Details of data from Melanoma clinical trials

Investigated (inv)

Comparator (comp)

CRIZ

chemo

173

174

Phase:

3

Randomisation:

Open label

Primary tumour:

NSCLC

Subtype (biomarker):

ALK poz.

Stage:

Line of therapy:

L2

Primary

CRIZ

chemo

HR

p

PFS

7.7 mo

3.0 mo

0.49 (0.37-0.64)

<0.001

—

Secondaries

CRIZ

chemo

HR

p

ORR

65%

20%

na

<0.001

OS interim

na

1.02 (0.68-1.54)

0.54 DoR

31.1 mo

24.4 mo

—

Time to response

6.3 mo

12.6 mo

—

(all grades, %)

CRIZ

chemo

p

Vision disorder

60

9 NA

Diarrhea

60

19 NA

Nausea

55

37 NA

Vomiting

47

18 NA

Constipation

42

23 NA

AST increased

38

15 NA

Edema

31

16 NA

Upper respiratory infection

26

13 NA

Dysgeusia

26

9 NA

Rash

9

17 NA

—

Inclusion
Exclusion

- histologically or cytologically proven diagnosis of non-small cell lung cancer - positive for the ALK fusion gene (test provided by a central laboratory) - must have had disease progression after only one prior chemotherapy and that regimen but must have included one platinum drug - tumors must be measurable

- prior treatment with crizotinib (PF-02341066) - current treatment in another clinical trial

Characteristics

CRIZ

chemo

Agedc-comma sex

Median age (range) yr

51 (22-81)

49 (24-85)

<65 yr

146 (84)

151 (87)

≥65 yr

27 (16)

23 (13)

Male - no.(%)

75 (43)

78 (45)

Race - no.(%)

White

90 (52)

91 (52)

Asian

79 (46)

78 (45)

Other

4 (2)

5 (3)

—

Smoking status - no.(%)

Never

108 (62)

111 (64)

Former

59 (34)

54 (31)

Current

5 (3)

9 (5)

—

Tumor histologic type - no.(%)

Adenocarcinoma

164 (95)

164 (94)

Non-adenocarcinoma

5 (3)

7 (4)

—

ECOG performance status - no.(%)

0 72 (42)

65 (37)

1 84 (49)

95 (55)

2 16 (9)

14 (8)

—

Extent of disease - no.(%)

Locally advanced

7 (4)

16 (9)

Metastatic

165 (95)

158 (91)

—

Brain metastases - no.(%)

Presence of brain metastases

60 (35)

60 (34)

—

Ad-hoc:

no.pts inv.

no.pts comp.

CRIZ

chemo

HR

p

—

PFS
—

analisys of PFS

CRIZ

chemo

HR (95% CI)

Age (n)

<65 yr (297)

—

0.49 (0.37-0.65)

≥65 yr (50)

—

0.54 (0.27-1.08)

Race (n)

Non-Asian (190)

—

0.45 (0.30-0.66)

Asian (157)

—

0.53 (0.36-0.76)

Smoking status (n)

Non-smoker (219)

—

0.45 (0.32-0.63)

Smoker or ex-smoker (127)

—

0.53 (0.34-0.83)

Tumor histologic type (n)

Adenocarcinoma (328)

—

0.50 (0.38-0.66)

Non-adenocarcinoma (12)

—

0.12 (0.01-1.02)

ECOG (n)

0 or 1 (313)

—

0.48 (0.36-0.63)

2 (34)

—

0.31 (0.12-0.86)

Brain metastases (n)

Present (120)

—

0.67 (0.44-1.03)

Absent (227)

—

0.43 (0.30-0.60)

Prior EGFR TKI therapy (n)

Yes (41)

—

0.48 (0.22-1.03)

No (306)

—

0.49 (0.37-0.66)

—

analisys of —

CRIZ

chemo

HR (95% CI)

—

Investigated (inv)

Comparator (comp)

IPIL

PLB

475

476

Phase:

3

Randomisation:

Double blind

Primary tumour:

Melanoma

Subtype (biomarker):

Any

Stage:

early

Line of therapy:

ADJ

Primary

IPIL

PLB

HR

p

RFS @5yr

40.8%

30.3%

0.76 (0.64-0.89)

<0.001

OS @5yr

65.4%

54.4%

0.72 (0.58–0.88)

0.001 Secondaries

IPIL

PLB

HR

p

RFS

27.6 mo

17.1 mo

0.77 (0.65-0.91)

0.002 dMFS @5yr

48.3%

38.9%

0.76 (0.64-0.92)

0.002 dMFS

48.3 mo

27.5 mo

—

(all grades, %)

