ESMO E-Learning Melanoma Adjuvant Setting · CA209-238: BASELINE PATIENTS CHARACTERISTICS Most of...

MELANOMA ADJUVANT SETTINGState of the Art

Riccardo Marconcini

U.O. Oncologia Medica, Ospedale S. Chiara – Pisa, Italy

ADJUVANT TREATMENTS

IN MELANOMA

Agenda

Risk category

90s – 2016: Interferon

2016: Ipilimumab

2017: New treatments

Immunotherapy: AntiPD1

Nivolumab

Pembrolizumab

Targeted therapies:

Vemurafenib

Dabrafenib + trametinib

AJCC 7TH EDITION –

RISK CATEGORY

Balch CM, et al. J Clin Oncol 2009; 27 (36):6199-206. Reprinted with permission. © 2009. American Society of Clinical Oncology. All rights reserved.

Survival curves from the American Joint Committee on Cancer Melanoma Staging Database comparing (A) the

different T categories and (B) the stage groupings for stages I and II melanoma. For patients with stage III disease,

survival curves are shown comparing (C) the different N categories and (D) the stage groupings

AJCC 8TH EDITION –

RISK CATEGORY

Survival according to T subcategory Survival according to N Ccategory (A) and

subcategory (B)

Gershenwald JE, et al. CA Cancer J Clin 2017;67:472–92. Published by John Wiley and Sons; © 2017 American Cancer Society.

INTERFERON Α

Schedule Dose Frequency Duration

Low dose

3 miu 3 x weekly 18-24 months

Intermediate dose

Induction 10 miu 5 x weekly 4 weeks

Maintenance 10 miu 3 x weekly 12-24 months

5 miu 3 x weekly 24 months

High dose

Induction 20 MIU/m2 5 x weekly 4 weeks

Maintenance 10 MIU/m2 3 x weekly 11 months

Short course

Induction x 1 20 MIU/m2 5 x weekly 4 weeks

Intermittent

Induction x 3 20 MIU/m2 5 x weekly4 weeks

Q4 months

INTERFERON USE: DIFFERENCE

IN NATIONAL GUIDELINES

Presented at ASCO 2017 by Dr Peter Mohr.Image adapted from https://commons.wikimedia.org/wiki/File:Europe_map_de_2.png. Creative Commons Attribution-Share Alike 3.0 Unported license

Use of adjuvant interferon

treatment in Europe

L = low-dose

H = high-dose

I = intermediate-dose

P = pegylated

0 = no dose

Guidelines in adjuvant melanoma therapy

Country Agents and Recommendation Level of evidence

United

States

(NCCN)

Clinical trial

Observation

High-dose interferon or

PEG-interferon

High-dose Ipilimumab 10 mg/Kg

Interferon: (DFS) 1

Ipilimumab: 1

Australia/

New Zealand

Clinical Trial

Currently systemic therapy after

lymphadenectomy can not be recommended

(toxicity high-dose interferon and ipilimumab)

Germany Clinical trial

Patients with stage IIB/C and III A-C melanoma

(AJCC 2010) are to be informed about an

adjuvant interferon therapy.

Ipilimumab may be offered (stage III A-C)

Interferon: 1a

Ipilimumab: 1b

INTERFERON Α –

META ANALYSIS 2017

Event-free survival for trials of IFN versus no IFN by dose

Reprinted from Eur Cancer, 82, Ives NJ, et al. Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis; 171-183.

Copyright 2017, with permission from Elsevier.

High dose

PEG-IFN

Intermediate dose

Low dose

Very low dose

Total

HR 0.83

HR 0.87

HR 0.84

HR 0.85

HR 0.99

HR 0.86

INTERFERON Α –

META ANALYSIS 2017

Survival curve for event-free survival



INTERFERON Α –

META ANALYSIS 2017

Overall survival for trials of IFN versus no IFN by dose



High dose

PEG-IFN

Intermediate dose

Low dose

Very low dose

Total

HR 0.93

HR 0.96

HR 0.91

HR 0.86

HR 0.96

HR 0.90

INTERFERON Α –

META ANALYSIS 2017

Survival curve for Overall Survival



INTERFERON Α –

META ANALYSIS 2017

Subgroup analysis for relapse free survival



RFS

RFS

DMFS

DMFS

INTERFERON Α – DEBATE ON

DURATION OF TREATMENT

1. Pectasides D, et al. J Clin Oncol 2009, 27(6): 939-44. Reprinted with permission. © 2009. American Society of Clinical Oncology. All rights reserved

