Adjuvant Treatment of Resected Node-Positive

Melanoma With Immune Checkpoint Inhibitors

Supported by a grant from Merck & Co., Inc.

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Faculty
Michael B. Atkins, MD
Deputy Director
Lombardi Comprehensive Cancer Center
Georgetown University
Washington, DC
Ahmad Tarhini, MD, PhD
Acting Professor, Hematology and Medical Oncology
Emory University School of Medicine
Co-Director, Melanoma and Skin Cancer Program
Winship Cancer Institute of Emory University
Atlanta, Georgia
Faculty Disclosures
Michael B. Atkins, MD, has disclosed that he has received funds for research support
(to his institution) from Bristol-Myers Squibb, Genentech, Merck, and Pfizer, consulting
fees from Acceleron, Aduro, Alexion, Amgen, Array, AstraZeneca, Aveo, Boehringer-
Ingelheim, Bristol-Myers Squibb, Cota, Genentech-Roche, Eisai, Exelixis, Ideera,
ImmunoCore, Iovance, Lynx, Merck, Newlink, Novartis, Pfizer, and Surface, has served
on advisory boards for Arrowhead, Bristol-Myers Squibb, Fathom, Galactone, Merck,
Novartis, Pfizer, and Werewolf, and has stock options in Werewolf.
Ahmad Tarhini, MD, PhD, has disclosed that he has received funds for research
support from Bristol-Myers Squibb, Genentech/Roche, Idera, Incyte, Merck, and
Novartis and consulting fees from Array, Bristol-Myers Squibb, EMD Serono/Pfizer,
Genentech/Roche, HUYA, Immunocore, Incyte, Merck, NewLink Genetics, Novartis,
and Sanofi-Genzyme/Regeneron.
Program Overview
 Adjuvant Treatment of Resected Node-Positive Melanoma With
Immune Checkpoint Inhibitors
 Identifying and Managing Treatment-Related Adverse Events
 High-Risk Surgically Resected Melanoma
KM Melanoma-Specific Survival Curves According to T Category KM Melanoma-Specific Survival Curves
Stage Group for Patients With Stage I and II Melanoma According to Stage III Subgroups
1.0 1.0
Melanoma-Specific Survival Probability

Melanoma-Specific Survival Probability

0.8 0.8

0.6 0.6

0.4 0.4
N 5 Yrs 10 Yrs
IA 5225 99% 98% N 5 Yrs 10 Yrs
IB 5749 97% 94%
0.2 IIA 2338 94% 88% 0.2 IIIA 1006 93% 88%
IIIB 1170 83% 77%
IIB 1688 87% 82% IIIC 2201 69% 60%
IIC 691 82% 75% IIID 205 32% 24%
0 0
0 2 4 6 8 10 0 2 4 6 8 10
Yrs Since Diagnosis Yrs Since Diagnosis

 Adjuvant therapy provides an opportunity to cure

Gershenwald. CA Cancer J Clin. 2017;67:472. Slide credit: clinicaloptions.com
 Key Trials Leading to US Regulatory Approval for IFN and
Ipilimumab
Impact on
Median Follow-up,
Study Stage N Regimen
Yrs RFS (HR) OS (HR)

6.9 0.61 0.67

E1684[1,2] T4, N+ 287 HD-IFN vs observation
12.6 0.72 0.82*
4.3 0.78 --
E1690 [2,3]
T4, N+ 642 HD-IFN or LD-IFN vs observation
6.6 0.81 --
1.3 0.68 0.66
E1694[2,4] T4, N+ 880 HD-IFN vs GMK vaccine
2.1 0.75 0.76
EORTC 3.8 0.82 --
N1,2 1256 Pegylated IFN vs observation
18991[5,6] 7.6 0.87 --
EORTC
N1,2,3 951 Ipilimumab 10 mg/kg vs placebo 5.3 0.76 0.72
*P18071
[7]
= .18

1. Kirkwood. JCO. 1996;14:7. 2. Kirkwood. Clin Cancer Res. 2004;10:1670. 3. Kirkwood. JCO. 2000;18:2444. 4. Kirkwood. JCO. 
2001;19:2370. 5. Eggermont. Lancet. 2008;372:117. 6. Eggermont. JCO. 2012;30:3810. 7. Eggermont. NEJM. 2016;375:1845. Slide credit: clinicaloptions.com
 Cochrane Analysis of Adjuvant IFN for High-Risk
Melanoma
Parameter RFS OS
Studies analyzed, n 17 15
Patients analyzed, n 10,345 9,927
HR (95% CI) 0.83 (0.78-0.87) 0.91 (0.85-0.97)
Relative risk reduction, % 17 9
NNT, n -- 35

