Details of data from Melanoma clinical trials

Investigated (inv)

Comparator (comp)

NIVO+IPI

NIVO

314

316

Phase:

3

Randomisation:

Double blind

Primary tumour:

Melanoma

Subtype (biomarker):

Any

Stage:

Line of therapy:

L1

Primary

NIVO+IPI

NIVO

HR

p

OS

60.0 mo

36.9 mo

0.83 (0.67-1.03)

NA

PFS

11.5 mo

6.9 mo

0.79 (0.64-0.96)

NA

Secondaries

NIVO+IPI

NIVO

HR

p

OS (@5yr)

52%

44%

—

PFS (@5yr)

36%

29%

—

ORR

58%

45%

—

CR

22%

19%

—

(all grades, %)

NIVO+IPI

NIVO

p

Diarrhea

45

22 NA

AE leading to discontinuation

42

13 NA

Fatigue

38

36 NA

Pruritus

36

23 NA

Rash

30

24 NA

Nausea

28

13 NA

Pyrexia

19

7 NA

Increased ALT

19

4 NA

Increased AST

17

4 NA

Hypothyroidism

17

10 NA

Vomiting

15

7 NA

Arthralgia

14

11 NA

Increased lipase

14

10 NA

Increased amylase

8

7 NA

Inclusion
Exclusion

- Histologically confirmed stage III (unresectable) or stage IV melanoma - Treatment naïve patients - Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria - Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

- Active brain metastases or leptomeningeal metastases - Ocular melanoma - Subjects with active, known or suspected autoimmune disease - Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment - Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody.

Characteristics

NIVO+IPI

NIVO

Age & sex

Median agedc-comma year (range)

61 (18‒88)

60 (25‒90)

Maledc-comma no.

206 (66%)

202 (64%)

Femaledc-comma no.

108 (34%)

114 (36%)

—

ECOG performance status

0 230 (73%)

237 (75%)

1 83 (26%)

78 (25%)

2

0.0 1 (<1%)

Not reported

1 (<1%)

0.0 M stage

M1c

181 (58%)

184 (58%)

M0dc-comma M1adc-comma or M1b

133 (42%)

132 (42%)

—

Lactate dehydrogenase

≤ULN

199 (63%)

197 (62%)

>ULN

114 (36%)

112 (35%)

≤2 x ULN

276 (88%)

272 (86%)

>2 x ULN

37 (12%)

Brain metastases at baseline

Yes

11 (4%)

7 (2%)

No

303 (97%)

309 (98%)

—

PD-L1 status

Positive

68 (22%)

80 (25%)

Negative

210 (67%)

208 (66%)

Indeterminate or not evaluable

36 (11%)

28 (9%)

—

BRAF status

Mutant

101 (32%)

100 (32%)

Wild-type

213 (68%)

216 (68%)

—

Number of lesion sites

1 89 (28%)

80 (25%)

2 - 3

165 (53%)

176 (56%)

>3

60 (19%)

59 (19%)

—

Sum of reference diameters of ta

mediandc-comma mm (range)

54.5 (10‒372)

54.0 (10‒384)

—

Ad-hoc:

no.pts inv.

no.pts comp.

NIVO+IPI

NIVO

HR

p

—

OS
PFS

analisys of OS

NIVO+IPI

NIVO

HR (95% CI)

BRAF (@5yr)

mutant

60

46 0.70 (0.46-1.05)

wild-type

48

43 0.89 (0.69-1.15)

Age (@5yr)

< 65 yr

54

45 0.80 (0.60-1.06)

≥ 65 yr

48

43 0.86 (0.62-1.20)

PD-L1 (@5yr)

< 1%

50

36 069 (0.50-0.97)

≥ 1%

54

52 0.97 (0.70-1.32)

PD-L1 (@5yr)

< 5%

51

43 0.81 (0.62-1.06)

≥ 5%

57

51 0.91 (0.57-1.46)

Tumor burden (@5yr)

≤ 31 mm

65

63 0.99 (0.60-1.64)

> 31 and ≤ 97 mm

53

39 0.69 (0.50-0.94)

LDH (@5yr)

≤ ULN

60

53 0.83 (0.62-1.12)

> ULN

38

28 0.82 (0.59-1.13)

Lesion sites (@5yr)

1

64

61 0.92 (0.57-1.50)

2 or 3

49

40 0.78 (0.58-1.03)

Region (@5yr)

United States

62

46 0.60 (0.36-1.01)

Europe

48

41 0.87 (0.65-1.15)

Stage (@5yr)

M0/M1a/M1b

64

58 0.82 (0.56-1.21)

M1c

43

35 0.82 (0.63-1.07)

—

analisys of PFS

NIVO+IPI

NIVO

HR (95% CI)

