2019:Trattamento Adiuvante Melanoma Maligno
Vanna Chiarion Sileni IOV-IRCCS, Padova
vanna.chiarion@iov.veneto.it
MSS
according
to stage III subgroupsVerver et al. EJC 2018 Van Akkoi et al. Ann Surg 2008
Survival in III stage
Adjuvant therapy in melanoma patients
Advantages
• Better clinical/psychological conditions
• Clear end point
• Certainty of duration
• Shorter drug exposure
• Reduced health resource impact
Disadvantages
• Overtreatment in cured patients
• Risk of long lasting toxicities
• Impact on fertility
• More difficult tumor
monitoring
Efficacy of interferon by ulceration
HR: 1.02 (CI 0.87-1.20)
HR: 0.77
(CI 0.64-0.92)
Adjuvant trials
Study PTS Stage Endpoint Expe. Drug Control Duration
DERMA 1350 IIIB/C RFS MAGE-A3 vaccine Placebo 1 year
AVAST-M 1343 IIB/IIC/III OS Bevacizumab Observation 1 year
CA184-029/EORTC 18071
1211 IIIA (>1 mm)/IIIB/C RFS Ipilimumab Placebo 3 years
Intergroup E1609 1673 IIIB/C
resected IV
RFS/OS Ipilimumab 3 mg Ipilimumab 10 mg
HD-IFN 1 year
BRIM8 500 IIC/IIIA (>1 mm)/IIIB/C RFS Vemurafenib Placebo 1 year
COMBI-AD 852 IIIA (>1 mm)/IIIB/C RFS Dabrafenib + trametinib Placebo 1 year
CA209-238 800 IIIB/C/
resected IV
RFS Nivolumab Ipilimumab 1 year
KEYNOTE-054 900 IIIA (>1 mm)/IIIB/C RFS Pembrolizumab Placebo 1 year
CA209-915 2000 IIIB/C/D
resected IV (8th ed.)
RFS Nivoumab+low dose ipilimumab
Nivolumab 1 year
Keynote-716 954 IIB/C RFS Pembrolizumab Placebo 1 year
ASCO 2016
B.Dreno et al Lancet Oncol .2018
Ipilimumab 10 mg (Checkmate-029)
Eggermont NEJM 2016
*myocarditis, Guillain-Barré, GI
*
AM Eggermont et al. NEJM 2016
Checkmate-029: safety summary
Slide 7
Presented By Jeffrey Weber at 2018 ASCO Annual Meeting
HR: 0.66
Subgroup Analysis of RFS: 5% PD-L1 Expression Level
Presented By Jeffrey Weber at 2018 ASCO Annual Meeting
Subgroup Analysis of RFS: Disease Stage III and IV
Presented By Jeffrey Weber at 2018 ASCO Annual Meeting
Subgroup Analysis of RFS: BRAF Mutation Status
Presented By Jeffrey Weber at 2018 ASCO Annual Meeting
Eggermont et al. NEJM 2018
75.4%
61.0%
71.4%
53.2%
RFS
HR =0.57Long-lasting
Eggermont ESMO 2018
COMBI-AD: STUDY DESIGN—EXTENDED FOLLOW-UP ANALYSIS
Key eligibility criteria
• Completely resected stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma
• BRAF V600E/K mutation
• ECOG performance status 0 or 1
• No prior radiotherapy or systemic therapy
• Tissue collection was mandatory at baseline and optional upon recurrence
R A N D O M I Z A T I O
Stratification N
• BRAF mutation status (V600E, V600K)
• Disease stage (IIIA, IIIB, IIIC)
1:1
• Primary endpoint: RFS
• Secondary endpoints: OS, DMFS, FFR, safety
N = 870
Treatment duration:
12 months
Primary analysis D+T median FU,
33 months
Updated analysis D+T median FU,
44 months
PRESENTED BY GV LONG AT ESMO 2018
Dabrafenib 150 mg BID + trametinib 2 mg
QD (n = 438)
2 matched placebos (n = 432)
Long GV, et al. N Engl J Med. 2017;377:1813-1823
COMBI AD RFS
Haushild et al. JCO 2019
HR=0.49 (95% CI, 0.40 to 0.59)
Stage IIIA Stage IIIB
Stage IIIC Stage IIID
Haushild et al. JCO 2019
RFS by restaging (8
thed.)
