Actualñizacion Melanoma esmo summit

1. ESMO SUMMIT LATIN AMERICA 2023
Buenos Aires, 28-29 April 2023
Teresa Amaral, MD, PhD
Head of Interdisciplinary Skin Cancer Center, University Medical Center Tuebingen
Head of Translational Research, University Medical Center Tuebingen
Chair of the ESMO Leadership Development Committee, Member of the ESMO Faculty Melanoma and Other Skin Tumors
CURRENT MANAGEMENT OF LOCALLY
ADVANCED MELANOMA

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DECLARATION OF INTERESTS
Teresa Amaral
Teresa Amaral
Last DOI update: January 20, 2022
Financial Interests
,
BMS Invited Speaker, Personal
,
CeCaVa Writing Engagement, Personal
,
Novartis Invited Speaker, Personal
,
Pierre Fabre Invited Speaker, Personal
,
iFIT Research Grant, Institutional, Financial interest
,
Neracare Funding, Institutional, Financial interest
,
Novartis Funding, Institutional, Financial interest
,
Novartis Research Grant, Institutional, Financial interest
,
Sanofi Funding, Institutional, Financial interest
,
Skyline-Dx Funding, Institutional, Financial interest
Non-Financial Interests
,
ASCO Member
,
Portuguese Society for Medical Oncology Member
,
Portuguese Society of Medical Oncology - Young Oncologists Group Member
Other
,
INFARMED Other, Clinical expert

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SUMMARY
Teresa Amaral
ü Locally advanced operable
Ø Adjuvant therapies
Ø Neoadjuvant therapies

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The golden circle

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WHY?

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In Denmark, their proportion until 2012e2016, grew
to 1201 new cases in women and 1034 cases in men, cor-
Simultaneously, the CM burden due to demographic
changes decreased in both countries.
In Denmark, less than 5% (4.3% in men, and 3.9% in
women) of CM diagnosed in 2012e2016 were attribut-
able to changes in the demographic age distribution,
higher was their proportion in the Saarland (8.7% in
men, and 11.1% in women).
Sensitivity analysis (Tables S3a/b, S4a/b, S5a/b),
assuming a baseline PAF for UVR of around 10% and
30%, respectively, changed the estimates only marginally.
4. Discussion
In the present study, the UVR-related CM burden was
estimated to be approximately 95% for both pop-
ulations. A similar study, published by Armstrong et al.,
in 1993, estimated the proportion of CM due to UVR
exposure in Queensland, Australia to be 97% in men and
96% in women [6].
Proportions of over 95% were also estimated for the
United States (95.1%) and Canada (98.8%) [7,8]. Lower
PAFs, but still high (over 80%), were reported for
Western Europe. Estimates of 86% and 91.2% for Ger-
many and Denmark, respectively, were published by a
study investigating the global burden of CM attribut-
able to UVR for 2012 [10,11,21].
For the UK, Parkin et al. calculated a PAF of 90%
for men and 82% for women in 2010 [10]. For France,
the overall PAF was calculated to be 83% in 2015 [9].
PAFs estimated in our study are comparable to those
computed for North America and Australia. Results
from this study also underline the predominant role of
UVR exposure in the burden of CM.
In contrast, current and future changes in the age
structure of the population have only a marginal impact
on the number of CM cases.
The population attributable fraction (PAF) provides
Fig. 2. a: Number of melanoma cases attributable to UVR
exposure and demographics in the federal state Saarland/Germany
(1943/1946e2032/2036), Males. b: Number of melanoma cases
attributable to UVR exposure and demographics in the federal
state Saarland/Germany (1943/1946e2032/2036), Females.
Abbreviation: CM: cutaneous melanoma; PAF: population
attributable fraction.
Fig. 1. a: Number of melanoma cases attributable to UVR
exposure and demographics in Denmark (1943/1946e2032/2036),
Males. b: Number of melanoma cases attributable to UVR
exposure and demographics in Denmark (1943/1946e2032/2036),
Females. Abbreviation: CM: cutaneous melanoma; PAF: popu-
lation attributable fraction.

