Paziente BRAF mutato: immunoterapia vs targeted therapy nella malattia metastatica

Novità in tema di Melanoma- Paziente BRAF mutato:

immunoterapia vs targeted therapy nella malattia metastatica

Dr.ssa Lorenza Di Guardo

Fondazione IRCCS Istituto Nazionale dei Tumori Milano Oncologia Medica 1 , SS Oncologia Melanomi

lorenza.diguardo@istitutotumori.mi.it

Perugia 6-7 luglio 2018

BRAF Mutations Are the Most Common Driver Mutation in Metastatic Melanoma ¹

• BRAF and NRAS are the most commonly mutated genes in cutaneous melanoma

• BRAF mutation most commonly occurs in exon 15 and involves a single point mutation resulting in substitution of valine with glutamic acid

• Other common mutations in melanoma:

• 22% AKT/PI3K

• 5%-20% PTEN

• 3% c-KIT (35%-40% in acral and mucosal melanomas)

• BRAF-mutated melanomas are most commonly found in the

truncal region and are not typically associated with chronic sun

damage

NF1, neurofibromin 1; PI3K, phosphoinositide 3-kinase; WT, wild type.

1. The Cancer Genome Atlas Network. Cell. 2015;161:1681-1696. 2. Curry JL, et al. Semin Cutan Med Surg. 2012;31:267-276; 3. Carlino MS et al.

Crit Rev Oncol Hematol. 2015.96:385-398;

4. Vultur A, et al. Clin Cancer Res. 2011;17:1658-1663; 5. Long GV, et al. J Clin Oncol. 2011;29:1239-1246.

BRAF 52%

NF1 14%

RAS (NRAS

predominant)

28%

Triple WT 6%

BRAF NF1 RAS (NRAS predominant) Triple WT

Mutation Status of Cutaneous Melanoma

(N = 331)

BRAF Mutations Are Associated With Poor Prognosis in Melanoma

 Patients with BRAF-mutant melanoma are generally younger and have been shown to have worse overall survival than patients with BRAF-WT melanoma ^1,2

• Prospective cohort of patient treated at the Melanoma Institute Australia (N=197)

• Patients with BRAF-mutant melanoma had worse OS than patients with BRAF WT melanoma

• Mitigated by treatment with a BRAF inhibitor and/or MEK inhibitor

• BRAF mutation had no impact on time from primary tumor appearance to distant metastases but was associated with a poorer outcome once metastasis did occur

• Authors speculated that this may be because the BRAF activating mutation facilitates further genetic instability

100

80

20

0 1 2 3 4

Time, years OS From Di agnosi s of Me tas ta tic Melan oma, %

0 60

5 40

Overall P < .001 A vs C P < .003 B vs C P = .006 A vs B P = .138

A. BRAF mutant on inhibitor B. BRAF WT

C. BRAF mutant, no inhibitor

1. Jakob JA, et al. Cancer. 2012;18:4014-4023; 2. Long GV, et al. J Clin Oncol. 2011; 29:1239-1246.

BRAF Mutations Associated With Poor Prognosis in Higher-AJCC Stage Primary Melanoma

100

80

60

40

20

0

Melanoma-Specific Survival, %

No. at risk WT

NRAS+

Log-rank test, P = .28

Melanoma-Specific Survival in Patients With Stage

T2b/T3a/T3b/T4a/T4b Primary Melanoma by BRAF/NRAS Mutation

Status (n = 144)

90

70

50

30

10

0 1 2 3 4 5 6 7 8

Years From Diagnosis 76

35 33

76 35 33

71 31 28

65 28 25

51 24 23

56 23 21

52 22 18

51 20 17

• Population based study evaluated clinicopathologic characteristics in a multivariable model in 912 patients (median follow-up 7.6 years):

– BRAF+ 30%; NRAS+ 13%; WT 57%

• BRAF mutations were associated with:

– Increased tumor thickness and ulceration – Significantly correlated with an

~ 3-fold increase in death from advanced (stage T2b or higher) tumours

• For higher-risk tumours, 5-year survival was:

– WT 82%

– BRAF+ 71%

– NRAS+ 73%

Thomas NE, et al. JAMA Oncol. 2015;1(3):359-368.

