From: Effectiveness and cost-effectiveness of combination therapy versus monotherapy in malignant melanoma
Sample | PFS [%] | OS [%] | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Authors, year, countries [study name] | Intervention | Comparator | N | Randomization | Average age | Women [%] | Blinding | Mean observation time [months] | Median PFS [months] | 12 | 24 | 36 | 48 | 60 | 78 | Median OS [months] | 12 | 24 | 36 | 48 | 60 | 78 | OR [%] | TRAE of grade 3 or 4 [%] | Sponsor | Conclusion |
PD-1-Inhibitor plus CTLA-4-Inhibitor versus CTLA-4-Inhibitor or PD-1-Inhibitor | ||||||||||||||||||||||||||
Hodi et al. 2018, A, AU, B, CDN, CH, CS, D, DK, E, F, FIN, GB, I, IR, ISR, NO, NL, NZ, PL, S, US [CheckMate 067] | [1] NIVO (1 mg/kg) + IPI (3 mg/kg) once every three weeks for 4 doses, then NIVO (3 mg/kg) only every 2 weeks | [2] IPI (3 mg/kg) once every 3 weeks for a total of 4 doses + placebo [3] NIVO (3 mg/kg) once every 2 weeks + placebo | N= 945 [1] 314 [2] 315 [3] 316 | 1:1:1 | 59.6 | 35.4 | DB | [1] 46.9 [2] 18.6 [3] 36.0 | [1] 11.5 [2] 2.9 [3] 6.9 [1] vs. [2]: HR: 0.42 [95% CI: 0.35–0.51; p<0.0001] [1] vs. [3]: HR: 0.79 [95% CI: 0.64–0.96]* | n.s. | n.s. | n.s. | [1] 37 [2] 9 [3] 31 | n.s. | n.s. | [1] >48.0 [2] 19.9 [3] 36.9 [1] vs. [2]: HR: 0.54 [95% CI: 0.44–0.67; p<0.0001] [1] vs. [3]: HR: 0.84 [95% CI: 0.67–1.05]* | n.s. | n.s. | n.s. | [1] 53 [2] 30 [3] 46 | n.s. | n.s. | [1] 58 [2] 19 [3] 45 | [1] 59 [2] 28 [3] 22 | Bristol-Myers Squibb | NIVO plus IPI is more effective than IPI and NIVO in stage III or IV patients. |
Larkin et al. 2019a, A, AU, B, CDN, CH, CS, D, DK, E, F, FIN, GB, I, IR, ISR, NO, NL, NZ, PL, S, US [CheckMate 067] | [1] NIVO + IPI | [2] IPI + placebo [3] NIVO + placebo | N= 945 [1] 314 [2] 315 [3] 316 | 1:1:1 | 59.6 | 35.4 | O | [1] 54.6 [2] 18.6 [3] 36.0 | [1] 11.5 [2] 2.9 [3] 6.9 [1] vs. [2]: HR: 0.42 [95% CI: 0.35–0.51; p<0.001] [1] vs. [3]: HR: 0.79 [95% CI: 0.64–0.96]* | n.s. | n.s. | n.s. | n.s. | [1] 36 [2] 8 [3] 29 | n.s. | [1] >60 [2] 19.9 [3] 36.9 [1] vs. [2]: HR: 0.52 [95% CI: 0.42–0.64; p<0.001] [1] vs. [3]: HR: 0.83 [95% CI: 0.67–1.03]* | n.s. | n.s. | n.s. | n.s. | [1] 52 [2] 26 [3] 44 | n.s. | [1] 58 [2] 19 [3] 45 | [1] 59 [2] 28 [3] 23 | Bristol-Myers Squibb | The 5-year analysis continues to show an improvement in effectiveness with NIVO plus IPI compared with IPI and NIVO. |
Wolchok et al. 2021a, A, AU, B, CDN, CH, CS, D, DK, E, F, FIN, GB, I, IR, ISR, NO, NL, NZ, PL, S, US [CheckMate 067] | [1] NIVO + IPI | [2] IPI + placebo [3] NIVO + placebo | N= 945 [1] 314 [2] 315 [3] 316 | 1:1:1 | 59.6 | 35.4 | O | [1] 57.5 [2] 18.6 [3] 36.0 | [1] 11.5 [2] 2.9 [3] 6.9 [1] vs. [2]: HR: 0.42 [95% CI: 0.35–0.51; p<0.0001][1] vs. [3]: HR: 0.79 [95% CI: 0.65–0.97]* | n.s. | n.s. | n.s. | n.s. | [1] 36 [2] 8 [3] 29 | [1] 34 [2] 7 [3] 29 | [1] 72.1 [2] 19.9 [3] 36.9[1] vs. [2]: HR: 0.52 [95% CI: 0.43–0.64; p<0.0001] [1] vs. [3]: HR: 0.84 [95% CI: 0.67–1.04]* | n.s. | n.s. | n.s. | n.s. | [1] 52 [2] 26 [3] 44 | [1] 49 [2] 23 [3] 42 | [1] 58 [2] 19 [3] 45 | [1] 59 [2] 28 [3] 24 | Bristol-Myers Squibb | The 6.5-year analysis continues to demonstrate an improvement in effectiveness with the combination drug over IPI and NIVO |