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Prognosis of Patients With Primary
Melanoma Stage I and II According to American
Joint Committee on Cancer Version 8 Validated in
Two Independent Cohorts: Implications for
Adjuvant Treatment
Claus Garbe, MD1
; Ulrike Keim, PhD1
; Teresa Amaral, MD, PhD1
; Carola Berking, MD2
; Thomas K. Eigentler, MD3
; Lukas Flatz, MD1
;
Anja Gesierich, MD4
; Ulrike Leiter, MD1
; Rudolf Stadler, MD5
; Cord Sunderkötter, MD6
; Thomas Tüting, MD7
; Jochen Utikal, MD8,9
;
Uwe Wollina, MD10
; Lisa Zimmer, MD11,12
; Christos C. Zouboulis, MD, PhD13
; Paolo A. Ascierto, MD14
; Alexander M.M. Eggermont, MD, PhD15,16,17
;
Jean-Jacques Grob, MD18
; Axel Hauschild, MD19
; Lidija Kandolf Sekulovic, MD, PhD20
; Georgina V. Long, MD, PhD21,22
; Jason J. Luke, MD23
;
Olivier Michielin, MD24
; Ketty Peris, MD25,26
; Dirk Schadendorf, MD11,12
; John M. Kirkwood, MD27
; and Paul C. Lorigan, MD28
; on behalf of the
Central Malignant Melanoma Registry (CMMR)
HOW?

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adjuvant therapy for stage IIB and IIC melanoma, and in the
first adjuvant trial of pembrolizumab versus placebo re-
cently reported, the HR for recurrence was 0.65 after
12 months and 0.61 after 18 months of follow-up, and this
agent received US Food and Drug Administration (FDA)
Tübingen with more than 6,000 patients; subsequently, a
confirmatory data set with more than 10,000 patients
originating from 11 selected German university hospitals
that had documented follow-up for more than 90% of
patients. For these two cohorts, not only MSS but also
CONTEXT
Key Objective
To reassess whether the prognosis of patients with stage I and II melanoma, particularly IB and IIA, are really as favorable as
reported in the American Joint Committee on Cancer classification version 8 (AJCCv8)?
Knowledge Generated
In two independent cohorts of patients with stage I and II disease in the German Central Malignant Melanoma Registry, we
found significantly less favorable survival probabilities than those published in the AJCCv8 classification. Melanoma-
specific 10-year survival rates were 89.7%-90.9% in stage IB, instead of 94% according to AJCCv8, and 80.7%-83.1% in
stage IIA, instead of 88% according to AJCCv8. Similar differences were found for the other substages.
Relevance
The difference shown here should be considered in clinical decision making such as the indication for adjuvant therapy and
in the design of clinical trials.
Garbe et al

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0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10
MSS
Time Since Diagnosis (years)
IA
IB
IIA
IIB
IIC
A
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10
MSS
Time Since Diagnosis (years)
IA
IB
IIA
IIB
IIC
B
FIG 2. The MSS of patients with primary melanoma staged according to the AJCC classification version 8 was substantially lower in the CMMR in Germany
compared with the IMDDP published with the AJCC classification version 8. Patients with stage IB and above are sentinel lymph node biopsy staged.
Curves were generated using an interactive digitizing software program (DigitizeIt19
) on the basis of the originals. (A) Patients in the exploratory cohort of the
CMMR with first diagnosis in 2000-2015 (n 5 6,725). (B) Patients in the IMDDP diagnosed since 1998 (n 5 15,691). AJCC, American Joint Committee on
Cancer; CMMR, Central Malignant Melanoma Registry; IMDDP, International Melanoma Database and Discovery Platform; MSS, melanoma-specific
survival.

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Yi Que et al. J Immunother Cancer 2021;9:e002920
WHAT?

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STAGE III
BRAF wt and BRAFV600 mutated melanoma

