An indirect treatment comparison of the efficacy of pembrolizumab versus competing regimens for the adjuvant treatment of stage III melanoma

Figures & data

Table 1. Study selection criteria to identify trials for the SLR.

Criteria	Description
Population	Stage III melanoma
	Sub-groups of interest: • BRAF mutation status
Interventions	Pembrolizumab
	Interferon (IFN)-α2a
	IFN-α2b
	Pegylated IFN-α2b
	Nivolumab
	Ipilimumab
	Dabrafenib in combination with trametinib
	Temozolomide in combination with cisplatin
	Vemurafenib
Comparisons	Placebo or best supportive care (BSC)
	Any intervention of interest as monotherapy or in combination
	Any treatment that facilitates an indirect treatment comparison
Outcomes	Recurrence-free (or relapse-free) survival (RFS)
Study design	Randomized controlled trials
	Systematic literature reviews
	Meta-analyses
Other	English language
	No time restriction

Table 2. List of publications and key trial characteristics, arranged by trial.

Trial ID	Phase	Masking	Multi-center	Age (years)	Disease stage	Performance score	Trial number	Principal publication	Subsequent publications
BRIM-8*	III	Double-blind	Yes	≥18	IIC–IIIC	ECOG 0-1	NCT01667419	Maio et al.^14	Lewis et al.^13
Caraceni 1998	—	—	—	18–70	IIIB	Karnofsky 100	—	Caraceni et al.^24	—
CheckMate 238*	III	Double-blind	Yes	≥15	IIIB–IV	ECOG 0-1	NCT02388906	Weber et al.^10	Weber et al.^25
COMBI-AD	III	Double-blind	Yes	≥18	IIIA–IIIC	ECOG 0-1	NCT01682083	Long et al.^26	Hauschild et al.^27
EORTC 18071	III	Double-blind	Yes	≥18	IIIA–IIIC	ECOG 0-1	EUCTR2007-001974-10	Eggermont et al.^9	Coens et al.^28
							NCT00636168		Eggermont et al.^29
									Eggermont et al.^30
EORTC 18952	III	Open-label	Yes	18–70	IIB–IIIC	—	NCT00002763	Eggermont et al.^31	Eggermont et al.^32
							CDR0000064718
EORTC 18991	III	Open-label	Yes	18–70	III	ECOG 0-1	NCT00006249	Eggermont et al.^33	Fusi et al.^34
									Bottomley et al.^35
									Eggermont et al.^36
									Herndon et al.^37
KEYNOTE 054	III	Double-blind	Yes	≥18	III	ECOG 0-1	NCT02362594	Eggermont et al.^11	—
Lian 2013	II	—	No	≥18	II–III	ECOG 0-1	ChiCTR-TRC-11001798	Lian et al.^38	—
Nordic IFN trial*	III	Open-label	Yes	≥18	IIB–III	ECOG 0-1	NCT01259934	Hansson et al.^39	Vihinen et al.^40
SWOG S0008	II	Open-label	Yes	≥10	IIIA–IIIC	Zubrod 0-1	NCT00006237	Flaherty et al.^41	—
WHO MPT 16	II	Open-label	Yes	18–70	III	—	—	Cascinelli et al.^42	—

Note: Trials are listed in alphabetical order; * denotes trials that provide stage III sub-group data.

Table 3. List of publications and key patient characteristics, arranged by trial.