Mocellin. Cochrane Database Syst Rev. 2013:CD008955.  Slide credit: clinicaloptions.com

 EORTC 18071: Phase III Trial of Ipilimumab 10 mg/kg vs
Placebo in Stage III Melanoma
 Randomized, double-blind phase III trial of ipilimumab 10 mg/kg vs placebo as
adjuvant therapy for stage III melanoma after surgical resection (N = 951)
RFS OS
100 100 5-Yr Rate, %
Median RFS, Mos 5-Yr Rate, % (95% CI)
Patients Alive and Without

90 90 Ipilimumab 65.4 (60.8-69.6)

(95% CI) (95% CI)
80 Ipilimumab 27.6 (19.3-37.2) 40.8 (36.0-45.6) 80 Placebo 54.4 (49.7-58.9)

Patients Alive (%)

Recurrence (%)

70 Placebo 17.1 (13.6-21.6) 30.3 (26.0-34.6) 70

60 60
50 50
40 40
30 30
20 20 HR for death: 0.72
HR for recurrence or death: 0.76 Ipilimumab Ipilimumab
10 (95% CI: 0.64-0.89; P < .001) Placebo 10 (95.1% CI: 0.58-0.88; P = .001) Placebo
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Yr Yr
Eggermont. NEJM. 2016;375:1845. Slide credit: clinicaloptions.com
 EORTC 18071: Safety
Ipilimumab
AEs, % (n = 471)
Any Grade Grade 3/4
Any AE 98.7 54.1
Treatment-related AE 94.1 45.4
Treatment-related AE leading to d/c 48.0 32.9
Any immune-related AE 90.4 41.6
 Deaths due to treatment-related AEs
‒ 5 patients (1.1%) in ipilimumab arm (3 colitis, 1 myocarditis, 1 multiorgan failure with
Guillain-Barre syndrome)

Eggermont. NEJM. 2016;375:1845. Eggermont. ESMO 2016. Abstr LBA2_PR. Slide credit: clinicaloptions.com
 E1609: Ipilimumab 3 mg/kg or 10 mg/kg vs High-Dose
IFN for High-Risk Resected Melanoma
 Randomized, double-blind phase III trial of ipilimumab 3 mg/kg or 10 mg/kg vs
HD IFN for patients with resected stage IIIB, IIIC, or IV melanoma (N = 1673)
1.0 RFS Ipi 3 mg/kg Ipi 10 mg/kg
0.9 (n = 516) (n = 503)
AEs, %
0.8 Any Grade Any Grade
0.7 Grade 3/4 Grade 3/4
Probability

0.6 Any 98.4 53.3 100 65.4

0.5
TRAE 96.0 36.6 98.8 56.5
0.4
0.3 TRAE
10 mg lpi (n = 406) leading to 34.9 25.0 53.7 42.9
0.2 d/c
3 mg lpi (n = 367)
0.1 HR: 1.0 (95% CI: 0.81- 1.24)
Any irAE 73.6 18.8 86.9 34.0
0
0 1 2 3 4 5
Yrs
Tarhini. ASCO 2017. Abstr 9500. Slide credit: clinicaloptions.com
PD-1 Inhibitors in the Adjuvant Setting
 Adjuvant PD-1 Inhibition in Stage III/IV Melanoma
 Nivolumab
‒ FDA approved: indicated in the adjuvant setting for patients with lymph
node involvement or metastatic disease who have undergone complete
resection (240 mg Q2W or 480 mg Q4W IV)[1]
‒ Supported by phase III CheckMate 238 trial[2]
 Pembrolizumab
‒ FDA approved: indicated in the adjuvant setting for patients with
unresectable or metastatic melanoma, or with lymph node involvement who
have undergone complete resection (200 mg Q3W)[3]
‒ Supported by phase III KEYNOTE-054 trial[4]
1. Nivolumab PI. 2. Weber. NEJM. 2017;377:1824. 3. Pembrolizumab PI. 4. Eggermont. NEJM. 2018;378:1789. Slide credit: clinicaloptions.com
 CheckMate 238: Adjuvant Nivolumab vs Ipilimumab in
High-Risk Melanoma
 Randomized, double-blind phase III trial