BRAF (@5yr)

mutant

38

22 0.60 (0.43-0.86)

wild-type

35

32 0.89 (0.70-1.13)

Age (@5yr)

<65 yr

39

29 0.73 (0.56-0.94)

≥65 yr

33

28 0.89 (0.65-1.23)

PD-L1 (@5yr)

<1%

34

23 0.66 (0.480.91)

≥1%

39

36 0.91 (0.68-1.22)

PD-L1 (@5yr)

<5%

35

28 0.77 (0.60-0.98)

≥5%

40

36 0.89 (0.57-1.37)

Tumor burden (@5yr)

≤ 31 mm

40

35 0.74 (0.49-1.12)

> 31 and ≤ 97 mm

37

25 0.75 (0.56-1.00)

LDH (@5yr)

≤ ULN

41

34 0.76 (0.59-0.99)

> ULN

28

18 0.77 (0.56-1.05)

Lesion sites (@5yr)

1

43

33 0.70 (0.47-1.06)

2 or 3

36

26 0.74 (0.56-0.97)

Region (@5yr)

United States

43

31 0.71 (0.45-1.14)

Europe

33

24 0.76 (0.58-0.98)

Stage (@5yr)

M0/M1a/M1b

45

36 0.70 (0.50-0.98)

M1c

30

24 0.85 (0.66-1.09)

—

Investigated (inv)

Comparator (comp)

NIVO+IPI

IPI

314

315

Phase:

3

Randomisation:

Double blind

Primary tumour:

Melanoma

Subtype (biomarker):

Any

Stage:

Line of therapy:

L1

Primary

NIVO+IPI

IPI

HR

p

OS

60.0 mo

19.9 mo

0.52 (0.42-0.64)

<0.001

PFS

11.5 mo

2.9 mo

0.42 (0.35-0.51)

<0.001

Secondaries

NIVO+IPI

IPI

HR

p

OS (@5yr)

52%

26%

—

PFS (@5yr)

36%

8%

—

ORR

58%

19%

—

<0.001

CR

22%

6%

—

(all grades, %)

NIVO+IPI

IPI

p

Diarrhea

45

34 NA

AE leading to discontinuation

42

15 NA

Fatigue

38

28 NA

Pruritus

36

36 NA

Rash

30

22 NA

Nausea

28

16 NA

Pyrexia

19

7 NA

Increased ALT

19

4 NA

Increased AST

17

4 NA

Hypothyroidism

17

5 NA

Vomiting

15

8 NA

Arthralgia

14

7 NA

Increased lipase

14

6 NA

Increased amylase

8

5 NA

Inclusion
Exclusion

- Histologically confirmed stage III (unresectable) or stage IV melanoma - Treatment naïve patients - Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria - Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Active brain metastases or leptomeningeal metastases - Ocular melanoma - Subjects with active, known or suspected autoimmune disease - Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment - Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody.

Characteristics

NIVO+IPI

IPI

Age & sex

Median agedc-comma year (range)

61 (18‒88)

62 (18‒89)

Maledc-comma no.

206 (66%)

202 (64%)

Femaledc-comma no.

108 (34%)

113 (36%)

—

ECOG performance status

0 230 (73%)

224 (71%)

1 83 (26%)

91 (29%)

2

0.0

0.0 Not reported

1 (<1%)

0.0 M stage

M1c

181 (58%)

183 (58%)

M0dc-comma M1adc-comma or M1b

133 (42%)

132 (42%)

—

Lactate dehydrogenase

≤ULN

199 (63%)

194 (62%)

>ULN

114 (36%)

115 (37%)

≤2 x ULN

276 (88%)

279 (89%)

>2 x ULN

37 (12%)

30 (10%)

Brain metastases at baseline

Yes

11 (4%)

15 (5%)

No

303 (97%)

300 (95%)

—

PD-L1 status

Positive

68 (22%)

75 (24%)

Negative

210 (67%)

202 (64%)

Indeterminate or not evaluable

36 (11%)

38 (12%)

—

BRAF status

Mutant

101 (32%)

97 (31%)

Wild-type

213 (68%)

218 (69%)

—

Number of lesion sites

1 89 (28%)

84 (27%)

2 - 3

165 (53%)

170 (54%)

>3

60 (19%)

61 (19%)

—

Sum of reference diameters of ta

mediandc-comma mm (range)

54.5 (10‒372)

55.0 (10‒283)

—

Ad-hoc:

no.pts inv.

no.pts comp.