WT

BRAF+

NRAS+

Jacob et al. Cancer 2012;118:4014-23. VC 2011

Patients with BRAF or NRAS mutations were more likely than WT

patients to have central nervous system involvement.

Personalized Treatment Strategies for Metastatic Melanoma

BRAF V600–Mutant Metastatic Melanoma

Immunotherapy

?

?

BRAF/MEK inhibition

No head-to-head data currently available

TARGETED THERAPIES OR IMMUNOTHERAPY

PFS and OS

COMBI-v and COMBI-d: Overall Survival Curves

D + T in COMBI-v D + T in COMBI-d¹

2-year OS 53% (95% CI, 48-58) 52% (95% CI, 45-59) 3-year OS 45% (95% CI, 39-50) 44% (95% CI, 37-51)

Vem in COMBI-v D + Pbo in COMBI-d¹

2-year OS 39% (95% CI, 34-45) 43% (95% CI, 36-50) 3-year OS 31% (95% CI, 26-36) 32% (95% CI, 25-38)

OS Pr o b ab ili ty

Months From Randomization

0 6 12 18 24 30 36 42

1.00

0.75

0.50

0.25

0.00

Patients at risk, n COMBI-d: D + Pbo

COMBI-d: D + T COMBI-v: D + T COMBI-v: Vem

212 211 352 352

175 187 311 289

138 143 245 203

104 111 201 154

84 96 171 119

69 86 150 103

57 76 127 81

7 13 33 22

Pbo, placebo. 1. Flaherty KT, et al. J Clin Oncol. 2016;34 (suppl) [abstract 9502].

PRESENTED AT ESMO 2016

PFS (Intent-to-Treat)

Presented by: Jeffrey Weber

0

0 6 12 18 24 30 36 42 48 54 60 66 72

54 25 3 2 1 1 1 1 1 1 1 0 0

54 36 20 15 12 1 1 10 7 5 5 4 1 0

54 33 17 7 4 3 3 3 2 2 2 0 0

20 40 60 80 100

Time From Randomization, months

P rogre s s ion -Fre e S urv iv a l, % D Monotherapy

D+T 150/1 D+T 150/2 Treatment

Patients at risk, n

13% 13%

9% 9%

3% 3%

Median (95% CI), mo

5.8 (4.6-7.4) 9.2 (6.4-11.0) 9.4 (8.6-16.6)

21%

9%

3%

OS (Intent-to-Treat)

Presented by: Jeffrey Weber

0

0 6 12 18 24 30 36 42 48 54 60 66 72

54 50 38 30 24 20 16 14 1 1 9 8 2 0

54 52 43 33 27 23 20 18 15 14 14 4 0

54 48 38 25 23 19 17 15 1 1 10 10 4 0

20 40 60 80 100

Time From Randomization, months

Ov e ra ll S urv iv a l, %

Patients at risk, n

28%

33%

21%

30%

33%

23%

D Monotherapy D+T 150/1 D+T 150/2

Treatment Median (95% CI), mo

20.2 (14.5-27.1) 22.5 (14.2-42.3) 25.0 (17.5-36.5)

38%

35%

31%

0 10 20 30 40 50 60 70 80 COMBI-V (D+T)

(n = 352) COMBI-D (D+T)

(n = 211) coBRIM (V+C)

(n = 247) KEYNOTE-006 (Pem q3w)

(n = 97) Checkmate-067 (nivo + ipi)

(n = 101)

Checkmate-067 (nivo) (n = 100)

Summary of Response Rates and BRAF-Mutant Patient Populations Across Clinical Trials

BRAF-Mutant Population

*Circles are representative of BRAF mutant patient population; size is relative to COBMI-V (D+T) population.

1. Larkin J, et al. N Engl J Med. 2015;373:23-34; 2. Schachter J, et al. ASCO 2016 [abstract 9504]; 3. Larkin J, et al. ASCO 2015 [abstract 9006]; 4. Long GV, et al.