BRAF-inhibitor plus MEK-inhibitor versus BRAF-inhibitor | ||||||||||||||||||||||||||
Ascierto et al. 2016, A, AU, B, CDN, CH, D, E, F, GB, H, I, ISR, NL, NO, NZ, R, S, US[coBRIM] | [1] COB (60 mg 1x daily for 3 weeks, followed from day 1 to day 21 in each 28-day cycle) + VEM (960 mg 2x daily) | [2] VEM (960 mg 2x daily) + placebo | N= 495 [1] 247 [2] 248 | 1:1 | [1] 56 [2] 55 | 42.2 | 225742519050000DB | 14.2 | [1] 12.3 [2] 7.2HR: 0.58 [95% CI: 0.46–0.72; p<0.0001] | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | [1] 22.3 [2] 17.4HR: 0.70 [95% CI: 0.55–0.90; p=0.005] | [1] 74.5 [2] 63.8 | [1] 48.3 [2] 38.0 | n.s. | n.s. | n.s. | n.s. | [1] 70 [2] 50 | [1] 60 [2] 52 | Hoffmann-La Roche | COB plus VEM is more effective than VEM in patients with stage III or IV BRAF-mutated melanoma |
Ascierto et al. 2021, A, AU, B, CDN, CH, D, E, F, GB, H, I, ISR, NL, NO, NZ, R, S, US[coBRIM] | [1] COB + VEM | [2] VEM + placebo | N= 495 [1] 247 [2] 248 | 1:1 | [1] 56 [2] 55 | 42.2 | 225742520955000DB | [1] 21.2 [2] 16.6 | [1] 12.6 [2] 7.2 | n.s. | [1] 32 [2] 16 | [1] 23 [2] 13 | [1] 17 [2] 12 | [1] 14 [2] 10 | n.s. | [1] 22.5 [2] 17.4 | n.s. | [1] 49 [2] 39 | [1] 38 [2] 31 | [1] 34 [2] 29 | [1] 31 [2] 26 | n.s. | [1] 70[2] 50 | [1] 78 [2] 63 | Hoffmann-La Roche | The 5-year analysis shows improved effectiveness with COB plus VEM versus VEM in patients with BRAF-mutated stage III or IV melanoma. |
Dummer et al. 2018, AMS, ARG, AU, BRA, CDN, CH, COL, COR, D, E, F, GB, GR, H, I, ISR, J, MEX, NL, NO, P, PL, R, S, SIN, SLK, TRK, US[COLUMBUS] | [1] ENCO (450 mg 1x daily) + BIN (45 mg 2x daily) | [2] VEM (960 mg 2x daily)[3] ENCO (300 mg 2x daily) | N= 577 [1] 192 [2] 191 [3] 194 | 1:1:1 | 55 | 42.1 | O | 742950383857500 [1] 16.7 [2] 14.4 [3] 16.6 | [1] 14.9 [2] 7.3 [3] 9.6 [1] vs. [2]: HR: 0.54 [95% CI: 0.41–0.71; p<0.0001] [1] vs. [3]: HR: 0.75 [95% CI: 0.56–1.00; p=0.051] | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | [1] 63 [2] 40 [3] 51 | [1] 58 [2] 63 [3] 66 | Array BioPharma und Novartis Pharmaceuticals | ENCO plus BIN is more effective than VEM and ENCO in patients with stage III or IV BRAF-mutated melanoma |
Long et al. 2015, ARG, AU, CDN, D, E, F, GB, GR, I, NL, R, S, UKR, US[COMBI-d] | [1] DAB (150 mg 2x daily ) + TRAM (2 mg 1x daily) | [2] DAB (150 mg 2x daily) + placebo | N= 423 [1] 211 [2] 212 | 1:1 | [1] 55 [2] 56.5 | 46.8 | DB | [1] 20 [2] 16 | [1] 11.0 [2] 8.8HR: 0.67 [95% CI: 0.53–0.84; p=0.0004] | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | [1] 25.1 [2] 18.7HR: 0.71 [95% CI: 0.55–0.92; p=0.0107] | [1] 74 [2] 68 | [1] 51 [2] 42 | n.s. | n.s. | n.s. | n.s. | [1] 69 [2] 53 | [1] 32 [2] 31 | GlaxoSmithKline | DAB plus TRAM is more effective in patients with BRAF-mutated stage IIIC or IV melanoma compared with DAB. |