NIVO+IPI

IPI

HR

p

—

OS
PFS

analisys of OS

NIVO+IPI

IPI

HR (95% CI)

BRAF (@5yr)

mutant

60

30 0.44 (0.30-0.64)

wild-type

48

25 0.57 (0.45-0.73)

Age (@5yr)

< 65 yr

54

26 0.48 (0.37-0.63)

≥ 65 yr

48

27 0.59 (0.43-0.81)

PD-L1 (@5yr)

< 1%

50

26 0.53 (0.38-0.74)

≥ 1%

54

27 0.51 (0.38-0.69)

PD-L1 (@5yr)

< 5%

51

24 0.50 (0.39-0.65)

≥ 5%

57

33 0.58 (0.37-0.91)

Tumor burden (@5yr)

≤ 31 mm

65

40 0.48 (0.30-0.76)

> 31 and ≤ 97 mm

53

26 0.51 (0.38-0.69)

LDH (@5yr)

≤ ULN

60

34 0.48 (0.37-0.64)

> ULN

38

15 0.58 (0.43-0.79)

Lesion sites (@5yr)

1

64

31 0.43 (0.28-0.65)

2 or 3

49

24 0.52 (0.39-0.68)

Region (@5yr)

United States

62

33 0.43 (0.27-0.71)

Europe

48

22 0.51 (0.39-0.67)

Stage (@5yr)

M0/M1a/M1b

64

35 0.44 (0.31-0.63)

M1c

43

20 0.56 (0.44-0.73)

—

analisys of PFS

NIVO+IPI

IPI

HR (95% CI)

BRAF (@5yr)

mutant

38

11 0.44 (0.31-0.62)

wild-type

35

7 0.41 (0.33-0.52)

Age (@5yr)

<65 yr

39

6 0.41 (0.31-0.52)

≥65 yr

33

10 0.44 (0.33-0.59)

PD-L1 (@5yr)

<1%

34

6 0.39 (0.29-0.54)

≥1%

39

9 0.41 (0.31-0.54)

PD-L1 (@5yr)

<5%

35

7 0.42 (0.33-0.53)

≥5%

40

12 0.37 (0.24-0.56)

Tumor burden (@5yr)

≤ 31 mm

40

12 0.38 (0.26-0.56)

> 31 and ≤ 97 mm

37

7 0.42 (0.32-0.55)

LDH (@5yr)

≤ ULN

41

3 0.46 (0.34-0.62)

> ULN

28

0 0.40 (0.23-0.70)

Lesion sites (@5yr)

1

43

9 0.37 (0.25-0.53)

2 or 3

36

7 0.40 (0.31-0.53)

Region (@5yr)

United States

43

11 0.47 (0.30-0.72)

Europe

33

9 0.42 (0.33-0.54)

Stage (@5yr)

M0/M1a/M1b

45

10 0.34 (0.25-0.47)

M1c

30

7 0.48 (0.37-0.61)

—

Investigated (inv)

Comparator (comp)

NIVO

IPI

316

315

Phase:

3

Randomisation:

Double blind

Primary tumour:

Melanoma

Subtype (biomarker):

Any

Stage:

Line of therapy:

L1

Primary

NIVO

IPI

HR

p

OS

36.9 mo

19.9 mo

0.63 (0.52-0.76)

<0.001

PFS

6.9 mo

2.9 mo

0.53 (0.44-0.64)

<0.001

Secondaries

NIVO

IPI

HR

p

OS (@5yr)

44%

26%

—

PFS (@5yr)

29%

8%

—

ORR

45%

19%

—

<0.001

CR

19%

6%

—

(all grades, %)

NIVO

IPI

p

Diarrhea

22

34 NA

AE leading to discontinuation

13

15 NA

Fatigue

36

28 NA

Pruritus

23

36 NA

Rash

24

22 NA

Nausea

13

16 NA

Pyrexia

7

7 NA

Increased ALT

4

4 NA

Increased AST

4

4 NA

Hypothyroidism

10

5 NA

Vomiting

7

8 NA

Arthralgia

11

7 NA

Increased lipase

10

6 NA

Increased amylase

7

5 NA

Inclusion
Exclusion

- Histologically confirmed stage III (unresectable) or stage IV melanoma - Treatment naïve patients - Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria - Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

- Active brain metastases or leptomeningeal metastases - Ocular melanoma - Subjects with active, known or suspected autoimmune disease - Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment - Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody.

Characteristics

NIVO

IPI

Age & sex

Median agedc-comma year (range)

60 (25‒90)

62 (18‒89)

Maledc-comma no.

202 (64%)

Femaledc-comma no.