Lancet. 2015;386:444-451;

5. Robert C, et al. ESMO 2015 [abstract 3301].

1

1

2

3

4

5

Overall Response Rate, Total Population (%)

Pts (N)

BRAF MT*

CA209-067: Study Design

Randomized, double-blind, phase III study

to compare NIVO alone or NIVO + IPI to IPI alone

Unresectable or Metatastic Melanoma

• Previously untreated

• 945 patients

Treat until progression**

or

unacceptable toxicity NIVO 3 mg/kg Q2W +

IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W

for 4 doses then NIVO 3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo

Randomize 1:1:1

Stratify by:

• PD-L1 status*

• BRAF status

• AJCC M stage

*Verfied PD-L1 assay with 5% cutoff was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses.

**Patients could have been treated beyond progression under protocol-defined circumstances.

N=316

N=314

N=315

CheckMate 067 – Phase III 1° Line

Nivo + ipi (N=314)

Nivo (N=316)

Ipi (N=315) Median range, years

(range) 61 (18–88) 60 (25–90) 62 (18–89)

Age ≥65 years, % 41.1 37.3 42.2

Sex – Male, % 65.6 63.9 64.1

ECOG PS of 0*,% 73.2 75.3 71.1

M stage – M1c, % 57.6 58.2 58.1

LDH - >ULN, % 36.3 35.4 36.5

LDH - >2x ULN, % 11.8 11.7 9.5

Brain metastases, % 3.5 2.5 4.8

PD-L1 expression ≥5%

, % 21.7 25.3 23.8

BRAF V600 mutant, % 32.2 31.6 30.8

Why only 31,6 % BRAF mut pts ?

BRAF Mutant

OS in Patients with BRAF Wild-type and Mutant Tumors

Months

0 3 6 9 12 15 18 21 24 27 30 33 36 39

OS%

100 90 80 70 60 50 40 30 20 10 0

212 218 215

194 199 194

170 179 166

157 163 147

144 155 134

142 144 118

133 134 106

127 127 96

126 124 87

120 119 82

108 105 67

31 38 21

5 2 3

0 0 0 Patients at risk:

NIVO+ IPI NIVO IPI

61%

57%

42%

NIVO+ IPI NIVO IPI

102 96 100

98 93 91

95 86 88

90 81 81

82 75 71

79 69 64

76 67 58

73 64 53

72 57 49

62 52 37

18 17 13

2 1 1

0 0 0 72

56 47 Patients at risk:

NIVO+ IPI NIVO IPI

71%

OS%

100 90 80 70 60 50 40 30 20 10 0

Months

0 3 6 9 12 15 18 21 24 27 30 33 36 39 NIVO+ IPI

NIVO IPI

62%

51%

NIVO + IPI NIVO IPI

Median, mo (95% CI)

NR (27.6-NA)

NR (25.8-NR)

18.5 (14.8-23.0) HR (95% CI) vs.

NIVO

0.97

(0.74-1.28) – –

NIVO + IPI NIVO IPI

Median, mo

(95% CI) NR NR

(26.4-NR)

24.6 (17.9-31.0) HR (95% CI) vs.

NIVO

0.71

(0.45-1.13) – –

BRAF Wild-type

Larkin J, et al. AACR 2017;[abstract CT075].

...because in COMBO Nivo+Ipi in CheckMate-069

16

• First-line patients with BRAF-mutant disease derived less PFS and ORR benefit from nivolumab + ipilimumab vs patients with BRAF WT disease

• Although data is based on a small number of patients, the curves appear to separate

Postow MA, et al. N Engl J Med. 2015;372(21):2006-2017.