Nivolumab
Patients with 3 mg/kg IV Q2W + Placebo
resected high-risk (n = 453)
stage IIIB, IIIC, or IV Treatment up to 1 yr
melanoma Ipilimumab
(N = 906) 10 mg/kg IV Q3W + Placebo
(n = 453)

 Coprimary endpoints: RFS in ITT population

 Secondary endpoints: OS, safety, RFS by PD-L1 status, QoL
 Exploratory endpoint: DMFS
Weber. NEJM. 2017;377:1824. Slide credit: clinicaloptions.com
 CheckMate 238: Relapse-Free Survival

100
90
RFS, ITT Population (%)

80 Nivolumab: 154 events/453 patients

70
60
50
40 Ipilimumab: 206 events/453 patients
30
20 HR: 0.65 (97.56% CI: 0.51-0.83; P < .001)
10 Median RFS not reached in either arm
0
0 3 6 9 12 15 18 21 24 27
Mos

 Minimum follow-up: 18 mos (median: 19.5)

Weber. NEJM. 2017;377:1824. Slide credit: clinicaloptions.com
 CheckMate 238: RFS by PD-L1 Expression
RFS in Patients With PD-L1 Expression < 5% RFS in Patients With PD-L1 Expression ≥ 5%
100 100 Nivolumab: 31 events/152 patients
90 Nivolumab: 90 81.9%
114 events/275 patients
80 80
70 64.3% 70
60 60 73.8%
RFS (%)

RFS (%)
50 50 Ipilimumab:
40 53.7% 40 57 events/154 patients
30 Ipilimumab: 30
20 HR: 0.71 143 events/286 patients 20 HR: 0.50
10 (95% CI: 0.56-0.91) 10 (95% CI: 0.32-0.78)
0 0
0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 21 24 27
Mos Mos

Weber. NEJM. 2017;377:1824. Slide credit: clinicaloptions.com

 CheckMate 238: RFS by BRAF Status

RFS When BRAF Mutated RFS When BRAF Wildtype

100 100
Nivolumab: Nivolumab: 67 events/197 patients
90 90
63 events/187 patients
80 80 72%
68%
70 70
60 60
RFS (%)

RFS (%)
50 63% 50 57%
40 Ipilimumab: 40
30 84 events/194 patients 30 Ipilimumab:
105 events/214 patients
20 HR: 0.72 20 HR: 0.58
10 (95% CI: 0.52-1.00) 10 (95% CI: 0.43-0.79)
0 0
0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 21 24 27
Mos Mos

Weber. ESMO 2017. Abstr LBA8_PR. Slide credit: clinicaloptions.com

 CheckMate 238: RFS in Prespecified Groups
Events/Patients
Nivo 3 mg/kg Ipi 10 mg/kg Unstratified Unstratified HR
Subgroup HR (95% CI) (95% CI)
Overall Overall 154/453 206/453 0.66 (0.53-0.81)
Age < 65 yrs 106/333 147/339 0.65 (0.51-0.84)
≥ 65 yrs 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 IIIB 41/163 54/148 0.67 (0.44-1.00)
IIIC 79/204 109/218 0.65 (0.49-0.87)
IV M1a-M1b 25/62 35/66 0.63 (0.38-1.05)
IV M1c 8/20 8/21 1.00 (0.37-2.66)
Not reported 1/2 0/0
Ulceration in stage III 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)
Lymph node involvement Microscopic 41/125 55/134 0.71 (0.47-1.07)
in stage III 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 status Mutation 63/187 84/194 0.72 (0.52-1.00)
No mutation 67/197 105/214 0.58 (0.43-0.79)
Not reported 24/69 17/45 0.83 (0.45-1.54)
0 1 2
Nivolumab Ipilimumab

Weber. NEJM. 2017;377:1824. Slide credit: clinicaloptions.com

 KEYNOTE-054: Adjuvant Pembrolizumab vs Placebo for
Stage III Melanoma
 Randomized, double-blind phase III study
Pembrolizumab
Patients with resected 200 mg IV Q3W*
high-risk stage IIIA, B, C (n = 514) Treatment administered 18 doses
melanoma (~ 1 yr) or until recurrence,
Placebo unacceptable toxicity, or withdrawal
(N = 1019)
IV Q3W*
(n = 505)
*Patients with recurrence eligible for crossover
or repeat treatment with pembrolizumab.