IPIL

PLB

p

Discontinued treatment due to AE

53.3%

4.6%

NA

Any immune-related AE

90.4

39.7 NA

Any dermatologic AE

63.3

20.9 NA

Any gastrointestinal event

46.1

17.9 NA

Diarrhea

41.2

16.9 NA

Colitis

15.5

1.5 NA

Any endocrine-system event

37.8

8.0 NA

Hypophysitis

16.3

0.2 NA

Any hepatic event

24.4

4.2 NA

Any neurologic event

4.5

1.9 NA

—

Inclusion
Exclusion

- Age ≥18 years - Complete and adequate resection of Stage III melanoma with histologically confirmed melanoma metastatic to lymph node - Disease-free - Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 - Randomization within 12 weeks of surgery.

- Prior therapy for melanoma except surgery - Auto-immune disease.

Characteristics

IPIL

PLB

Agedc-comma sex

Median age (range)dc-comma yr

51 (20–84)

52 (18–78)

<50 yr

214 (45.1)

211 (44.3)

51 to <65 yr

180 (37.9)

178 (37.4)

Male - no.(%)

296 (62.3)

293 (61.6)

Disease stage (AJCC 2002) - no.(%)

IIIA

98 (20.6

88 (18.5)

IIIB

213 (44.8)

207 (43.5)

IIIC with 1–3 positive lymph nodes

69 (14.5)

83 (17.4)

IIIC with ≥4 positive lymph nodes

95 (20.0)

98 (20.6)

Type of lymph-node involvement - no.(%)

Microscopic

210 (44.2)

193 (40.5)

Macroscopic

265 (55.8)

283 (59.5)

—

No. of positive lymph nodes on pathological testing - no.(%)

1 217 (45.7)

220 (46.2)

2 or 3

163 (34.3)

158 (33.2)

≥4

95 (20.0)

98 (20.6)

—

Ulceration - no.(%)

Yes

197 (41.5)

203 (42.6)

No

257 (54.1)

244 (51.3)

Unknown

21 (4.4)

29 (6.1)

—

Ad-hoc:

no.pts inv.

no.pts comp.

IPIL

PLB

HR

p

—

RFS @5yr
OS @5yr

analisys of RFS @5yr

IPIL

PLB

HR (95% CI)

Disease stage

IIIA

—

0.98 (0.46–2.09)

IIIB

—

0.75 (0.50–1.14)

Disease stage

IIIC with 1–3 positive lymph nodes

—

1.00 (0.56–1.80)

IIIC with ≥4 positive lymph nodes

—

0.48 (0.28–0.81)

No. of positive lymph nodes

1 —

—

0.79 (0.52–1.21)

2 or 3

—

0.83 (0.53–1.30)

Type of positive lymph node

Microscopic

—

0.61 (0.39–0.96)

Macroscopic

—

0.80 (0.58–1.11)

Ulceration

Yes

—

0.64 (0.44–0.94)

No

—

0.80 (0.54–1.20)

Lymph-node and ulceration status

Microscopic and ulceration

—

0.54 (0.29–0.99)

Macroscopic and ulceration

—

0.76 (0.46–1.23)

Lymph-node and ulceration status

Microscopic and no ulceration

—

0.62 (0.30–1.29)

Macroscopic and no ulceration

—

0.90 (0.56–1.45)

No. of positive lymph nodes

≥4

—

0.48 (0.28–0.81)

—

analisys of OS @5yr

IPIL

PLB

HR (95% CI)

Disease stage

IIIA

—

0.98 (0.46-2.09)

IIIB

—

0.75 (0.50-1.14)

Disease stage

IIIC with 1–3 positive lymph nodes

—

1.00 (0.56-1.80)

IIIC with ≥4 positive lymph nodes

—

0.48 (0.28-0.81)

No. of positive lymph nodes

1 —

—

0.79 (0.52-1.21)

2 or 3

—

0.83 (0.53-1.30)

Type of positive lymph node

Microscopic

—

0.61 (0.39-0.96)

Macroscopic

—

0.80 (0.58-1.11)

Ulceration

Yes

—

0.64 (0.44-0.94)

No

—

0.80 (0.54-1.20)

Lymph-node and ulceration status

Microscopic and ulceration

—

0.54 (0.29-0.99)

Macroscopic and ulceration

—

0.76 (0.46-1.23)

Lymph-node and ulceration status

Microscopic and no ulceration

—

0.62 (0.30-1.29)

Macroscopic and no ulceration

—

0.90 (0.56-1.45)

No. of positive lymph nodes

≥4

—

0.48 (0.28-0.81)

—

Investigated (inv)

Comparator (comp)

VEMR

NA

132

NA

Phase:

2

Randomisation:

Open label

Primary tumour:

Melanoma

Subtype (biomarker):

V600E MT

Stage:

Line of therapy:

L2

Primary

VEMR

NA

HR

p

ORR @12,9mo.