Trial ID	Treatment	n	Median age (range)	Male (%)	ECOG 0 or 1 (%)	Stage IIIA (%)	Stage IIIB (%)	Stage IIIC (%)	Stage III (%)
BRIM-8 cohort 1	Vemurafenib	157	51.0 (43.0–60.0)**	84 (54%)	155 (100%)	36 (23%)	106 (68%)	—	—
	Placebo	157	49.0 (40.0–59.0)**	88 (56%)	157 (100%)	39 (25%)	106 (68%)	—	—
BRIM-8 cohort 2	Vemurafenib	93	55.0 (40.0–61.0)**	52 (56%)	92 (100%)	—	—	93 (100%)	—
	Placebo	91	50.0 (38.0–58.0)**	59 (65%)	91 (100%)	—	—	91 (100%)	—
Caraceni 1998	IFN-α2a	37	46.0 (39.0–53.0)**	22 (60%)	—	—	—	—	—
	Control	30	49.5 (41.0–58.0)**	20 (67%)	—	—	—	—	—
CheckMate 238	Nivolumab	453	56.0 (19.0–83.0)	258 (57%)	—	—	163 (36%)	204 (45%)	—
	Ipilimumab (1 year)	453	54.0 (18.0–86.0)	269 (59%)	—	—	148 (33%)	218 (48%)	—
COMBI-AD	Dabrafenib + trametinib	438	50.0 (18.0–89.0)	195 (45%)	—	83 (19%)	169 (39%)	181 (41%)	—
	Placebo	432	51.0 (20.0–85.0)	193 (45%)	—	71 (16%)	187 (43%)	166 (38%)	—
EORTC 18071	Ipilimumab (3 years)	475	50.7* (20.0–84.0)	296 (62%)	474 (99%)	98 (21%)	213 (45%)	164 (34%)	475 (100%)
	Placebo	476	51.5* (18.0–78.0)	293 (62%)	476 (100%)	88 (18%)	207 (44%)	181 (38%)	476 (100%)
EORTC 18952	IFN-α2b (13 months)	553	49.0 (17.0–74.0)	312 (56%)	—	412 (74%)	—	—	—
	IFN-α2b (25 months)	556	50.0 (16.0–75.0)	308 (55%)	—	414 (74%)	—	—	—
	Observation	279	47.0 (20.0–75.0)	152 (54%)	—	206 (74%)	—	—	—
EORTC 18991	Pegylated IFN-α2b	627	50.0 (19.0–70.0)	366 (58%)	627 (100%)	—	—	—	627 (100%)
	Observation	629	50.0 (18.0–70.0)	367 (58%)	629 (100%)	—	—	—	629 (100%)
KEYNOTE 054	Pembrolizumab	514	54.0 (19.0–88.0)	324 (63%)	514 (100%)	80 (16%)	237 (46%)	197 (38%)	514 (100%)
	Placebo	505	54.0 (19.0–83.0)	304 (60%)	505 (100%)	80 (16%)	230 (46%)	195 (39%)	505 (100%)
Lian 2013	Observation	63	57.0 (25.0–80.0)	28 (44%)	—	—	—	—	21 (33%)
	High-dose IFN-α2b	63	55.0 (26.0–84.0)	25 (40%)	—	—	—	—	16 (25%)
	Temozolomide + cisplatin	63	59.0 (18.0–75.0)	23 (37%)	—	—	—	—	19 (30%)
Nordic IFN trial	Observation	284	51.0 (18.0–76.0)	167 (59%)	284 (100%)	—	—	—	229 (81%)
	IFN-α2b (12 months)	285	53.0 (18.0–73.0)	177 (62%)	285 (100%)	—	—	—	227 (80%)
	IFN-α2b (24 months)	286	51.0 (22.0–77.0)	183 (64%)	286 (100%)	—	—	—	233 (82%)
SWOG S0008	IFN-α2b	203	48.0 (12.0–73.0)	141 (69%)	—	—	—	—	—
	Biochemotherapy†	199	46.0 (10.0–74.0)	141 (71%)	—	—	—	—	—
WHO MPT 16	IFN-α2a	225	—	131 (58%)	222 (99%)	—	—	—	—
	Surgery + observation	219	—	114 (52%)	212 (97%)	—	—	—	—

* Mean age used in trials where median age is not reported.

** IQR minimum and IQR maximum used in trials where age range is not reported.

† Biochemotherapy is a combination of cisplatin + vinblastine + dacarbazine + interleukin-2 (IL-2) + IFN-α + filgrastim (G-CSF).

Figure 1. Network of evidence for recurrence-free survival, Stage III.

Figure 2. Network of evidence for recurrence-free survival, BRAF + sub-group.