2. Reprinted from Eur J Cancer, 2016; 55, Eggermont AM, et al. 111-121. Copyright 2016, with permission from Elsevier.

Immunotherapy

(Checkpoints inhibitors)

Targeted therapies

Metastatic settingAdjuvant setting

Local diseaseSurgery of primary melanoma +

lymphonodes

Evaluation of

adjuvant

treatment

Metastatic

disease

Drugs used in metastatic setting have been experimented in the adjuvant setting

MELANOMA PATIENT HISTORY:

RESEARCH AREAS

INTERACTION BETWEEN IMMUNE

SYSTEM AND CANCER

Immune checkpoint inhibitors

Reprinted from Immunity 2013; 39(1), Chen DS, Mellman I, Oncology Meets Immunology: The Cancer-Immunity Cycle; 1-10. Copyright 2013, with permission from Elsevier.

EORTC18071 IPI VS. PLACEBO

EORTC 18071/CA184-0.29: Study design

Randomised, double-blind, Phase 3 study evaluating the efficacy and safety of

ipilimumab in the adjuvant setting for high-risk melanoma

Eggermont AMM, et al. N Engl J Med, 2016, 375 (19): 1845-1855. Presented at ESMO 2016


RECURRENCE-FREE SURVIVAL (PER IRC)

From N Engl J Med, Eggermont AMM, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy, 375 (19): 1845-1855. Copyright © 2016,

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Presented at ESMO 2016


OVERALL SURVIVAL





DISTANT METASTASIS FREE

SURVIVAL (PER IRC)





OVERALL SURVIVAL

Forest Plot

†95% CI for total, 99% CI elsewhere.From N Engl J Med, Eggermont AMM, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy, 375 (19): 1845-1855. Copyright © 2016,




High incidence of

G3-G4 adverse event

Eggermont AMM, et al. N Engl J Med, 2016, 375 (19): 1845-1855. Presented at ESMO 2016

E1609 IPI 3 VS. 10 MG/KG

Abstract 9500: Intergroup E1609: Study design

Presented by Dr Ahmad Tarhini at ASCO Annual Meeting 2017

Stratification factors: IIIB, IIIC, M1a, M1b

Co primary endpoints: RFS and OS

Unscheduled interim analysis: Only RFS ipilimumab 3 mg vs. ipilimumab 10 mg

E1609 IPI 3 VS. 10 MG/KG

Abstract 9500: RFS: Ipi 10 vs. Ipi 3 (concurrently randomised patients)

Presented by Dr Ahmad Tarhini at ASCO Annual Meeting 2017

Treatment Total Failed Censored Median

10 mg IPI 406 173 233 3.9

3 mg IPI 367 156 211 -

Overlapping curves for

the two different dosage

0.1

0.2

0.0

0.4

0.5

0.3

0.7

0.8

0.6

0.9

1.0

Pro

babi

lity

Years0 1 2 3 4 5

HR = 1.0, 95% CI (0.81, 1.24)

NIVOLUMAB IN THE

ADJUVANT SETTING

CA209-238: Study design

Patients with high-risk, completely resected stage

IIIB/IIIC or stage IV melanoma

Follow-up

Maximum

treatment

duration of

1 year

NIVO 3 mg/kg IV Q2W and IPI placebo IV

Q3W for 4 doses then Q12W from week 24

IPI 10 mg/kg IV Q3W for 4 doses then Q12W

from week 24 and NIVO placebo IV Q2W

n = 453

n = 453

Stratified by:

1) Disease stage: IIIB/C vs. IV M1a-M1b vs. IV M1c

2) PD-L1 status at a 5% cutoff in tumour cells

Weber J, et al. N Engl J Med 377(19), 1824-1835. 2017. Presented at ESMO 2017

Enrollment period: March 30, 2015 to November 30, 2015

1:1

CA209-238: BASELINE PATIENTS

CHARACTERISTICS

Most of the patients had cutaneous melanoma (85%), and 4% had acral and 3% had mucosal melanoma

All 905 patients are off treatment; median doses were 24 (1-26) in the NIVO group and 4 (1-7) in the IPI group

397 patients completed 1 year of treatment (61% of the NIVO group and 27% of the IPI group)

NIVO (n = 453)

IPI(n = 453)

