Table 1.

Main features of included trials—(A) BRAFi or MEKi trials and (B) Immunotherapy trials

Study Acronym NCT	Population (line of therapy)	Treatments	N	OS HR (95% CI)	PFS HR (95% CI)	Response (%)
BREAK‐38, 24 NCT01227889	Unresectable stage III or IV BRAF V600E mutated (1st or 2nd)	Dabrafenib 150 mg po bd	187	0.77 (0.52–1.13)	0.35 (0.20–0.61)	93 (50)
		DTICc	63	Reference	Reference	4 (6)
BRIM‐36, 30 NCT01006980	Previously untreated metastatic BRAF V600E mutated (1st)	Vemurafenib 960 mg po bd	337	0.70 (0.57–0.87)	0.38 (0.32–0.46)	192 (57)
		DTICc	338	Reference	Reference	29 (9)
BRF113220a 7, 22 NCT01072175	Metastatic, no previous BRAFi; BRAF mutated (1st, 2nd, 3rd)	Dabrafenib 150 mg po bd + trametinib 2 mg po od	54	0.79 (0.49–1.27)	0.39 (0.25–0.62)	41 (76)
		Dabrafenib 150 mg po bd + trametinib 1 mg po od	54	0.96 (0.57–1.60)	0.56 (0.37–0.87)	27 (50)
		Dabrafenib 150 mg po bd	54	Reference	Reference	29 (54)
coBRIM 26, 28 NCT01689519	Previously untreated; unresectable stage III or IV; BRAF mutated (1st)	Vemurafenib 960 mg po bd + cobimetinib 60 mg po od 3 weeks on 1 week off	247	0.70 (0.55–0.90)	0.58 (0.46–0.72)	172 (70)
		Vemurafenib 960 mg po bd + placebo	248	Reference	Reference	124 (50)
COMBI‐d9, 10 NCT01584648	Previously untreated; unresectable stage IIIC or IV; BRAF mutated (1st)	Dabrafenib 150 mg po bd + trametinib 2 mg po od	211	0.71 (0.55–0.92)	0.67 (0.53–0.84)	144 (68)
		Dabrafenib 150 mg po bd+ placebo po od	212	Reference	Reference	112 (53)
COMBI‐v34, 35 NCT01597908	Previously untreated; metastatic; BRAF mutated (1st)	Dabrafenib 150 mg po bd + trametinib 2 mg po od	352	0.66 (0.53–0.81)	0.61 (0.51–0.73)	226 (64)
		Vemurafenib 960 mg po bd	352	Reference	Reference	180 (51)
METRIC23, 29 NCT01245062	Unresectable stage III or IV BRAF mutated (no previous BRAFi, MEKi or ipilimumab) (1st or 2nd)	Trametinib 2 mg po od	214	0.54 (0.32–0.92)	0.42 (0.29–0.59)	47 (22)
		DTICc or Paclitaxelf	108	Reference	Reference	9 (8)
NCT0033813025	Previously untreated; unresectable stage III or IV (1st)b	Selumetinib 100 mg po bd continuously	45	1.65 (0.91–3.01)	1.24 (0.73–2.10)	5 (11)
		Temozolomide	28	Reference	Reference	3 (11)
NCT0093622133	Previously untreated; advanced BRAF‐mutated cutaneous or unknown primary (1st)b	Selumetinib 75 po bd + DTICc	45	0.93 (0.57–1.53)	0.63 (0.40–0.98)	18 (40)
		Placebo po bd + DTICc	46	Reference	Reference	12 (26)
(B)
CheckMate 037 NCT0172174613	Progression after ipilimumab (and BRAFi if BRAF mutated) (2nd or further)	Nivolumab 3 mg/kg iv every 2 weeks	272	–	–	38 (32)
		Carbotaxold or DTICc	133	Reference	Reference	5 (11)
CheckMate 066 NCT0172177215	Previously untreated; unresectable, stage III or IV non‐uveal, BRAF wild type (1st)	Nivolumab 3 mg/kg iv every 2 weeks + DTIC‐placebo	210	0.42 (0.25–0.73)	0.43 (0.34–0.56)	84 (40)
		DTICc + nivo‐placebo iv every 2 weeks	208	Reference	Reference	29 (14)
