16	0.71	0.50–1.02	0.06
Dabrafenib+trametinib vs dabrafenib	527	475	11, 16	0.85	0.57–1.26	0.17
Vemurafenib+cobimetinib vs vemurafenib	254	239	12	0.81	0.64–1.03	0.08
Dabrafenib+trametinib vs vemurafenib	350	349	14	0.47	0.38–0.58	<0.0001

Abbreviations: RR, relative risk; MEK, mitogen-activated extracellular signal-regulated kinase.

Figure 3 Subgroup analysis of the relative risk (RR) of all-grade adverse events for combined BRAF and MEK inhibition versus BRAF inhibition alone. (A) Pyrexia, (B) nausea, (C) diarrhea, (D) vomiting, and (E) arthralgia.

Abbreviations: CI, confidence interval; IV, inverse variance; M–H, Mantel–Haenszel; SE, standard error.

Table 3 Overall incidence of all-grade adverse events in patients receiving combined targeted therapy

Subgroup	Sample size		Analysis number	All-grade incidence	95% CI
	Events	Total
Pyrexia
Combined BRAF and MEK inhibition	477	1,003	10–16	0.50	0.37–0.62
Dabrafenib+trametinib	411	756	10–11, 14–16	0.55	0.46–0.64
Vemurafenib+cobimetinib	66	247	12	0.27	0.22–0.33
Nausea
Combined BRAF and MEK inhibition	351	991	10–16	0.38	0.29–0.49
Dabrafenib+trametinib	252	737	10–11, 14–16	0.39	0.27–0.52
Vemurafenib+cobimetinib	99	254	12	0.39	0.33–0.45
Diarrhea
Combined BRAF and MEK inhibition	410	991	10–16	0.39	0.26–0.54
Dabrafenib+trametinib	266	737	10–11, 14–16	0.36	0.22–0.53
Vemurafenib+cobimetinib	144	254	12	0.57	0.51–0.63
Vomiting
Combined BRAF and MEK inhibition	166	991	10–12, 14–16	0.29	0.21–0.39
Dabrafenib+trametinib	205	737	10–11, 14–16	0.31	0.21–0.41
Vemurafenib+cobimetinib	54	254	12	0.21	0.17–0.27
Arthralgia
Combined BRAF and MEK inhibition	213	1,157	10–12, 14, 16	0.24	0.18–0.32
Dabrafenib+trametinib	159	694	10–11, 14–16	0.22	0.14–0.32
Vemurafenib+cobimetinib	54	254	12	0.30	0.24–0.35

Figure 4 Subgroup analysis of the incidence of all-grade adverse events for combined BRAF and MEK inhibition. (A) Pyrexia, (B) nausea, (C) diarrhea, (D) vomiting, and (E) arthralgia.

Abbreviations: CI, confidence interval; W, weight.

Figure 5 Funnel plot analysis for publication bias assessment.

Abbreviations: RR, relative risk; SE, standard error.

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