Median age, years 56 54

Male, % 57 59

Stage, IIIB+IIIC, % 81 81

Macroscopic lymph node involvement (% of stage IIIB+IIIC) 60 58

Ulceration (% of stage IIIB+IIIC) 42 37

Stage IV, % 18 19

M1c without brain metastases (% stage IV) 17 17

PD-L1 expression ≥5%, % 34 34

BRAF mutation, % 41 43

LDH ≤ ULN, % 91 91

Weber J, et al. N Engl J Med 2017;377(19):1824–35. Presented at ESMO 2017

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

453 353 311 249 5 0399 332 291 71NIVO

453 314 252 184 2 0364 269 225 56IPI

Number of patients at risk

NIVO

IPI

NIVO IPI

Events/patients 154/453 206/453

Median (95% CI) NR NR (16.6, NR)

HR (97.56% CI) 0.65 (0.51, 0.83)

Log-rank P value <0.0001

66%

53%

71%

61%

CA209-238: RFS

(PRIMARY ENDPOINT)

From N Engl J Med, Weber J, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma, 377:1824–35. Copyright © 2017 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

CA209-238: RFS (PRIMARY ENDPOINT)

ASCO 2018 UPDATE

Courtesy of Prof Jeffrey S. Weber. Presented at 2018 ASCO Annual Meeting

PD-L1 Expression Level <5% PD-L1 Expression Level ≥5%

NIVO IPI


Median (95% CI) NR 15.9 (10.4, NR)

HR (95% CI) 0.71 (0.56, 0.91)

NIVO IPI


Median (95% CI) NR NR

HR (95% CI) 0.50 (0.32, 0.78)

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

NIVO

IPI

275 204 171 129 3 0242 189 159 41NIVO

286 184 139 100 2 0219 153 124 31IPI


RF

S (

%)

Months

152 130 122 105 2 0135 125 114 26NIVO

154 120 105 78 0 0133 108 93 21IPI


CA209-238 – SUBGROUP ANALYSIS

OF RFS: PD-L1 EXPRESSION LEVEL

64%

54%

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

NIVO

IPI

82%

74%



CA209-238 – SUBGROUP ANALYSIS

OF RFS: PD-L1 EXPRESSION LEVEL

ASCO 2018 UPDATE


Stage III Stage IV

CA209-238 - SUBGROUP ANALYSIS

OF RFS: DISEASE STAGE

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

367 290 257 203 3 0322 272 239 58NIVO

366 259 208 152 1 0299 223 186 45IPI


72%

62%

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

82 59 51 43 2 073 56 49 12NIVO

87 55 44 32 1 065 46 39 11IPI


63%

58%

NIVO IPI



HR (95% CI) 0.65 (0.52, 0.83)

NIVO IPI


Median (95% CI) NR (15.9, NR) 16.8 (8.5, NR)

HR (95% CI) 0.70 (0.45, 1.10)

NIVO

IPI

NIVO

IPI




OF RFS: DISEASE STAGE

ASCO 2018 UPDATE


BRAF Mutant BRAF Wild type

NIVO IPI



HR (95% CI) 0.72 (0.52, 1.00)

NIVO IPI


Median (95% CI) NR 16.6 (12.3, NR)

HR (95% CI) 0.58 (0.43, 0.79)

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

NIVO

IPI

187 142 126 102 2 0159 135 118 32NIVO

194 142 112 78 1 0155 118 100 26IPI


RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

197 154 137 108 2 0175 145 127 26NIVO

214 140 111 80 1 0174 122 96 22IPI


NIVO

IPI

72%

57%

68%

63%


OF RFS: BRAF MUTATION STATUS

Weber J, et al. Presented at ESMO 2017


OF RFS: BRAF MUTATION STATUS

ASCO 2018 UPDATE


J Clin Oncol 36, 2018 (suppl; abstr 9502)

RFS: PRE-SPECIFIED SUBGROUPS

Subgroup

No. of events/no. of patients Unstratified

HR (95% CI)

Unstratified HR

(95% CI)NIVO 3 mg/kg IPI 10 mg/kg

Overall Overall 154/453 206/453 0.66 (0.53, 0.81)

Age <65 years 106/333 147/339 0.65 (0.51, 0.84)

≥65 years 48/120 59/114 0.66 (0.45, 0.97)

Sex Male 99/258 133/269 0.68 (0.53, 0.88)

Female 55/195 73/184 0.63 (0.44, 0.89)

