Mechanism

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	0.72 [0.58 0.89]	p=0.04	0	951	1	EORTC 18071 (Eggermont),
progression or death (progression free survival PFS)	0.76 [0.64 0.90]	p=0.04	0	951	1	EORTC 18071 (Eggermont),
Adverse events leading to treatment discontinuation	no data
objective response (ORR)	no data
Grade 3–5 drug-related AEs	2.07 [1.57 2.72]	p=0.04	0	945	1	EORTC 18071 (Eggermont),
Grade 3–5 drug-related AEs	2.07 [1.57 2.72]	p=0.04	0	945	1	EORTC 18071 (Eggermont),
serious drug-related adverse events	no data
recurrence free survival	0.76 [0.64 0.90]	p=0.04	0	951	1	EORTC 18071 (Eggermont),
toxic death	no data
vitiligo any grade	no data
vitiligo grade 3-4	no data
distant metastasis free survival	0.76 [0.63 0.91]	p=0.04	0	951	1	EORTC 18071 (Eggermont),
aaa	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
EORTC 18071 (Eggermont), 2015	ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred	placebo	high risk patients who had undergone complete resection of stage III melanoma

Nivolumab

melanoma, in adjuvant 1 - NOVARTIS

by 35% [demonstrated]

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	no data
progression or death (progression free survival PFS)	0.65 [0.51 0.83]	p=0.04	0	906	1	CheckMate 238,
Adverse events leading to treatment discontinuation	0.23 [0.16 0.33]	p=0.04	0	906	1	CheckMate 238,
objective response (ORR)	no data
Grade 3–5 drug-related AEs	0.31 [0.23 0.43]	p=0.04	0	905	1	CheckMate 238,
Grade 3–5 drug-related AEs	0.31 [0.23 0.43]	p=0.04	0	905	1	CheckMate 238,
serious drug-related adverse events	no data
recurrence free survival	0.65 [0.51 0.83]	p=0.04	0	906	1	CheckMate 238,
toxic death	no data
vitiligo any grade	no data
vitiligo grade 3-4	no data
distant metastasis free survival	no data
aaa	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
CheckMate 238, 2017	nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks	ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks	patients with Complete Resection of Stage IIIb/c or Stage IV Melanoma

Pembrolizumab

melanoma, in adjuvant 1 - NOVARTIS

vs placebo

by 43%

by 335%

by 43% [demonstrated]

by 196%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	no data
progression or death (progression free survival PFS)	0.57 [0.43 0.75]	p=0.04	0	1019	1	KEYNOTE-054,
Adverse events leading to treatment discontinuation	no data
objective response (ORR)	no data
Grade 3–5 drug-related AEs	4.35 [2.53 7.48]	p=0.04	0	1011	1	KEYNOTE-054,
Grade 3–5 drug-related AEs	4.35 [2.53 7.48]	p=0.04	0	1011	1	KEYNOTE-054,
serious drug-related adverse events	no data
recurrence free survival	0.57 [0.43 0.75]	p=0.04	0	1019	1	KEYNOTE-054,
toxic death	no data
vitiligo any grade	2.96 [1.32 6.65]	p=0.04	0	1011	1	KEYNOTE-054,
vitiligo grade 3-4	0.99 [0.02 49.80]	p=1.00	0	1011	1	KEYNOTE-054,
distant metastasis free survival	no data
aaa	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
KEYNOTE-054, 2018	Pembrolizumab (Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle for up to 1 year)	placebo	patients with complete Resection of High-Risk Stage III Melanoma

Vemurafenib

melanoma, in adjuvant 1 - NOVARTIS

vs placebo

by 35%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	0.72 [0.45 1.16]	p=1.00	0	498	1	BRIM 8,
progression or death (progression free survival PFS)	0.65 [0.50 0.85]	p=0.04	0	-18	1	BRIM 8,
Adverse events leading to treatment discontinuation	no data
objective response (ORR)	no data
Grade 3–5 drug-related AEs	no data
Grade 3–5 drug-related AEs	no data
serious drug-related adverse events	no data
recurrence free survival	no data
toxic death	no data
vitiligo any grade	no data
vitiligo grade 3-4	no data
distant metastasis free survival	no data
aaa	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
BRIM 8, 2018	e twice-daily adjuvant oral vemurafenib 960 mg tablets for52 weeks (13×28-day cycles)	placebo	patients with resected,BRAFV600 mutation-positive melanoma: IC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2)

Trametinib + dabrafenib

melanoma, in adjuvant 1 - NOVARTIS

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	0.57 [0.42 0.78]	p=0.04	0	-18	1	COMBI-AD,
progression or death (progression free survival PFS)	0.47 [0.39 0.57]	p=0.04	0	-18	1	COMBI-AD,
Adverse events leading to treatment discontinuation	no data
objective response (ORR)	no data
Grade 3–5 drug-related AEs	no data
Grade 3–5 drug-related AEs	no data
serious drug-related adverse events	no data
recurrence free survival	no data
toxic death	no data
vitiligo any grade	no data
vitiligo grade 3-4	no data
distant metastasis free survival	no data
aaa	0.51 [0.40 0.65]	p=0.04	0	-18	1	COMBI-AD,

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
COMBI-AD, 2017	dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months	placebo	Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma

Trametinib + dabrafenib

melanoma, in adjuvant 1 - NOVARTIS

vs SOC

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	no data
progression or death (progression free survival PFS)	no data
Adverse events leading to treatment discontinuation	no data
objective response (ORR)	no data
Grade 3–5 drug-related AEs	no data
Grade 3–5 drug-related AEs	no data
serious drug-related adverse events	no data
recurrence free survival	no data
toxic death	no data
vitiligo any grade	no data
vitiligo grade 3-4	no data
distant metastasis free survival	no data
aaa	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
COMBI neo, 2018

Interferon alpha

melanoma, in adjuvant 1 - NOVARTIS

vs observation

by 13%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
death (overall survival)	0.93 [0.84 1.03]	p=1.00	0	-72	4	EORTC18871/DKG 80-1 (Kleeberg), EORTC18952 (Eggermont), EORTC18991 (Eggermont), Nordic IFN Trial,
progression or death (progression free survival PFS)	0.87 [0.79 0.96]	p=0.04	0	-72	4	EORTC18871/DKG 80-1 (Kleeberg), EORTC18952 (Eggermont), EORTC18991 (Eggermont), Nordic IFN Trial,
Adverse events leading to treatment discontinuation	no data
objective response (ORR)	no data
Grade 3–5 drug-related AEs	no data
Grade 3–5 drug-related AEs	no data
serious drug-related adverse events	no data
recurrence free survival	no data
toxic death	no data
vitiligo any grade	no data
vitiligo grade 3-4	no data
distant metastasis free survival	0.91 [0.80 1.02]	p=1.00	0	-36	2	EORTC18952 (Eggermont), EORTC18991 (Eggermont),
aaa	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
EORTC18871/DKG 80-1 (Kleeberg), 2004	rIFN-alpha2b	observation	High-risk stage II patients (thickness >3 mm) and stage III patients (positivelymph nodes) without distant metastasis
EORTC18952 (Eggermont), 2005			patients who had had a thick primary tumour (thickness4 mm) resected (stage IIb) or regional lymph node metastases dissected (stage III)
EORTC18991 (Eggermont), 2008	pegylated interferon alfa-2b 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years		patients with resected stage III melanoma
Nordic IFN Trial, 2011	intermediate-dose interferon alfa-2b duration 1	duration 2	patients with stage IIB-IIC or III resected cutaneous melanoma.

A EFFACER