 Coprimary endpoints: RFS in ITT population, RFS in PD-L1+ subgroup

 Secondary endpoints: DMFS, OS, safety, QoL
Eggermont. NEJM. 2018;378:1789. Slide credit: clinicaloptions.com
 KEYNOTE-054: Relapse-Free Survival

HR (98.4% CI)
100 Pembrolizumab 0.57 (0.43-0.74) P < .001
RFS, ITT Population (%) 90 Placebo 1.00
80
70 Pembrolizumab
60
50 Placebo
40
30
20
10 1-yr RFS: pembrolizumab, 75.4%; placebo, 61.0%
0
0 3 6 9 12 15 18 21 24
Mos
 Median follow-up: 15.1 mos
Eggermont. NEJM. 2018;378:1789. Slide credit: clinicaloptions.com
 KEYNOTE-054: RFS by PD-L1 Status
RFS in Patients With RFS in Patients With
PD-L1–Positive Tumors PD-L1–Negative Tumors
100 100
90 90
80 Pembrolizumab 80

Recurrence Free (%)

Recurrence Free (%)

Pembrolizumab
Patients Alive and

Patients Alive and

70 70
60 Placebo 60
50 50 Placebo
40 40
Total/ Total/
30 Event HR (95% CI) 1-Yr RFS (%) 30 Event HR (95% CI) 1-Yr RFS (%)
20 Pembrolizumab 428/102 0.54 (0.42-0.69) 77.1 20 Pembrolizumab 59/20 0.47 (0.26-0.85) 72.2
10 Placebo 425/176 1.00 62.6 10 Placebo 57/27 1.00 52.2
P < .001 P = .01
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Mos Mos

Eggermont. NEJM. 2018;378:1789. Slide credit: clinicaloptions.com

 KEYNOTE-054: RFS in Stage IIIA Population
100 93.4%
Patients Alive and Recurrence Free (%)
89.8%
90
80
70 81.1%
76.8%
60
50
40
Total Event HR (99% CI)
30 Pembrolizumab 77 6 0.32 (0.09-1.23)
Placebo 76 15 Reference
20
P = .0217
10
0
0 3 6 9 12 15 18 21 24
Mos

Eggermont. AACR 2018. Abstr CT001. Slide credit: clinicaloptions.com

 KEYNOTE-054: RFS in Stage IIIB and IIIC Populations
RFS in Patients With Stage IIIB Disease RFS in Patients With Stage IIIC Disease
100 100
90 Pembrolizumab 90
75.8% Pembrolizumab
80 80
Recurrence Free (%)

Recurrence Free (%)

71.4%
Patients Alive and

Patients Alive and

67.7% 64.3%
70 70
60 Placebo 60
Placebo
50 62.4% 50
40 54.8% 40 51.5%
30 30
42.5%
20 20
10 10
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Mos Mos
Total Event HR (99% CI) Total Event HR (99% CI)
Pembrolizumab 240 62 0.56 (0.37-0.86) P = .0004 Pembrolizumab 197 67 0.58 (0.39-0.88) P = .0005
Placebo 232 97 Reference Placebo 197 104 Reference

Eggermont. AACR 2018. Abstr CT001. Slide credit: clinicaloptions.com

 KEYNOTE-054: RFS by BRAF Mutation Status
RFS in Patients With BRAF V600E/K Mutation RFS in Patients With BRAF WT
100 100
90 Pembrolizumab 90 Pembrolizumab
80 72.5% 80 73.0%
Recurrence Free (%)

Recurrence Free (%)

69.2%
Patients Alive and

Patients Alive and

66.7%
70 70
60 Placebo 60 Placebo
50 58.6% 50
59.7%
40 52.4% 40 48.8%
30 30
20 20
10 10
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Mos Mos
Total Event HR (99% CI) Total Event HR (99% CI)
Pembrolizumab 186 54 0.57 (0.37-0.89) P = .0009 Pembrolizumab 233 69 0.64 (0.42-0.96) P = .0039
Placebo 209 94 Reference Placebo 214 97 Reference