Stage (CRF) Stage IIIb 41/163 54/148 0.67 (0.44, 1.00)

Stage IIIc 79/204 109/218 0.65 (0.49, 0.87)

Stage IV M1a-M1b 25/62 35/66 0.63 (0.38, 1.05)

Stage IV M1c 8/20 8/21 1.00 (0.37, 2.66)

Not reported 1/2 0/0

Stage III: Ulceration Absent 58/201 94/216 0.59 (0.42, 0.82)

Present 60/153 64/135 0.73 (0.51, 1.04)

Not reported 2/15 5/15 0.39 (0.07, 2.00)

Stage III: Lymph node

involvement

Microscopic 41/125 55/134 0.71 (0.47, 1.07)

Macroscopic 72/219 101/214 0.62 (0.46, 0.84)

Not reported 7/25 7/18 0.60 (0.21, 1.72)

PD-L1 status <5%/indeterminate 123/300 149/299 0.71 (0.56, 0.90)

≥5% 31/152 57/154 0.50 (0.32, 0.78)

BRAF mutation status Mutant 63/187 84/194 0.72 (0.52, 1.00)

Wild-type 67/197 105/214 0.58 (0.43, 0.79)

Not reported 24/69 17/45 0.83 (0.45, 1.54)

NIVO IPI0 1 2

From N Engl J Med, Weber J, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma, 377:1824–35. Copyright © 2017


POST-PROTOCOL TREATMENT

Treatment, n (%)a NIVO (n = 453) IPI (n = 453)

Any 129 (28.5) 171 (37.7)

Systemic therapy 90 (19.9) 136 (30.0)

Chemotherapy 25 (5.5) 24 (5.3)

Immunotherapy 50 (11.0) 104 (23.0)

Anti-PD-1 agent 1 (0.2) 2 (0.4)

Nivolumabb 17 (3.8) 43 (9.5)

Pembrolizumab 10 (2.2) 63 (13.9)

Other CTLA-4 inhibitor 1 (0.2) 1 (0.2)

Ipilimumab 35 (7.7) 15 (3.3)

Ipilimumab/nivolumab combination 3 (0.7) 1 (0.2)

BRAF inhibitor 41 (9.1) 40 (8.8)

MEK inhibitor 31 (6.8) 40 (8.8)

BRAF/MEK combination 3 (0.7) 1 (0.2)

Surgeryc 69 (15.2) 64 (14.1)

Radiotherapy 24 (5.3) 26 (5.7)aPatients may have received more than one type of post-protocol therapy, and more than one agent within each type. All percentages are

based on total number of patients in each group. bMay include patients treated in combination with IPI. cIncludes tumour resection for

diagnostic purposes and biopsies


SAFETY SUMMARY

There were no treatment-related deaths in the NIVO group

There were 2 (0.4%) treatment-related deaths in the IPI group (marrow aplasia and colitis), both >100

days after the last dose

AE, n (%)

NIVO (n = 452) IPI (n = 453)

Any grade Grade 3/4 Any grade Grade 3/4

Any AE 438 (97) 115 (25) 446 (98) 250 (55)

Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46)

Any AE leading to discontinuation 44 (10) 21 (5) 193 (43) 140 (31)

Treatment-related AE leading

to discontinuation35 (8) 16 (4) 189 (42) 136 (30)

Acceptable toxicity profile


PEMBROLIZUMAB IN THE

ADJUVANT SETTINGEORTC 1325/KEYNOTE-054 : Study Design

Eggermont AMM, et al. Presented at AACR 2018

LATEST

NEWS!

AACR 2018

KEYNOTE-054: PATIENTS CHARACTERISTICS

From N Engl J Med 2018, Eggermont AMM, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma, 378(19) 1789-1801. Copyright © 2018


Presented at AACR 2018

KEYNOTE-054:

RFS (PRIMARY END POINT)




KEYNOTE-054

RFS: PRE-SPECIFIED SUBGROUPS




KEYNOTE-054

ADVERSE EVENTS




Cellular

proliferation

RTK

Raf

MEK inhibitors

ATP

ATP

ERK

MEK

BRAFV600E

RAS

BRAF inhibitors

Mechanism of action of BRAF and MEK inhibitors

BRAF AND MEK INHIBITORS

BIOMOLECULAR MODEL OF

PROGRESSION IN MELANOMA

BRAF mutation is a primary event in melanomagenesis

From N Engl J Med, Hunter Shain A, et al., The Genetic Evolution of Melanoma from Precursor Lesions. 2015; 372(26): 2509-20. Copyright 2015.


