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Table 1 Overview of included randomized controlled trials

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

  1. A Austria, AMS South America, ARG Argentina, ATE atezolizumab, AU Australia, B Belgium, BIN binimetinib, BRA Brazil, BRAF B-rapidly accelerated fibrosarcoma protein, CDN Canada, CH Switzerland, COB cobimetinib, COL Colombia, COR Korea, CS Czech Republic, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, D Germany, DAB dabrafenib, DB double-blind, DK Denmark, E Spain, ENCO encorafenib, EPA epacadostat, F France, FIN Finland, GB United Kingdom, GR Greece, H Hungary, HR hazard ratio, I Italy, IDO indoleamine 2,3-dioxygenase, IPI ipilimumab, IR Ireland, ISR Israel, J Japan, KI confidence interval, MEK mitogen-activated protein kinase, MEX Mexico, N study size, NIVO Nivolumab, NL Netherlands, NO Norway, NZ New Zealand, n.s. not specified, O Open, OS overall survival, P Portugal, PD-1 programmed cell death protein 1, PEM pembrolizumab, PFS progression-free survival, PL Poland, R Russia, S Sweden, SIN Singapore, SLK Slovakia, TRAE treatment-related adverse events, TRAM trametinib, TRK Turkey, TWN Taiwan, UKR Ukraine, US United States of America, VEM vemurafenib
  2. *The study design is not designed for a comparison between the combination drug and nivolumab. The analysis is performed without formal hypothesis testing. Therefore, only descriptive p-values are reported
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Journal of Pharmaceutical Policy and Practice

ISSN: 2052-3211

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