0 3 6 9 12 15 18

0 10 20 30 40 50 60 70 80 90 10

0

Months

PF S, %

IPI BRAF mutant (n = 10) IPI BRAF WT (n = 37)

NIVO + IPI BRAF mutant (n = 23) NIVO + IPI BRAF WT (n = 72)

BRAF WT BRAF V600 Mutant NIVO + IPI

(n = 72)

IPI (n = 37)

NIVO + IPI (n = 23)

IPI (n = 10)

ORR, % 61 11 52 10

Median PFS (95% CI), months

NR 4.4 (2.8- 5.7)

8.5 (2.8- NR)

2.7 (1.0- 5.4) HR (95% CI)

P value

0.40 (0.23-0.68)

< .001

0.38 (0.15-1.00)

—

19

Managing the Patient Treatment Experience

• HRQoL, health-related quality of life; CNS, central nervous system; LDH, lactate dehydrogenase

• ^a Support specialist include, but not limited to, psychiatrists and psychologists, social workers, palliative care specialists, sexual health experts, & support groups

CNS Involvement

Neurological Symptoms

Disease Stage

Site of Disease Resectability

Extent of Disease

Comorbidities

Age, Gender

Performance Status

LDH Level

Rate of Progression

HRQoL

Mutation Status

Tolerability

Poor

prognostic factors

CNS Involvement

LDH Level >UNL Extent of Disease

( High tumor burden)

Example response patterns IT

150 125 100 75 50 25 0 -25 -50 -75 -100 -125

19,373 17,242 15,111 12,980 10,849 8,718 6,587 4,456 2,325 194 -1,937

SPD (mm2)

Relative week from first dose date

50 25 0 –25 –50 –75 –100 –125

Change from baseline SPD (%)

Relative week from first dose date

1,272 1,124 975 827 678 530 382 233 85 -64 -212

SPD (mm2)

Change from baseline SPD (%)

-9 -3 3 9 15 21 27 33 39 45 51

Relative week from first dose date

Change from baseline SPD (%) SPD (mm2)

2,894 2,556 2,218 1,881 1,543 1,206 868 530 193 -145 -482 50

25 0 -25 -50 -75 -100 -125

Total tumour volume Index lesions New lesions Ipilimumab dosing

SPD = Sum of the Product of the perpendicular Diameters (a measure of tumour volume)

-9 -3 3 9 15 21 27 33 39 45 51 -9 -3 3 9 15 21 27 33 39 45 51

'Stable disease' with slow, steady decline in total tumour volume

Response after initial increase in total tumour volume Response in baseline lesions

Change from baseline SPD (%) SPD (mm2)

2,810 2,482 2,154 1,826 1,498 1,171 843 515 187 -140 -468 50

25 0 -25 -50 -75 -100 -125

-9 -3 3 9 15 21 27 33 39 45 51

9 months

Relative week from first dose date

PD

PR

CR

5.2 months 6 months

9.4 months

Response in index and new lesions at or after the appearance of new lesions

Wolchok JD, et al. Clin Cancer Res 2009;15:7412–7420

NIVOLUMAB

CheckMate 067 – Phase III 1° Line

Larkin J, et al. N Eng J Med 2015; 373:23–34.

KEYNOTE 006

RECIST RESPONSE: BRAFi + MEKi

Presented By Georgina Long at 2016 ASCO Annual Meeting

RECIST Response: BRAF + MEK Inhibitors and Anti–PD-1

KEYNOTE-006 ⁵

BRAF Status

WT 
(n = 217) Mutant 
(n = 74) Best overall response, n (%)

CR 9 (4.1) 2 (2.7)

PR 66 (30.4) 20 (27.0)

SD 53 (24.4) 13 (17.6)

PD 74 (34.1) 33 (44.6)

UKN 15 (6.9) 6 (8.1)

ORR (95% CI), % 34.6 (28.3- 41.3)

29.7 (19.7- 41.5) Mut/WT, OR (95% CI) 0.8 (0.5-1.4) Pooled Analysis of Outcomes With Nivolumab in BRAF-Mutant and BRAF-WT Patients

BRAFi + MEKi ORR CR

Dabra + Tram 68% 16%

Vemu + Cobi 70% 19%

Enco + Bini 75% 13%

BRAFi + MEKi phase 3 studies

BRAFi, BRAF inhibitor; CR, complete response; MEKi, MEK inhibitor; OR, odds ration; ORR, overall response rate; PD, progressive disease; PD-1, programmed death 1; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease; UKN, unknown.