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Table 4. Summary of stage subgroup eligibility criteria and RFS efficacy data for adjuvant trials
Stage—AJCC seventh edition (all patients NED)
Study Design IIC IIIA IIIB IIIC IV
EORTC 18071 [53] Ipilimumab 10 mg/kg versus placebo SN >1 mm
HR 0.98
HR 0.75 HR 1.00, 1–3 LNs
HR 0.48, !4 LNs
EORTC 1325 [57] Pembrolizumab versus placebo SN >1 mm
HR 0.38
HR 0.58 HR 0.58
CheckMate 238 [55, 56] Ipilimumab 10 mg/kg versus nivolumab HR 0.68 HR 0.68 HR 0.66 M1a, b
HR 0.78 M1c
BRIM8 [71] Vemurafenib versus placebo HR 0.0 NE SN >1 mm
HR 0.52
HR 0.63 HR 0.8
COMBI-AD [62] Dabrafenib/trametinib versus placebo SN >1 mm
HR 0.44
HR 0.50 HR 0.45
Note: All trials including stage IIIA patients requested a minimum SN diameter of 1 mm. All stage III patients included in these trials had radical LN
dissection.
AJCC, American Joint Committee on Cancer; EORTC, European Organisation for Research and Treatment of Cancer; HR, hazard ratio; LN, lymph node; NE,
not established; NED, no evidence of disease; RFS, recurrence-free survival; SN, sentinel node.
Annals of Oncology Special article
ESMO MCBS score A
ESMO MCBS score A

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(...) current evidence suggests that patients with BRAF-
mutated melanoma can derive an RFS benefit from either
adjuvant BRAF/MEK inhibition or adjuvant PD-1 blockade,
in the absence of a direct efficacy comparison (...)
individual treatment decisions should be made with the
patient, factoring in the toxicity profiles for the different
adjuvant treatment...
ESMO Consensus, locoregional: Michielin & al., Ann Oncol 2020

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19. Anti-PD-1 +/- anti-Lag 3
A Study to Assess Adjuvant Immunotherapy With Nivolumab Plus Relatlimab Versus Nivolumab Alone
After Complete Resection of Stage III-IV Melanoma (RELATIVITY-098)

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STAGE IIIA
ESMO Consensus, locoregional: Michielin & al., Ann Oncol 2020

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(...) a lymph node in which any metastatic tumor cells have been
identified, irrespective of how small the tumor deposit or whether it
has been identified on hematoxylin and eosin-stained or
immunostained sections, should be designated as a tumor-involved
lymph node.
CA Cancer J Clin. 2017 Nov; 67(6): 472–492.

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Recommendation 8.2. (...) insufficient evidence to support
the routine use of adjuvant therapy in AJCC8 stage IIIA
melanoma.
Level of evidence: I
Strength of recommendation: D
Level of consensus: 97% (29) yes, 3% (1) no (30 voters)
ESMO Consensus, locoregional: Michielin & al., Ann Oncol 2020

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Recommendation 8.3. (...) may be some subsets of stage IIIA
patients with a higher risk of relapse (e.g. tumour burden in
sentinel node >1 mm). In these patients, a balanced
discussion of risk reduction and long-term side-effects of
adjuvant therapy can be considered.
Level of evidence: II
Strength of recommendation: C
Level of consensus: 97% (29) yes, 3% (1) no (30 voters)
ESMO Consensus, locoregional: Michielin & al., Ann Oncol 2020

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NEOADJUVANT

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Neoadjuvant superior to adjuvant immunotherapy
Paolo A. Ascierto
Versluis, Long, and Blank, Nat Med 2020

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scans scans
scans
1:1 randomization
S1801 Study Schema
Resectable
stage IIIB-IV
clinically
assessable
melanoma
Adjuvant Arm
Neoadjuvant
Arm
Surgery
Surgery
18 cycles pembrolizumab
200 mg IV q3 wk
3 cycles
pembrolizumab
200 mg IV q3 wk
15 cycles
pembrolizumab 200
mg IV q3 wk
Primary endpoint: Event-free survival
Additional criteria: strata included AJCC 8th ed. stage and LDH, adjuvant radiation allowed, concomitant radiation &
pembrolizumab was not allowed, brain metastasis excluded, uveal melanoma excluded
Surgery type and extent was required to be pre-specified and carried out regardless of radiologic response to therapy
radiographic assessment
(scans)
scans
scans
Sapna P. Patel, MD

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S1801 primary endpoint: Event-free survival
Landmark 2-year EFS: 72% v. 49%
72%
49%
Sapna P. Patel, MD

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Overall survival
Sapna P. Patel, MD

30. Take home messages
Stage III
Ø BRAF/MEK vs anti-PD1 vs anti-PD1+anti-Lag3
Ø Stage IIIA – cautious recommendation
Neoadjuvant and peri-operative
Ø New kids on the block

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Thank you all very much for your attention
teresa.amaral@med.uni-tuebingen.de
@TeresaSAmaral