Eggermont. NEJM. 2018;378:1789. Slide credit: clinicaloptions.com

 KEYNOTE-054: RFS in Prespecified Groups
No. of Events/Total No.
Pembrolizumab Placebo P Value for
Subgroup HR (99% or 98.4% CI) Interaction
Tumor PD-L1 expression .60
Positive 102/428 176/425 0.54 (0.39-0.74)
Negative 20/59 27/57 0.60 (0.28-1.28)
Indeterminate 13/27 13/23 0.80 (0.29-2.19)
AJCC 2009 classification .69
Stage IIIA 6/77 15/76 0.38 (0.11-1.31)
Stage IIIB 62/240 97/232 0.58 (0.38-0.88)
Stage IIIC 67/197 104/197 0.58 (0.38-0.86)
Type of positive lymph nodes .86
Microscopic 35/187 50/161 0.56 (0.32-0.99)
Macroscopic 100/327 166/344 0.59 (0.42-0.81)
BRAF mutation status .89
Wild type 69/233 97/214 0.61 (0.41-0.92)
V600E mutation 54/186 94/209 0.59 (0.38-0.92)

All patients 135/514 216/505 0.57 (0.43-0.74)

(26.6%) (42.8%)
0.25 0.50 1.00 2.00 4.00
Pembrolizumab Better Placebo Better

Eggermont. NEJM. 2018;378:1789. Slide credit: clinicaloptions.com

 Select AEs in CheckMate 238 and KEYNOTE-054
CheckMate 238 KEYNOTE-054
AEs, % Nivolumab Ipilimumab Pembrolizumab Placebo
(n = 452) (n = 453) (n = 509) (n = 502)
AEs, %
Any Grade Any Grade Any Grade Any Grade
Grade 3/4 Grade 3/4 Grade ≥3 Grade ≥3
Any AE 96.9 25.4 98.5 55.2 Any AE 93.3 31.6 90.2 18.5
TRAE* 85.2 14.4 95.8 45.9 TRAE* 77.8 14.7 66.1 3.4
 Fatigue 34.5 0.4 32.9 0.9  Fatigue or asthenia 37.1 0.8 33.3 0.4
 Diarrhea 24.3 1.5 45.9 9.5  Rash 16.1 0.2 10.8 0
 Pruritus 23.2 0 33.6 1.1  Pruritus 17.7 0 10.2 0
 Rash 19.9 1.1 29.4 3.1  Diarrhea 19.1 0.8 16.7 0.6
 Nausea 15.0 0.2 20.1 0  Arthralgia 12.0 0.6 11.0 0
 Arthralgia 12.6 0.2 10.8 0.4  Nausea 11.4 0 8.6 0
 Asthenia 12.6 0.2 11.7 0.9  Hypothyroidism 14.3 0 2.8 0
 Hypothyroidism 10.8 0.2 6.8 0.4  Hyperthyroidism 10.2 0.2 1.2 0

TRAE leading to d/c 7.7 3.5 41.7 30.0 TRAE leading to d/c 13.0 NR 1.6 NR
*Occurring in ≥ 10% of patients in the experimental arm.

Long. NEJM. 2017;377:1813.
*Prespecified significance boundary (P=0.000019). Slide credit: clinicaloptions.com
 Key Ongoing Adjuvant Trials
Primary
Study Stage N Regimen Endpoint
US Intergroup IIIA (N2), IIIB, 1378 Pembrolizumab vs HD-IFN or RFS, OS,
S1404[1] IIIC, IV ipilimumab 10 mg/kg PD-L1 status
CheckMate IIIB, IIIC, IIID, 2000 Nivolumab + ipilimumab vs RFS
915[2] IV nivolumab
US Intergroup III (IIIB, IIIC), 1500 Ipilimumab 3 mg/kg vs RFS, OS
E1609[3] IV (M1a, M1b) ipilimumab 10 mg/kg vs HD-IFN

1. NCT02506153. 2. NCT03068455. 3. NCT01274338. Slide credit: clinicaloptions.com

Adjuvant Therapy Options for
Patients With Mutated BRAF
 Adjuvant BRAF + MEK Inhibition in Stage III Melanoma
 Dabrafenib + trametinib
‒ FDA approved: indicated in the adjuvant setting for patients with
BRAF V600E or BRAF V600K mutations with lymph node involvement who

have undergone complete resection (dabrafenib 150 mg BID PO,

trametinib 2 mg QD PO)[1,2]
‒ Supported by phase III COMBI-AD trial[3]