114 (36%)

113 (36%)

—

ECOG performance status

0 237 (75%)

224 (71%)

1 78 (25%)

91 (29%)

2 1 (<1%)

0.0 Not reported

0.0

0.0 M stage

M1c

184 (58%)

183 (58%)

M0dc-comma M1adc-comma or M1b

132 (42%)

—

Lactate dehydrogenase

≤ULN

197 (62%)

194 (62%)

>ULN

112 (35%)

115 (37%)

≤2 x ULN

272 (86%)

279 (89%)

>2 x ULN

37 (12%)

30 (10%)

Brain metastases at baseline

Yes

7 (2%)

15 (5%)

No

309 (98%)

300 (95%)

—

PD-L1 status

Positive

80 (25%)

75 (24%)

Negative

208 (66%)

202 (64%)

Indeterminate or not evaluable

28 (9%)

38 (12%)

—

BRAF status

Mutant

100 (32%)

97 (31%)

Wild-type

216 (68%)

218 (69%)

—

Number of lesion sites

1 80 (25%)

84 (27%)

2 - 3

176 (56%)

170 (54%)

>3

59 (19%)

61 (19%)

—

Sum of reference diameters of ta

mediandc-comma mm (range)

54.0 (10‒384)

55.0 (10‒283)

—

Ad-hoc:

no.pts inv.

no.pts comp.

NIVO

IPI

HR

p

—

OS
PFS

analisys of OS

NIVO

IPI

HR (95% CI)

BRAF (@5yr)

mutant

46

30 0.63 (0.44-0.90)

wild-type

43

25 0.64 (0.50-0.81)

Age (@5yr)

< 65 yr

45

26 0.60 (0.47-0.78)

≥ 65 yr

43

27 0.69 (0.51-0.93)

PD-L1 (@5yr)

< 1%

36

26 0.77 (0.56-1.05)

≥ 1%

52

27 0.53 (0.40-0.70)

PD-L1 (@5yr)

< 5%

43

24 0.62 (0.49-0.79)

≥ 5%

51

33 0.63 (0.42-0.96)

Tumor burden (@5yr)

≤31 mm

63

40 0.48 (0.31-0.76)

>31 and ≤ 97 mm

39

26 0.74 (0.57-0.98)

LDH (@5yr)

≤ ULN

53

34 0.58 (0.44-0.76)

> ULN

28

15 0.71 (0.53-0.96)

Lesion sites (@5yr)

1

61

31 0.46 (0.30-0.71)

2 or 3

40

24 0.67 (0.51-0.86)

Region (@5yr)

United States

46

33 0.72 (0.47-1.12)

Europe

41

22 0.59 (0.46-0.77)

Stage (@5yr)

M0/M1a/M1b

58

35 0.54 (0.38-0.75)

M1c

35

20 0.69 (0.54-0.87)

—

analisys of PFS

NIVO

IPI

HR (95% CI)

BRAF (@5yr)

mutant

22

11 0.73 (0.53-1.01)

wild-type

32

7 0.46 (0.37-0.58)

Age (@5yr)

<65 yr

29

6 0.56 (0.44-0.71)

≥65 yr

28

10 0.49 (0.37-0.66)

PD-L1 (@5yr)

<1%

23

6 0.59 (0.44-0.80)

≥1%

36

9 0.45 (0.35-0.58)

PD-L1 (@5yr)

<5%

28

7 0.54 (0.43-0.68)

≥5%

36

12 0.42 (0.28-0.62)

Tumor burden (@5yr)

≤31 mm

35

12 0.51 (0.35-0.74)

>31 and ≤ 97 mm

25

7 0.56 (0.43-0.73)

LDH (@5%)

≤ ULN

34

10 0.50 (0.39-0.63)

> ULN

18

3 0.60 (0.44-0.80)

Lesion sites (@5yr)

1

33

9 0.52 (0.36-0.75)

2 or 3

26

7 0.55 (0.43-0.70)

Region (@5yr)

United States

31

11 0.66 (0.44-0.99)

Europe

24

9 0.55 (0.43-0.71)

Stage (@5yr)

M0/M1a/M1b

36

10 0.49 (0.36-0.66)

M1c

24

7 0.56 (0.44-0.71)

—

Melanoma: CheckMate 067 trial

Melanoma: CheckMate 067 trial

Melanoma: CheckMate 067 trial

EMA SPC links

2017-10-05

J.D. Wolchok

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

2019-10-17

J. Larkin

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Investigated (inv)

Comparator (comp)

Randomisation:

Primary tumour:

Subtype (biomarker):

Stage:

Line of therapy:

Primary

NIVO+IPI

NIVO

HR

p

OS

60.0 mo

36.9 mo

0.83 (0.67-1.03)

NA

PFS

11.5 mo

6.9 mo

0.79 (0.64-0.96)

NA

Secondaries

NIVO+IPI

NIVO

HR

p

OS (@5yr)

52%

44%

—

—

PFS (@5yr)

36%

29%

—

—

ORR

58%

45%

—

—

CR

22%

19%

—

—

(all grades, %)

NIVO+IPI

NIVO

p

Diarrhea

45

22

NA

AE leading to discontinuation

42

13

NA

Fatigue

38

36

NA

Pruritus

36

23

NA

Rash

30

24