OS
Long et al. NEJM 2017
86%
77%
91%
83%
97%
94%
Δ=3%
Δ=8%
Δ=9%
Months Since Randomization
Relapse-Free Survival, %
100 90 80 70 60 50 40 30 20 10 0
0 6 12 18 24 30 36 42 48 54 60
Estimated cure ratesa 54% (95% CI, 49%-59%) 37% (95% CI, 32%-42%)
Cure-rate model for RFS
Dabrafenib + trametinib Placebo
Kaplan-Meier curves for RFS Dabrafenib + trametinib Placebo
Dabrafenib + trametinib 438 391 354 298 262 242 227 161 92 34 2
432 280 219 185 168 158 147 112 63 18 1
No. at risk Placebo
CURE-RATE MODEL RESULTS
A higher proportion of patients are estimated to be cured with dabrafenib + trametinib vs placebo
17%
absolute difference
PRESENTED BY GV LONG AT ESMO 2018
a Proportion of patients expected to remain relapse-free long term.
COMBI-AD Primary Analysis: Safety Summary
• Most common AEs in the dabrafenib plus trametinib arm were pyrexia (63%) and fatigue (47%)
27
AE Category, n (%)
Dabrafenib Plus Trametinib (n = 435)
Placebo (n = 432)
Any AE 422 (97) 380 (88)
AEs related to study treatment 398 (91) 272 (63)
Grade 3/4 AEs related to study treatment 136 (31) 21 (5)
Any SAE 155 (36) 44 (10)
SAEs related to study treatment 117 (27) 17 (4)
AEs leading to dose interruption 289 (66) 65 (15)
AEs leading to dose reduction 167 (38) 11 (3)
AEs leading to treatment discontinuationa 114 (26) 12 (3)
Fatal AEs related to study drug 0 0
a Most common AEs leading to treatment discontinuation in the dabrafenib plus trametinib arm were pyrexia (9%) and chills (4%).
AE, adverse event; SAE, serious adverse event.
Long GV, et al. N Engl J Med. 2017. [Epub ahead of print] PRESENTED BY GV LONG AT WCM/SMR 2017
Data cutoff: June 30, 2017
KM-curves of estimated RFS in adjuvant trials for melanoma
Eggermont et al. Nature Reviews Clinical Oncology 2018
HR for OS better than HR for RFS with ICI ?
Eggermont et al. NEJM 2016
HR for relapse: 0.76 HR for death: 0.72
HR 0.49
EORTC 1325-Keynote-054 COMBI AD
Crucial adjuvant trials determining adjuvant landscape in melanoma
Trial Stage RFS HR RFS at 2 years OS at 2 years OS at 5 years Os at 10 years COMBI AD
Vs Pbo
IIIA(<1mm) IIIB/C
0.47 67% vs 44% 91% vs 83% ? ?
EORTC18071 IPI vs Pbo
IIIA(<1mm) IIIB/C
0.72 52% vs 44% 83% vs 76 % 65% vs 54%
Checkmate238 Nivo vs IPI
IIIB/C IIIB/C/IV IV
0.65 0.65 0.70
64% vs 52%
63% vs 50%
58% vs 44%
? ?
EORTC 1325 Pembro Vs Pbo
IIIA(<1mm) IIIB/C
0.57 71% vs 53%* ? ?
IFN vs Obs Meta-analysis
II-III
Non –ulc Ulcerated
0.86 0.95 0.79
50% vs 46% 70% vs 68% 49% vs 46%
8% at 5 yrs 11% at 10 yrs
* 18 months
RFS at 18 months
COMBI AD : RFS at 24 months
33 not enough 48 38
44 not necessary 39 18
23 effective 33 34 ALL IIIC IIID
Prediction and monitoring of relapse in stage III melanoma using ctDNA
NAS +Tert 7%
Melanoma adjuvant EB choices
Stage IIB/C
Clinical study or
IFN if ulcerated
Stage III
Anti-PD-1 or
BRAF+MEKi
Stage IV ned
Anti-PD-1