BRAF MONOTHERAPY IN THE

ADJUVANT SETTING

Presented by Karl Lewis at ESMO 2017.


ADJUVANT SETTING

BRIM8 study design

Phase III, International, multicentre, double-blind, randomised, placebo-controlled study

BID, twice daily; DFS, disease-free survival; DMFS, distant metastasis-free survival; HRQoL, Health-related quality of life;

OS, overall survival.aPatients with stage IIIA melanoma were eligible if they had one or more nodal metastasis >1mm in diameter.

Presented by Lewis K at ESMO 2017. Courtesy of Dr Lewis


ADJUVANT SETTING

BRIM8: Primary DFS endpoint (Cohort 2, stage IIIC)

CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; NE, not estimable. Presented by Lewis K at ESMO 2017. Courtesy of Dr K Lewis

One year of adjuvant vemurafenib increased median DFS vs. placebo in stage IIIC BRAFV600

melanoma demonstrating a biologic effect, however it did not significantly reduce DFS risk


ADJUVANT SETTING

BRIM8: Primary DFS endpoint (Cohort 1, stage IIC-IIIB)

aCannot be considered significant because primary endpoint was not met in Cohort 2.

CI, confidence interval; HR, hazard ratio; NE, not estimable. Presented by Lewis K at ESMO 2017. Courtesy of Dr K Lewis

One year of adjuvant vemurafenib results in 46% DFS risk reduction in stage IIC-IIIB BRAFV600

melanoma, demonstrating a substantial clinical benefit vs. placebo

COMBI-AD: STUDY DESIGN

Key eligibility criteria

Completely resected, high-risk stage IIIA

(lymph node metastasis > 1 mm), IIIB, or IIIC

cutaneous melanoma

BRAF V600E/K mutation

Surgically free of disease ≤ 12 weeks before

randomisation

ECOG performance status 0 or 1

No prior radiotherapy or systemic therapy

R

A

N

D

O

M

I

S

A

T

I

O

N

Stratification

BRAF mutation status (V600E, V600K)

Disease stage (IIIA, IIIB, IIIC)

1:1

Dabrafenib 150 mg BID +

trametinib 2 mg QD

(n = 438)

2 matched placebos

(n = 432)

Treatment: 12 monthsa

Follow-upb until

end of studyc

Primary endpoint: RFSd

Secondary endpoints: OS, DMFS, FFR, safety

N=870

BID, twice daily; DMFS, distant metastasis–free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS,

overall survival; QD, once daily; RFS, relapse-free survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of

consent; b Patients were followed for disease recurrence until the first recurrence and thereafter for survival;

c The study will be considered complete and final OS analysis will occur when ≈ 70% of randomised patients have died or are lost to

follow-up; d New primary melanoma considered as an event.Presented by Dr A Hauschild at ESMO 2017.

Dabrafenib plus trametinib (n=438) Placebo (n=432) Total (N=870)

Median age (range), years 50 (18-89) 51 (20-85) 50 (18-89)

Male, n (%) 195 (45) 193 (45) 388 (45)

BRAF mutation status, n (%)V600EV600Kb

397 (91)41 (9)

395 (91)37 (9)

792 (91)78 (9)

ECOG performance status of 0, n (%) 402 (92) 390 (90) 792 (91)

Disease stage, n (%)IIIAIIIBIIICIII (unspecified)

83 (19)169 (39)181 (41)

5 (1)

71 (16)187 (43)166 (38)

8 (2)

154 (18)356 (41)347 (40)

13 (1)

Number of positive lymph nodes, n (%)12 or 3≥ 4

177 (40)158 (36)73 (17)

183 (42)150 (35)72 (17)

360 (41)308 (35)145 (17)

Type of lymph node involvement, n (%)MicroscopicMacroscopicNot reported

152 (35)158 (36)128 (29)

157 (36)161 (37)114 (26)

309 (36)319 (37)242 (28)

Primary tumour ulceration, n (%)YesNo

179 (41)253 (58)

177 (41)249 (58)

356 (41)502 (58)

In-transit disease, n (%)YesNo

51 (12)387 (88)

36 (8)395 (91)

87 (10)782 (90)

COMBI-AD: BASELINE

DEMOGRAPHICS AND PATIENT

CHARACTERISTICS

Long GV, et al., N Engl J Med 2017: 377(19): (presented by Dr A Hauschild at ESMO 2017).