CheckMate 067 NCT0184450527	Previously untreated; unresectable stage III or IV; BRAF mutated (1st)	Nivolumab 3 mg/kg iv every 2 weeks + ipi‐placebo iv	316	–	0.57 (0.43–0.76)	138 (44)
		Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg iv both every 3 weeks 4× then Nivolumab 3 mg/kg iv every 2 weeks	314	–	0.42 (0.31–0.57)	181 (58)
		Ipilimumab 3 mg/kg + nivo‐placebo iv every 3 weeks 4× then nivo‐placebo iv every 2 weeks	315	–	Reference	60 (19)
CheckMate 069 NCT0192741914, 39	Previously untreated; unresectable, stage III or IV (1st)	Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg iv every 3 weeks 4× then Nivolumab 3 mg/kg iv every 2 weeks (BRAF wild type)	72	d	0.40 (0.23–0.68)	44 (61)
		Ipilimumab 3 mg/kg + Placebo iv every 3 weeks 4× then Placebo iv every 2 weeks (BRAF wild type)	37	–	Reference	4 (11)
		Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg iv every 3 weeks 4× then Nivolumab 3 mg/kg iv every 2 weeks (BRAF mutated)	23	–	0.38 (0.15–1.00)	12 (52)
		Ipilimumab 3 mg/kg + Placebo iv every 3 weeks 4× then Placebo iv every 2 weeks (BRAF mutated)	10	–	Reference	1 (10)
Keynote 002 NCT0170428732	Progression after ipilimumab and BRAFi if BRAF mutated (2nd or 3rd)	Pembrolizumab 2 mg/kg iv every 2 weeks	180	–	0.57 (0.45–0.73)	38 (21)
		Pembrolizumab 10 mg/kg iv every 2 weeks	181	–	0.50 (0.39–0.64)	46 (25)
		DTICc or paclitaxeld or temozolomidee or carbotaxolf	179	Reference	Reference	8 (4)
Keynote‐006 NCT0186631936	Unresectable stage III or IV (1st or 2nd)	Pembrolizumab 10 mg/kg iv every 2 weeks	183	0.58 (0.41–0.84)	0.55 (0.42–0.72)	62 (34)
		Pembrolizumab 10 mg/kg iv every 3 weeks	185	0.68 (0.47–0.96)	0.50 (0.38–0.66)	60 (33)
		Ipilimumab 3 mg/kg iv every 3 weeks 4x	181	Reference	Reference	22 (12)
NCT0025720531	Previously untreated; unresectable stage III or IV (1st)	Tremelimumab 10 mg/kg every 90 days	328	0.9 (0.75–1.07)	0.94 (0.81–1.11)	36 (11)
		Temozolomidee or DTICc	327	Reference	Reference	32 (10)

NCT, National Clinical Trial (NCT) number found on clinicaltrials.gov; N, number of enrolled patients; OS, overall survival; PFS, progression‐free survival; HR, hazard ratio; BRAFi, BRAF inhibitor; MEKi, MEK inhibitor; po, oral; od, once a day; bd, twice a day; iv, intravenously; ipi‐placebo, placebo matched to ipilimumab; nivo‐placebo, placebo matched to nivolumab.

^aIncluded patients from randomized part (part C) of the trial.

^bBRAF mutation‐positive data extracted from subgroup analysis.

Data available after systematic review and not included in the meta‐analysis.

^cDTIC: Dacarbazine 1000 mg/kg iv every 3 weeks.

Paclitaxel: Paclitaxel 175 mg/m² every 3 weeks.

^dCarbotaxol: Paclitaxel 175 mg/m² plus carboplatin AUC 5 both iv every 3 weeks.

^eTemozolomide: temozolomide 200 mg/m²/d 5 days ON every 28 days.

^fCarbotaxol: Paclitaxel 225 mg/kg plus Carboplatin AUC 6 both iv every 3 weeks.