1. Dabrafenib PI. 2. Trametinib PI. 3. Long. NEJM. 2017;377:1813. Slide credit: clinicaloptions.com
 COMBI-AD: Adjuvant Dabrafenib + Trametinib for
Stage III Melanoma With BRAF V600 Mutation
 Randomized, double-blind phase III study
Patients with completely Dabrafenib 150 mg PO BD +
resected stage III melanoma Trametinib 2 mg PO QD Patients treated for
with BRAF V600E/K (n = 438) 12 mos or until
mutation; ECOG PS 0/1; no recurrence,
prior radiotherapy or unacceptable toxicity,
systemic therapy Placebo withdrawal, or death
(N = 870) (n = 432)

 Coprimary endpoints: RFS

 Secondary endpoints: OS, DMFS, FFR, safety

*Patients were followed for disease recurrence until the first recurrence and thereafter for survival. †The study will be
considered complete and final OS analysis will occur when ~70% of randomized patients have died or are lost to follow-up.
Long. NEJM. 2017;377:1813.
‡
New primary melanoma considered as an event. Slide credit: clinicaloptions.com
 COMBI-AD: Relapse-Free Survival

1.0
0.9 88%
Dabrafenib + trametinib
0.8
Recurrence Free (%)

67%
Patients Alive and

0.7
58%
0.6 Placebo
0.5
56%
0.4 44%
0.3 39%
0.2 P < .001 Total Event HR (95% CI)
0.1 D + T 438 166 0.47 (0.39-0.58)
Placebo 432 248 1.00
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
Mos
 Median follow-up: 2.8 yrs
Long. NEJM. 2017;377:1813. Slide credit: clinicaloptions.com
 COMBI-AD: Distant Metastasis–Free Survival
1.0
0.9
Dabrafenib + trametinib
Distant Metastasis Free (%)

0.8
Patients Alive and

0.7
0.6
0.5
Placebo
0.4
0.3
0.2 Total Event HR (95% CI)
D+T 438 110 0.51 (0.40-0.65)
0.1
P < .001 Placebo 432 152 1.00
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
Mos

Long. NEJM. 2017;377:1813. Slide credit: clinicaloptions.com

 COMBI-AD: RFS in Prespecified Subgroups
Events/Patients, n/N
Subgroup D+T Placebo Favors D + T Favors Placebo
BRAF V600K 16/41 19/37 0.54
BRAF V600E 150/397 229/395
0.48
Male 92/243 144/239
Female 73/195 104/193 0.43
Age < 65 yrs 135/353 201/359 0.55
Age ≥ 65 yrs 31/85 47/73 0.51
Disease stage IIIA 15/83 23/71 0.38
Disease stage IIIB 64/169 110/187 0.44
Disease stage IIIC 84/181 111/166 0.50
Micrometastasis 39/152 72/157
Macrometastasis 61/158 101/161 0.45
Micrometastasis and ulceration 24/64 47/79 0.44
Micrometastasis and no ulceration 15/87 25/78 0.43
Macrometastasis and ulceration 23/58 42/58 0.49
Macrometastasis and no ulceration 38/100 57/101 0.43
1 nodal metastatic mass 58/177 93/183 0.33
2-3 nodal metastatic masses 57/158 94/150
0.51
≥ 4 nodal metastatic masses 40/73 50/72
0.52
0.37
0.51

0.01 0.10 1.00 10.00

HR
Long. NEJM. 2017;377:1813. Slide credit: clinicaloptions.com
 COMBI-AD: OS at First Interim Analysis
1.0 97% Dabrafenib + trametinib
91%
0.9 86%
94%
0.8
83%
Patients Alive (%)

0.7 77%
Placebo
0.6
0.5
0.4
0.3
0.2
Total Event HR (95% CI)
0.1 D+T 438 60 0.57 (0.42-0.79)
P = .0006 Placebo
0 432 93 1.00

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
Mos

*Prespecified significance boundary (P=0.000019).