1. Long GV, et al. Lancet. 2015;386:444-451; 2. Robert C, et al. ESMO 2015 [abstract 3301].; 3. Larkin J, et al. ASCO 2015 [abstract 9006]; 4. Larkin J, et al. JAMA Oncol. 2015; 5. Puzanov I, et al. SMR 2015.

Pooled pembrolizumab arms Ipilimumab arm

60 50 40 30 20 10 0

ORR, %

BRAF V600 WT

BRAF V600 Mutant 38.3

32.3

12.9 12.1

BRAF V600 Mutant,

Prior BRAFi

BRAF V600 Mutant, No Prior BRAFi 9.6

14.5 40.7

21.8

OS by Tumor PD-L1 Expression, 5% Cutoff

30 NIVO+IPI NIVO IPI

Median OS, mo (95% CI)

NR (31.8–NR)

NR (23.1–NR)

18.5 (13.7–22.5) HR (95% CI)

vs NIVO

0.84

(0.63–1.12) ─ ─

PD-L1 Expression Level <5%

O S ( % )

Months

10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Patients at risk:

202 0

IPI 179 158 140 125 108 100 90 81 78 63 18 2

208 0

NIVO 189 169 151 144 133 123 118 112 110 99 34 2

210 0

NIVO+IPI 194 178 163 146 144 139 131 130 127 116 34 7

NIVO+IPI NIVO IPI

Median OS, mo

(95% CI) NR NR 28.9

(18.1–NR) HR (95% CI)

vs NIVO

1.05

(0.61–1.83) ─ ─

PD-L1 Expression Level ≥5%

O S ( % )

Months

10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Patients at risk:

75 0

IPI 72 67 65 61 55 46 43 40 39 33 13 1

80 0

NIVO 79 75 73 68 63 61 58 57 54 49 18 1

68 0

NIVO+IPI 63 56 55 52 50 45 45 45 44 35 11 0

55%

63%

41%

72%

68%

54%

• ORR of 73.5% for NIVO+IPI and 58.8% for NIVO

• ORR of 56.2% for NIVO+IPI and 42.3% for NIVO

M+ Brain

CNS Metastases:

Targeted Therapies and Immunotherapy

• Systematic review of survival of patients with metastatic melanoma and BM treated with targeted therapy and immunotherapy

• 22 studies

• 2153 patients treated with BRAFi and ipilimumab ^a

Targeted therapies may be preferred over

immunotherapy in a

"real-world" setting (for patients with BM)

a No survival data on BRAFi + MEKi and anti–PD-1 available at the time of the systematic review.

Spagnolo F, et al. Cancer Treatment Rev. 2016;45:38-45.

Median OS, mo Immunotherapy BRAFi

Clinical Trials 7 7.9

“Real-World” Studies 4.3 7.7

Reduction in Intracranial Target Lesion in Patients With Brain Metastases Treated With Dabrafenib

• BREAK-MB: open-label, single-agent dabrafenib in treatment-naive and previously treated patients with BRAF V600E mutation–positive

metastatic melanoma to the brain

M axi m u m Ch an ge Fr om Ba seli n e In tr acr an ia l M e asu re m e n t, %

100 80 60 40 20 0 -20 -40 -60 -80 -100

Cohort B (n = 65): prior brain treatment 100

80 60 40 20 0 -20 -40 -60 -80 -100

Intracranial ORR: 39.2%

Intracranial DCR: 81.1%

Cohort A (n = 74): no prior brain treatment

Dotted line at 20% represents cutoff for progressive disease (PD); dotted line at –30% represents cutoff for partial response (PR).

DCR, disease control rate.

Long GV, et al. Lancet Oncol. 2012;13:1087-1095.