COMBI-AD: RELAPSE-FREE

SURVIVAL (PRIMARY ENDPOINT)

438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0

432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0

Months from randomisation

Dabrafenib plus trametinib

Placebo

No. at risk

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Pro

po

rtio

n a

live

and

rel

apse

fre

e

1 y, 88%

2 y, 67%

3 y, 58%1 y, 56%

2 y, 44%

3 y, 39%

P=0.0000000000000153

NR, not reached.From N Engl J Med, Long GV, et al., Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma,2017; 377(19): 1813-1823

Copyright © 2017. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Presented by Dr A Hauschild at ESMO 2017

GroupEvents,

n (%)Median

(95% CI), moHR

(95% CI)


166 (38)NR

(44.5-NR) 0.47(0.39-0.58);

P < .001Placebo 248 (57)16.6

(12.7-22.1)

COMBI-AD: RELAPSE-FREE

SURVIVAL BY SUBGROUP

Macrometastasis and no ulceration (n = 201)

Micrometastasis and no ulceration (n = 165)

0.01 1.000.10

0.51

0.37

0.52

0.51

0.33

0.43

0.49

0.43

0.44

10.00HR

Favours dabrafenib plus trametinib Favours placebo

V600K (n = 78)

V600E (n = 792)

Male (n = 482)

Female (n = 388)

< 65 years (n = 712)

≥ 65 years (n = 158)

Disease stage IIIA (n = 154)

Disease stage IIIB (n = 356)

Disease stage IIIC (n = 347)

Micrometastasis (n = 309)

Macrometastasis (n = 319)

Macrometastasis and ulceration (n = 116)

Micrometastasis and ulceration (n = 143)

1 Nodal metastatic mass (n = 360)

2–3 Nodal metastatic masses (n = 308)

≥4 Nodal metastatic masses (n = 145)

0.45

0.50

0.44

0.38

0.51

0.55

0.43

0.48

0.54

From N Engl J Med, Long GV, et al., Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma,2017; 377(19): 1813-1823



COMBI-AD: DISTANT

METASTASIS–FREE SURVIVAL

438 413 407 390 381 373 353 336 327 302 285 278 265 258 235 203 195 146 116 110 66 52 42 19 7 2 0

432 392 330 282 265 247 221 206 201 187 179 176 169 168 159 144 140 107 88 87 51 33 30 9 3 0 0

Pro

po

rtio

n a

live

and

dis

tan

t m

etas

tasi

s fr

ee

1 y, 91%

2 y, 77%3 y, 71%

1 y, 70%

2 y, 60%3 y, 57%

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52



Placebo

No. at risk

GroupEvents,

n (%)Median

(95% CI), moHR

(95% CI)


110 (25)NR

(NR-NR)0.51

(0.40-0.65);nominal P < .001Placebo 152 (35)

NR(41.2-NR)

From N Engl J Med, Long GV, et al., Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma,2017; 377(19): 1813-1823



COMBI-AD: OVERALL SURVIVAL

(FIRST INTERIM ANALYSIS)

438 426 416 414 408 401 395 387 381 376 370 366 362 352 328 301 291 233 180 164 105 82 67 28 12 5 0

432 425 415 410 401 386 378 362 346 337 328 323 308 303 284 269 252 202 164 152 94 64 51 17 7 1 0

0

0

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Pro

po

rtio

n a

live

1 y, 97%

2 y, 91%3 y, 86%

1 y, 94%

2 y, 83%

3 y, 77%



Placebo

No. at Risk

aPrespecified significance boundary (P=0.000019).From N Engl J Med, Long GV, et al., Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma,2017; 377(19): 1813-1823



GroupEvents,

n (%)Median

(95% CI), moHR

(95% CI)


60 (14)NR

(NR-NR) 0.57(0.42-0.79);P = .0006aPlacebo 93 (22)

NR(NR-NR)

COMBI–AD: POST-RECURRENCE

THERAPY AMONG PATIENTS

WITH RELAPSEPost-recurrence therapy

Dabrafenib plus trametinib (n=163 relapses)

Placebo (n=247 relapses)

Any post-recurrence anticancer therapy, n (%) 148 (91) 217 (88)

Surgery 78 (48) 131 (53)