Long. NEJM. 2017;377:1813. Slide credit: clinicaloptions.com
 COMBI-AD: Safety Summary
Dabrafenib + Trametinib Placebo
AEs, % (n = 435) (n = 432)
Any Grade Grade 3/4 Any Grade Grade 3/4

Any AE 97 41 88 14
 Pyrexia 63 5 11 <1
 Fatigue 47 4 28 <1
 Nausea 40 1 20 0
 Headache 39 1 24 0
 Chills 37 1 4 0
 Diarrhea 33 1 15 <1
AEs leading to dose interruption 66 NA 15 NA
AEs leading to dose reduction 38 NA 3 NA
AEs leading to d/c of study regimen 26 NA 3 NA

Long. NEJM. 2017;377:1813.
*Prespecified significance boundary (P=0.000019). Slide credit: clinicaloptions.com
 BRIM8: Adjuvant Vemurafenib vs Placebo in Resected
Stage III Melanoma
 Randomized, double-blind phase III study of adjuvant vemurafenib vs placebo for 1 yr
in patients with resected stage IIC-IIIC, BRAF mutation–positive melanoma (N = 498)
DFS, Stage IIIC (Cohort 2) DFS, Stage IIC-IIIB (Cohort 1)
100 ++ 100 +++ +
+++
Vemurafenib + + + ++++ +
80 + 80 + Vemurafenib
+ ++++++++++++
++ +
++++++ +
+ + ++ ++ +++
+ +++++++++ ++++
60 + 60 + ++ ++ ++++
DFS (%)

DFS (%)
++++ ++++ +++++++ ++++ +
+++ ++++ +
+ + ++++ +++ +
40 +++++ + + + 40
Placebo ++++++++
+++++ ++ Placebo
20 + 20
HR: 0.80 (95% CI: 0.54-1.18; P = .26) HR: 0.54 (95% CI: 0.37-0.78; P = .0010)
0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Mos Since Randomization Mos Since Randomization

 Study did not meet overall primary endpoint due to lack of improvement in DFS in
cohort 2
Maio. Lancet Oncol. 2018;19:510. Slide credit: clinicaloptions.com
 ANZMTG 01.02/TROG 02.01: Adjuvant Radiotherapy vs
Observation After Lymphadenectomy for Melanoma
 Randomized, phase III trial (n = 217)
 Adjuvant RT reduced LNF relapse by 48% (P = .023)
‒ LNF relapse at 5 yrs for adjuvant RT vs observation: 18% vs 33% (P = .011)
 No significant differences in RFS or OS outcomes between arms

5-Yr Outcomes, % Adjuvant Observation HR P Value

Radiotherapy
RFS 34 28 0.89 .51
OS 40 45 1.27 .21

Henderson. Lancet Oncol. 2015;16:1049. Henderson. ASCO 2013. Abstr 9001. Slide credit: clinicaloptions.com
Online Treatment Decision Tool for Advanced
Melanoma
 Enter specific patient/disease
characteristics by answering a
series of multiple choice questions
to get recommendations for your
specific case from 5 melanoma
experts
‒ Drs. Michael Postow, Michael B.
Atkins, Adil Daud, Kim Margolin, and
Hussein Tawbi
 Recommendations provided in
December 2018/January 2019
‒ Pembrolizumab may now be
considered for adjuvant therapy
(FDA approved in February 2019)
Available at: www.clinicaloptions.com/melanomatool
Slide credit: clinicaloptions.com
Conclusions: Adjuvant Therapy for Melanoma
 Adjuvant trials of PD-1 (pembrolizumab and nivolumab) and
BRAF + MEK inhibitors (dabrafenib + trametinib) have changed the
standard of care
‒ Survival follow-up in these modern trials ongoing
 Key adjuvant trials findings are anticipated
‒ E1609: ipilimumab 3 or 10 mg/kg vs HD-IFN
‒ S1404: pembrolizumab vs HD-IFN or ipilimumab 10 mg/kg
‒ CheckMate 915: nivolumab + ipilimumab vs nivolumab