Intracranial ORR: 30.8%

Intracranial DCR: 89.2%

CNS Metastases: Pembrolizumab

• Patients with asymptomatic BM not requiring steroids (N = 18)

• Cerebral response available for 14 patients (78%): 4 PR, 3 SD, and 7 PD

• PFS in 4 responders was 6+, 10+, 13+, and 17+ months (22%)

• Strong concordance between CNS and systemic responses

• Responses were durable

Changes in Sum of Diameter of Brain Lesions Time on Study and CNS Activity

Maximum Response From Baseline, %

−50

−100 150 200

−30 0

50 100 250

Data lock, June 2015

0 2 4 10 12

Time, months

PR

Partial response SD PD NE

Ongoing treatment

6 8

– Neurological AEs included focal symptoms related to CNS oedema (n = 5), seizure (n = 3), headache (n = 3), dizziness (n = 1), and cognitive dysfunction (n = 1; grade 3/4)

BM, brain metastases; PD-L1, programmed death ligand 1; SD, stable disease.

Kluger H, et al. Goldberg Lancet Oncol 2016

From Kluger HM, et al. In: Proceedings from the American Society of Clinical Oncology; May 29-June 2, 2015; Chicago, IL [abstract 9009]. Reprinted with author's permission.

Favorable

prognostic factors

Low tumor burden

LDH <UNL

COMBI-d: Normal LDH

Presented by: Keith T. Flaherty, MD +, censored.

140 90 55 34 24 7 5 1 0

133 96 67 57 44 36 24 0

D+Pbo D+T

Number at risk

P FS P roba bili ty

1.0

0.8

0.6

0.4

0.2

0.0 0

Months From Randomization

6 12 18 24 30 36 42 48

3-yr PFS, 27%

3-yr PFS, 17%

2-y PFS, 37%

2-y PFS, 21%

Dabrafenib + Trametinib (n = 133)

Dabrafenib + Placebo (n = 140)

140 133 111 89 73 59 50 6 0

133 126 104 87 80 71 61 10 0

OS P roba bili ty

D+Pbo D+T

Number at risk

Dabrafenib + Trametinib (n = 133)

Dabrafenib + Placebo (n = 140)

3-y OS, 54%

3-y OS, 41%

1.0

0.8

0.6

0.4

0.2

0.0 0

Months From Randomization

2-y OS, 65%

2-y OS, 55%

6 12 18 24 30 36 42 48

PFS OS

COMBI-d: Normal LDH ^a and < 3 Disease Sites ^b

Presented by: Keith T. Flaherty, MD

a Baseline LDH ≤ ULN; ^b Any organ at baseline with ≥ 1 metastasis could be counted as a single disease site; +, censored.

96 93 77 65 56 45 36 2 0

76 72 62 52 46 41 35 4 0

D+Pbo D+T

Number at risk

Dabrafenib + Trametinib (n = 76)

Dabrafenib + Placebo (n = 96)

3-y OS, 62%

3-y OS, 45%

1.0

0.8

0.6

0.4

0.2

0.0 0

Months From Randomization

OS P roba bili ty

2-y OS, 68 % 2-y OS, 61%

6 12 18 24 30 36 42 48

96 64 41 25 16 5 3 0

76 56 39 34 28 25 19 0

D+Pbo D+T

Number at risk 0

Months From Randomization

6 12 18 24 30 36 42

1.0

0.8

0.6

0.4

0.2

0.0

3-y PFS, 15%

3-y PFS, 38%

Dabrafenib + Trametinib (n = 76)

Dabrafenib + Placebo (n = 96)

P FS P roba bili ty

PFS OS

LDH ≤ ULN and < 3 Metastatic Sites (ITT)

Presented by: Jeffrey Weber

0

0 6 12 18 24 30 36 42 48 54 60 66

20 40 60 80 100

0

19 16 12 10 9 8 8 5 3 3 3 0

12 9 0 0 0 0 0 0 0 0 0 0 12 12 12 12 9 8 7 7 5 3 3 1 0

19 19 18 15 15 14 14 13 10 9 9 3 0

20

40 60 80 100

Time From Randomization, months Time From Randomization, months

0 6 12 18 24 30 36 42 48 54 60 66 72

P rogres sion -Free S urv iv al, % O v eral l S urv iv al, %

Progression-Free Survival Overall Survival

Patients at risk, n Patients at risk, n

25% 25%

8% 8%

57%

42%

51%

31%

74%

58%

47%

8%

1

line

Nivolumab IPI

Immunotherapy ^Ipi+Nivo

Median PFS (95%CI)

Nivo Nivo + Ipi Ipi

Total population (n 945) 6.9 (4.3-9.5) 11.5 (8.9-16.7) 2.9 (2.8-3.4)

Baseline LDH

≤ ULN 9.7 (6.9-22.0) Not reached (11.3-NR) Not reported

> ULN 2.8 (2.6-4.0) 4.2 (2.8-9.3) Not reported

Presented by P. Queirolo Post ASCO Melanoma Congress Munich 07/2016 Larkin J, et al. AACR 2017;[abstract CT075].