Figure 3. Results of fixed-effects time-varying hazards network meta-analyses for recurrence-free survival (a) in Stage III melanoma patients with treatment effects as hazard ratio over time relative to observation under the best-fitting second order fractional polynomial model, (p1 = 0, p2 = 0) and (b) in BRAF + melanoma patients with treatment effects as hazard ratio over time relative to observation under the best-fitting 2nd order fractional polynomial model (p1 = 0, p2 = 0).

Table 4. Time-varying hazard ratios of recurrence-free survival at select follow-up times for competing interventions vs observation, Stage III.

Months	HR vs observation (95% CrI)
	Pembrolizumab	Ipilimumab	Biochemotherapy	Interferon-α2a	Interferon-α2b (12 months)	Interferon-α2b (24 months)	Pegylated Interferon-α2b
3	0.62 (0.50–0.77)*	0.80 (0.64–1.00)	0.34 (0.18–0.65)*	0.74 (0.51–1.07)	0.46 (0.29–0.71)*	0.75 (0.51–1.13)	0.80 (0.65–1.00)
6	0.51 (0.41–0.65)*	0.76 (0.63–0.91)*	0.47 (0.30–0.73)*	0.85 (0.66–1.10)	0.61 (0.45–0.84)*	0.78 (0.59–1.03)	0.83 (0.71–0.98)*
9	0.46 (0.35–0.61)*	0.74 (0.61–0.89)*	0.56 (0.38–0.82)*	0.93 (0.73–1.17)	0.73 (0.56–0.96)*	0.79 (0.61–1.03)	0.85 (0.74–0.98)*
12	0.43 (0.32–0.58)*	0.72 (0.58–0.89)*	0.64 (0.44–0.92)*	0.98 (0.76–1.26)	0.83 (0.64–1.08)	0.80 (0.61–1.05)	0.87 (0.75–1.00)
15	0.40 (0.29–0.57)*	0.71 (0.56–0.90)*	0.70 (0.48–1.03)	1.03 (0.78–1.34)	0.91 (0.70–1.20)	0.81 (0.60–1.09)	0.88 (0.75–1.02)
18	0.39 (0.27–0.56)*	0.70 (0.54–0.91)*	0.76 (0.51–1.14)	1.06 (0.79–1.43)	0.99 (0.74–1.32)	0.82 (0.59–1.13)	0.88 (0.75–1.04)
21	0.37 (0.25–0.55)*	0.69 (0.52–0.92)*	0.81 (0.53–1.26)	1.10 (0.80–1.51)	1.05 (0.78–1.44)	0.82 (0.58–1.17)	0.89 (0.75–1.06)
24	0.36 (0.23–0.54)*	0.69 (0.51–0.93)*	0.86 (0.55–1.38)	1.13 (0.80–1.59)	1.12 (0.81–1.56)	0.83 (0.57–1.20)	0.90 (0.75–1.08)

* Statistically significant results.

Table 5. Time-varying hazard ratios of recurrence-free survival at select follow-up times for competing interventions versus observation, BRAF + sub-group analysis.

Months	HR vs observation (95% CrI)
	Pembrolizumab	Dabrafenib + trametinib	Vemurafenib
3	0.60 (0.41–0.89)*	0.09 (0.06–0.15)*	0.19 (0.08–0.40)*
6	0.48 (0.34–0.66)*	0.24 (0.17–0.32)*	0.48 (0.28–0.79)*
9	0.42 (0.28–0.63)*	0.41 (0.32–0.52)*	0.83 (0.53–1.31)
12	0.38 (0.23–0.63)*	0.60 (0.48–0.76)*	1.23 (0.78–2.00)
15	0.35 (0.19–0.63)*	0.82 (0.64–1.04)	1.66 (1.02–2.90)*
18	0.33 (0.17–0.64)*	1.04 (0.80–1.37)	2.13 (1.23–4.00)*
21	0.32 (0.15–0.65)*	1.28 (0.96–1.74)	2.63 (1.43–5.28)*
24	0.30 (0.14–0.65)*	1.54 (1.11–2.16)*	3.16 (1.62–6.77)*

* Statistically significant results.

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