Slide credit: clinicaloptions.com

Identifying and Managing Treatment-Related AEs:
Preserving Efficacy and Reducing Toxicity
NCCN Guidelines® in Oncology for Managing Immune
Checkpoint Inhibitor–Related Toxicities

www.clinicaloptions.com/immuneAEtool
 Increase in Reporting of Fatal Severe Immune
Checkpoint Inhibitor–Associated Myocarditis
Characteristics of Patients Who Experienced Severe Myocarditis Following ICI Treatment (Case Analysis, N = 101) [1]
Characteristic % Characteristic % Characteristic %
Male 66 Concurrent irAEs Regimen
Cancer Myositis/rhabdomyolysis 25 Nivolumab monotherapy 43
Melanoma 40 Myasthenia gravis 10 Pembrolizumab monotherapy 15
NSCLC 30 Colitis 4 Anti–PD-L1 monotherapy 3
Renal 7 Severe cutaneous events 4 Ipilimumab monotherapy 5
Other 23 Other 5 Anti–PD-1/PD-L1 + anti–CTLA-4 27
Concomitant Medications Fatal outcome 52 Anti–PD-1/PD-L1 + other agents 8
Aspirin 11
Statin 11 Reporting yr Median Timing, days (range)
Beta-blocker 7 25 (5-120)
ACE/ARB 12 2010-2014 3
Diabetes medication 9 2015 6
No CV/diabetes medications 75 2016 15
2017 (through December 6) 76

 Incidence (single-center analysis of 964 patients): anti–PD-1 monotherapy: 0.5%; anti–PD-1 + anti–CTLA-4: 2.4%[2]
 Mortality: anti–PD-1/PD-L1 monotherapy: 36%; anti–PD-1/PD-L1 + anti–CTLA-4: 67% (P = .008)[1]

1. Moslehi. Lancet. 2018:391:933. 2. Mahmood. J Am Coll Cardiol. 2018;71:1755. Slide credit: clinicaloptions.com
 Spectrum of Cardiovascular Complications With
Immune Checkpoint Inhibitors
 Myocarditis (50% mortality)
 Pericardial disease, including pericarditis (21% mortality)
 Vasculitis (6% mortality,
28% vision impairment)
 Arrhythmias

Hu. Cardiovasc Res. 2019;[Epub]. Salem. Lancet Oncol. 2018;19:1579. Slide credit: clinicaloptions.com
 Approach to Patients With Suspected Immune
Checkpoint Inhibitor–Associated Myocarditis
Baseline: check EKG and troponin; if abnormal, reconsider ICI
After starting ICI: check troponin QW for 4-6 wks; if abnormal:
Asymptomatic Troponinemia Myocarditis, Stable* Myocarditis, Unstable†
Hold ICI Hold ICI; admit to floor Discontinue ICI, admit to ICU
 Evaluate for s/s of CHF, ischemia,  Consult cardiology
arrythmia, or myositis  Rule out MI
 Check ECK, CK, CK-MB, and  Start telemetry
troponin serially  Obtain cardiac echo and cMRI
Workup

 Refer to cardiologist  Consider cardiac biopsy in formalin-fixed

 If all studies normalize in ≤ 2 wks tissue and frozen tissue
and no cardiac pathology, may
resume ICI  Methylprednisolone
 Start methylprednisolone
 If no improvement in 24 hrs or patient is  Consider adding investigational
unstable, see next pane agents (eg, infliximab)
 If studies worsen or symptoms  Place pacemaker at bedside in
Treatment

develop, treat as in next pane  If abnormalities resolve, taper over case of heart block
≥ 4 wks

*Symptoms, EKG or echo changes, or cMRI findings. †Hypotension, arrythmia, sudden EF drop.
Hu. Cardiovasc Res. 2019;[Epub]. Slide credit: clinicaloptions.com
Take-home Messages
 Spitzoid melanoma with TERT-p mutations appear to behave more like
cutaneous melanoma
 Several irAEs can occur with immune checkpoint inhibitor therapy
‒ Although most are rapidly reversible with treatment, some are
permanent/life threatening
 Myocarditis/myositis, although rare, is a severe irAE
‒ Knowledge and prompt management is essential
 Such irAEs need to be considered in decisions about adjuvant/
neoadjuvant therapy
 Go Online for More CCO
Educational Programs on Melanoma!
Downloadable slides from this symposium with all the key studies
On-demand CME-certified video Webcast of this symposium
Online module with additional expert recommendations on the use of immunotherapy for treating
patients with melanoma
Interactive Decision Support Tools for Melanoma and Immune-Related
Adverse Events into which you can enter your own patient’s specific
characteristics and see expert treatment recommendations

clinicaloptions.com/oncology
clinicaloptions.com/melanomatool
clinicaloptions.com/immuneAEtool