Tumor BRAF status

BRAF mut Normal LDH

NIVO + IPI NIVO IPI

Median, mo

(95% CI) NR NR

(26.4-NR)

24.6 (17.9-31.0)

HR (95% CI) vs.

NIVO

0.71

(0.45-1.13) – –

Median OS ^(95%CI)

Safety

Different frequency of Common AEs by Time with Immuno and Target

Robert C, et al. N Engl J Med. 2015;372(26):2521-2532.

KEYNOTE-006

AEs increase with time

POOLED Dabrafenib +Trametinib

AEs decrease with time

Grob J, et al. J Clin Oncol. 2016;34(suppl)

[abstract 9534].

QoL

52

Results: EORTC QLQ-C30 Analyses of Change From Baseline

* Clinically meaningful and statistically significant (P < .05) difference between study arms.

EORTC QLQ-C30 Global Health Status Score Changes From Baseline

Jean-Jacques Grob, Mayur M. Amonkar, Bogusława Karaszewska, Jacob Schachter, Reinhard Dummer, Andrzej Mackiewicz, Daniil Stroiakovski, Kamil Drucis, Florent Grange, Vanna Chiarion-Sileni, Piotr Rutkowski, Evgeny Levchenko, Pascal Wolter, Axel Hauschild, Georgina V. Long, Peng Sun, Diane Opatt McDowell, Bijoyesh Mookerjee, Caroline Robert. Presented at ECC 2015

CheckMate 067 – HRQoL Measured by EORTC QLQ-C30

EORTC QLQ-C30 Global Health:

Change From Baseline ^a Over Time by Treatment Arm

182 182 1 13 227 236 197 226 227 163

106 193 129

83 155 103

97 164

97 87 132

76 97 142

74 92 121

50 90 1 12

48 74 100

44 65 92 40

48 63 24

29 38 17

16 13 9 Number of Patients at Risk

NIVO+IPI (n = 314) NIVO (n = 316) IPI (n = 315)

20

-10

-20

0 5 7 1 1 13 17 19 23 25 31 37 43 49 55 61 67

EOR T T QL Q -C30 G lob al Hea lt h: Cha ng e From B as el in e

Weeks

10

0

MID

B et ter W or se

MID

a Values shown are mean with standard error bars; ^b MID Considered a change of ≥7 points from baseline (Pickard et al. 2007;5:70).

Note: Only time points where data were available for ≥ 5 patients are plotted on the graph. Patients could enter follow-up visits any time after baseline.

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer quality of life questionnaire C30; MID, minimally

important difference. Schadendorf D, et al. Oral presentation at SMR 2015.

Identifying a Therapeutic Algorhythm in advanced/metastatic melanoma

• mBRAF

BRAFi + MEKi ^Anti-PD1

Slow progressors Low Tumor Burden

ECOG PS 0-1 Low LDH levels

No Brain Mets Rapid progressors

High Tumor Burden (Bulky Disease)

ECOG PS ≥2 High LDH levels

Brain Mets Age?

PD

Anti-PD1

Clinical Trial, Chemotherapy, Supportive Care

PD

PD

Slow Progression Low tumor load

Clinical Trial or IPILIMUMAB

BRAFi + MEKi

BRAFI + MEKI

Anti-PD1

Targeted Therapy vs Immunotherapy: What is the Optimal Sequence?

BRAF/MEK Inhibitor

Immunotherapy

?

?

BRAF/MEK Inhibitor Immunotherapy

BRAF/MEK Inhibitor + Immunotherapy