53%

—

44-62

—

Secondaries

VEMR

NA

HR

p

PFS

6.8 mo

—

5.6-8.1

—

CR

6%

—

OS

15.9 mo

—

11.6-18.3

—

DoR

6.7 mo

—

5.6-8.6

—

(all grades, %)

VEMR

NA

p

Arthralgia

59 —

NA

Rash

52 —

NA

Photosensitivity reaction

52 —

NA

Fatigue

42 —

NA

Pruritus

29 —

NA

Skin papilloma

29 —

NA

Cutaneous squamous-cell carcinomaor keratoacanthoma

26 —

NA

Nausea

23 —

NA

Elevated liver enzymes

17 —

NA

Peripheral neuropathy

10 —

NA

PPE

10 —

NA

Facial palsy

2 —

NA

Hyperuricemia

2 —

NA

Delirium

1 —

NA

Inclusion
Exclusion

- adult patients >/=18 years of age - histologically confirmed metastatic melanoma (Stage IV, AJCC) - patients must have completed and failed at least one prior standard of care regimen (e.g. DTIC, temozolomide, etc.) - BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay) - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion.

- active CNS metastases on CT/MRI within 28 days prior to enrollment - history of or known carcinomatous meningitis - previous treatment with BRAF (sorafenib allowed) or MEK inhibitor - cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential - uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy - infectious disease including HIV, HBV and HCV.

Characteristics

VEMR

NA

Agedc-comma sex

Mediandc-comma yr

51.5 —

<65 yr

81%

—

≥65 yr

19%

—

Male

61%

—

Race or ethnic group - no.(%)

White

130 (98)

—

Hispanic

2 (2)

—

No. of prior therapies - no.(%)

1 67 (51)

—

2 36 (27)

—

≥3

29 (22)

—

Previous interleukin-2 - no.(%)

No

81 (61)

—

Yes

51 (39)

—

Previous ipilimumab - no.(%)

Yes

7 (5)

—

No

125 (95)

—

ECOG status score - no.(%)

0 61 (46)

—

1 71 (54)

—

Metastatic stage at diagnosis - no.(%)

M1a

33 (25)

—

M1b

18 (14)

—

M1c

81 (61)

—

Serum LDH - no.(%)

Normal

67 (51)

—

Elevated

65 (49)

—

BRAF mutation

BRAF V600E - no.

122 —

BRAF V600K - no.

10 —

—

Ad-hoc:

no.pts inv.

no.pts comp.

VEMR

NA

HR

p

—

ORR @12,9mo.
—

analisys of ORR @12,9mo.

VEMR

NA

HR (95% CI)

Age

<65 yr (n=107)

50%

—

≥65 yr (n=25)

64%

—

LDH at enrolment

Normal (n=67)

67%

—

>1.5x ULN (n=46)

33%

—

ECOG

0 (n=61)

56%

—

1 (n=71)

51%

—

Metastatic stage

M1a/M1b (n=51)

65%

—

M1c (n=80)

45%

—

No. of prior therapies

1 (n=67)

51%

—

>1 (n=65)

55%

—

Previous IL-2

Yes (n=51)

51%

—

No (n=81)

54%

—

Sex

Male (81)

53%

—

Female (51)

53%

—

analisys of —

VEMR

NA

HR (95% CI)

—

Melanoma: NA trial

Melanoma: NA trial

Melanoma: NA trial

EMA SPC links

2013-06-20

Alice T. Shaw

Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer

Investigated (inv)

Comparator (comp)

Randomisation:

Primary tumour:

Subtype (biomarker):

Stage:

Line of therapy:

Primary

CRIZ

chemo

HR

p

PFS

7.7 mo

3.0 mo

0.49 (0.37-0.64)

<0.001

—

—

—

—

—

Secondaries

CRIZ

chemo

HR

p

ORR

65%

20%

na

<0.001

OS interim

na

na

1.02 (0.68-1.54)

0.54

DoR

31.1 mo

24.4 mo

—

—

Time to response

6.3 mo

12.6 mo

—

—

(all grades, %)

CRIZ

chemo

p

Vision disorder

60

9

NA

Diarrhea

60

19

NA

Nausea

55

37

NA

Vomiting

47

18

NA

Constipation

42

23

NA

AST increased

38