Long et al. 2017, ARG, AU, CDN, D, E, F, GB, GR, I, NL, R, S, UKR, US[COMBI-d] | [1] DAB + TRAM | [2] DAB + placebo | N= 423 [1] 211 [2] 212 | 1:1 | [1] 55 [2] 56.5 | 46.8 | DB | 36 | n.s. | n.s. | [1] 30 [2] 16 | [1] 22 [2] 12 | n.s. | n.s. | n.s. | [1] 25.1 [2] 18.7HR: 0.75 [95% CI: 0.58–0.96] | n.s. | [1] 52 [2] 43 | [1] 44 [2] 32 | n.s. | n.s. | n.s. | [1] 68 [2] 55 | [1] 48 [2] 50 | Novartis | The 3-year analysis demonstrates improved efficacy with DAB plus TRAM versus DAB in patients with BRAF-mutated stage IIIC or IV melanoma. |
Robert et al. 2015, A, ARG, AU, B, BRA, CDN, COR, D, DK, E, F, FIN, GB, H, I, IR, ISR, NL, NO, NZ, PL, R, S, TWN, UKR, US[COMBI-v] | [1] DAB (150 mg 2x daily) + TRAM (2 mg 1x daily) | [2] VEM (960 mg 2x daily) | N= 704 [1] 352 [2] 352 | 1:1 | 55 | 45 | O | 11 | [1] 11.4 [2] 7.3HR: 0.56 [95% CI: 0.46–0.69; p<0.001] | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | [1] >12 [2] 17.2HR: 0.69 [95% CI: 0.53–0.89; p=0.005] | [1] 72 [2] 65 | n.s. | n.s. | n.s. | n.s. | n.s. | [1] 64 [2] 51 | [1] 52 [2] 63 | GlaxoSmithKline | DAB plus TRAM is more effective than VEM in patients with BRAF-mutated stage IIIC or IV melanoma |
PD-1-inhibitor plus MEK-inhibitor versus PD-1-inhibitor | ||||||||||||||||||||||||||
Gogas et al. 2020a, AU, B, BRA, COR, D, E, F, GB, GR, H, I, NL, PL, R, US[IMspire170] | [1] COB (60 mg 1x daily) + ATE (840 mg day 1 und 15 in each 28-day cycle) | [2] PEM (200 mg every 3 weeks) | N= 446 [1] 222 [2] 224 | 1:1 | 66 | 39.5 | O | [1] 7.1 [2] 7.2 | [1] 5.5 [2] 5.7HR: 1.15 [95% CI: 0.88–1.50; p=0.30] | [1] 30 [2] 39 | n.s. | n.s. | n.s. | n.s. | n.s. | [1] >12 [2] >12HR: 1.06 [95% CI: 0.69–1.61] | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | [1] 26 [2] 31.6 | [1] 66.8 [2] 33.3 | Hoffmann-La Roche | COB plus ATE is not more effective than PEM in patients with stage III or IV BRAF wild-type |
PD-1-inhibitor plus IDO-inhibitor versus PD-1-inhibitor | ||||||||||||||||||||||||||
Long et al. 2019a, AMS, AU, B, CDN, CH, COR, D, DK, E, F, GB, I, IR, ISR, J, MEX, NO, NZ, PL, R, S, US[ECHO-301] | [1] PEM (200 mg every 3 weeks) plus EPA (100 mg 2x daily) | [2] PEM (200 mg every 3 weeks) + placebo | N= 706 [1] 354 [2] 352 | 1:1 | [1] 64 [2] 63 | 40.1 | DB | 12.4 | [1] 4.7 [2] 4.9HR: 1.00 [95% CI: 0.83–1.21; p=0.52] | [1] 36.9 [2] 36.6 | n.s. | n.s. | n.s. | n.s. | n.s. | [1] >12 [2] >12HR: 1.13 [95% CI: 0.86–1.49; p=0.81] | [1] 74.4 [2] 74.1 | n.s. | n.s. | n.s. | n.s. | n.s. | [1] 34 [2] 32 | [1] 22 [2] 17 | Incyte Corporation | EPA plus PEM is not more effective compared with PEM in stage III or IV patients |