Radiotherapy 60 (37) 72 (29)

Any systemic post-recurrence anticancer therapy, n (%) 120 (74) 183 (74)

Small molecule–targeted therapy

Any BRAF inhibitora

Any MEK inhibitorb

Immunotherapy

Anti–PD-1/PD-L1

Anti–CTLA-4

Interferon T-VEC

63 (39)

63 (39)

47 (29)

89 (55)

71 (44)

53 (33)

6 (4)0

137 (55)

137 (55)

77 (31)

103 (42)

68 (28)

68 (28)

11 (4)1 (< 1)

Biologic therapy 1 (1) 1 (< 1)

Chemotherapy 20 (12) 23 (9)

Investigational treatment 6 (4) 19 (8)

Other therapy 2 (1) 0

Median time from disease recurrence to start of systemic

post-recurrence therapy, excluding radiotherapy and surgery (range), weeks

7.1 (0-136) 7.3 (0-78)

CTLA-4, cytotoxic T-lymphocyte–associated 4; PD-1, programmed cell death 1; PD-L1 programmed cell death ligand 1; T-VEC, talimogene

laherparepvec. aIncluded dabrafenib, vemurafenib, and encorafenib; bIncluded trametinib, cobimetinib, and binimetinib.Long GV, et al., N Engl J Med 2017: 377(19). Presented by Dr A Hauschild at ESMO 2017.

COMBI-AD: COMMON

ADVERSE EVENTS

Dabrafenib plus trametinib (n=435) Placebo (n=432)

AEs, n (%) All Grades Grade 3/4 All Grades Grade 3/4

Any AE (> 20% with dabrafenib

plus trametinib)a 422 (97) 180 (41) 380 (88) 61 (14)

Pyrexia 273 (63) 23 (5) 47 (11) 2 (< 1)

Fatigue 204 (47) 19 (4) 122 (28) 1 (< 1)

Nausea 172 (40) 4 (1) 88 (20) 0

Headache 170 (39) 6 (1) 102 (24) 0

Chills 161 (37) 6 (1) 19 (4) 0

Diarrhoea 144 (33) 4 (1) 65 (15) 1 (< 1)

Vomiting 122 (28) 4 (1) 43 (10) 0

Arthralgia 120 (28) 4 (1) 61 (14) 0

Rash 106 (24) 0 47 (11) 1 (< 1)

Acceptable toxicity profile

aEleven patients (3%) in the treatment arm and 10 patients (2%) in the placebo arm had new primary melanomas; 8 (2%) and 7 (2%),

respectively, had cutaneous squamous cell carcinoma/keratoacanthoma; 19 (4%) and 14 (3%), respectively, had basal cell carcinoma;

and 10 (2%) and 4 (1%), respectively, had noncutaneous malignancies.Long GV, et al., N Engl J Med 2017: 377(19): 1813-1823. Presented by Dr A Hauschild at ESMO 2017.

ADJUVANT SETTING:

OTHER ONGOING CLINICAL TRIAL

Study Phase Drugs Population

EORTC 18081 IIIPEG IFN alfa 2b versus

observationT2-4b (ulcerated) N0M0

S1404 IIIHigh-dose recombinant IFN alfa2b,

ipilimumab, or pembrolizumab

Stage III-IV high risk melanoma

(removed by surgery)

CheckMate 915 IIINivolumab plus ipilimumab versus

nivolumabStage IIIb/c/d or Stage IV (resected)

Metastatic settingAdjuvant setting

Local diseaseSurgery of primary melanoma +

lymphonodes

Evaluation of

adjuvant

treatment

Metastatic

disease

✓ BRAF + MEK i have a role in the adjuvant setting for stage III BRAF v600

mutant melanoma (Dabrafenib and Trametinib: FDA Approved and EMA

Approved)

✓ Nivolumab has a role in the adjuvant setting for stage IIIB-C resected stage

IV melanoma (Nivolumab: FDA Approved and EMA Approved);

Pembrolizumab showed efficacy in stage III (vs. Placebo)

✓ Ipilimumab showed less efficacy then Nivolumab

✓ IFN will probably soon be replaced (still a role for ulcerated primary melanoma?)

✓ Neo Adjuvant setting is a

new research area

✓ Stage III BRAF Mutant melanoma need more

predictive factors to choose between targeted

therapy or Immunotherapy

CONCLUSION

THANK YOU FOR YOUR ATTENTION

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